WO2023034336A2 - Traitements améliorés contre des cancers avancés/métastatiques avec une résistance aux inhibiteurs de points de contrôle ou une susceptibilité à une telle résistance - Google Patents

Traitements améliorés contre des cancers avancés/métastatiques avec une résistance aux inhibiteurs de points de contrôle ou une susceptibilité à une telle résistance Download PDF

Info

Publication number
WO2023034336A2
WO2023034336A2 PCT/US2022/042088 US2022042088W WO2023034336A2 WO 2023034336 A2 WO2023034336 A2 WO 2023034336A2 US 2022042088 W US2022042088 W US 2022042088W WO 2023034336 A2 WO2023034336 A2 WO 2023034336A2
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
cancer
weeks
administered
human
Prior art date
Application number
PCT/US2022/042088
Other languages
English (en)
Other versions
WO2023034336A3 (fr
Inventor
Andrew BEELEN
Rajesh Kumar MALIK
John Seung-Hoon YI
Original Assignee
G1 Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by G1 Therapeutics, Inc. filed Critical G1 Therapeutics, Inc.
Publication of WO2023034336A2 publication Critical patent/WO2023034336A2/fr
Publication of WO2023034336A3 publication Critical patent/WO2023034336A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies

Definitions

  • Ipilimumab a human IgGl k anti-CTLA-4 monoclonal antibody (sold under the brand name YERVOY®), was approved by the by the United States (US) Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma.
  • Ipilimumab is the first and only United State Food and Drug Administration-approved CTLA-4 inhibitor.
  • Pembrolizumab (KEYTRUDA®) monotherapy has also demonstrated improved objective response rates (ORR) in patients with PD-L1 positive TNBC tumors ranging from 18.5% to 21.4%, compared with response rates ranging from 5.3% to 9.6% in patients with PD-L1 negative tumors.
  • ORR objective response rates
  • ICI resistance Additional mechanisms of ICI resistance include genetic, epigenetic, and cellular signaling alterations that dysregulate neoantigen presentation/processing and disrupt cytotoxic T cells activity as well as mechanisms in which non-cancerous stromal or immune cells promote growth and resistance to ICIs (Liu et al., Mechanisms of resistance to immune checkpoint blockade. Am J Clin Dermatol. 2019; 20(1): 41-54; Barrueto et al., Resistance to checkpoint inhibition in cancer immunotherapy. Transl One. 2020; 13 : 100738; Jenkins et al., Mechanisms of resistance to immune checkpoint inhibitors. Brit J Cancer.
  • the present invention provides improved methods for treating select patients with locally advanced, recurrent, or metastatic cancer whose cancers have progressed on, have developed resistance to, or are susceptible to developing resistance to a PD-1 or PD-L1 checkpoint inhibitor, the methods including administering an effective amount of the short acting, selective, and reversible cyclin dependent kinase (CDK) 4/6 inhibitor trilaciclib, or a pharmaceutically acceptable salt thereof, in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor, or a Cluster of Differentiation 73 (CD73; Ecto-5 'nucleotidase (NT5E)) checkpoint inhibitor.
  • the treatment protocols described herein reduce tumor microenvironment immune changes or tumor cell immune effector signal downregulation allowing for tumor immune escape, and the synergistic combination of the administered agents can reverse and/or significantly delay the development of ICI resistance, providing for long-term efficacy of the therapeutic protocol in difficult to treat patient populations.
  • the treatment protocols described herein provide therapeutic efficacy through immune modulation of T cells, including the enhancement of cytotoxic CD8+ T-cell function and maturation into memory CD8+ T-cells and the inhibition of T reg function and differentiation.
  • the result of this extended efficacy is an improvement in host immune response to the tumor, providing improved survival outcomes, including overall survival (OS) and/or progression free survival (PFS), for these difficult to treat patients.
  • OS overall survival
  • PFS progression free survival
  • the methods provided herein can be used to activate an immune response in a subject.
  • administration of trilaciclib in combination with one or more additional agents leads to alterations in intratumor immune T cell subsets favoring effector T-cell function, including stimulation of IFN-y production in exhausted T-cells (Example 1, FIG. 1), reductions in the proportion of Tregs among CD4+ T cells in the tumor (see, e.g., Example 3, FIG. 6), an increase in CD8+ T cells to Tregs ratio in the tumor (see, e.g., Example 3, FIG. 7), and/or an increase in activated CD8+ T cells (see, e.g., Example 3, FIG. 8).
  • the synergistic combination of CDK4/6 inhibitor trilaciclib with one or more additional agents including but not limited to checkpoint inhibitors may reverse and/or significantly delay the resistance to checkpoint inhibition and provide better efficacies of therapeutic regimens in difficult to treat patient populations.
  • the administration of the CDK4/6 inhibitor trilaciclib synergizes when combined with a PD-1 or PD-L1 inhibitor and an additional checkpoint inhibitor, for example a checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, or a CD73 inhibitor, to provide substantially reduced tumor progression (see, e.g., Examples 5, 6, 7, 8, 9, 10, and 11; FIGs.
  • Adenosine accumulation favors tumor growth and metastasis through epidermal growth factor receptor (EGFR) signaling and inhibition of tumor apoptosis, whereas inactivation of CD73 can attenuate this adenosine-mediated process.
  • CD73 also releases matrix metalloproteinases (MMPs) that facilitate breakdown of extracellular matrix (ECM), thus enabling tumor cells to invade and migrate to distant organs.
  • MMPs matrix metalloproteinases
  • the immunosuppressive tumor microenvironment in the patient’s tumor which renders the previously administered ICI ineffective or less effective and allows the tumor to progress — can be significantly overcome, improving the ability of the patient’s immune system to reduce or control tumor burden, improving quality of life, and improving overall survival in these difficult to treat subsets of patients.
  • the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycles), and trilaciclib is administered again on day 7 of each 14-day cycle.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 42 -day cycle, and trilaciclib is administered again on day 7, day 14, day 21, day 28, and day 35 of each 42-day cycle.
  • trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week during treatment, and the PD-1 or PD-L1 and additional immune checkpoint inhibitor are administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week, the PD-Ll or PD-1 inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint inhibitor is administered concurrently with the PD-L1 or PD-1 inhibitor.
  • the additional immune checkpoint inhibitor is not administered concurrently with the PD-L1 or PD-1 inhibitor.
  • trilaciclib is administered one or more times per week. In some embodiments, an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above.
  • the cancer is a non-small cell lung cancer, triple negative breast cancer, colorectal cancer or urothelial cancer.
  • the patient has second-line metastatic non-squamous or squamous NSCLC.
  • the patient has second- line locally advanced or metastatic urothelial carcinoma.
  • the colorectal cancer has been shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • the treatment protocol provides for the administration of trilaciclib and the PD-1 or PD-L1 as described herein, and an oncolytic virus, for example, but not limited to an oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxviruses, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus.
  • an oncolytic virus for example, but not limited to an oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxviruses, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (
  • the patient is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or more treatment cycles.
  • the patient is administered a treatment cycle until disease progression.
  • anti-tumor activity is enhanced by cell cycle independent and dependent mechanisms, including the selective reduction of intra-tumoral T reg populations, preservation of pro-inflammatory immune effector cells such as tumor infiltrating lymphocytes, and an increased durability in treatment response.
  • the controlled inhibition of CDK4/6 with trilaciclib in combination with a chemotherapeutic agent and the multi- immune checkpoint inhibitors as described herein provides a significant increase in anti-tumor effects compared to the administration of a chemotherapeutic agent and immune checkpoint inhibitor alone, or the continuous inhibition of CDK4/6 with a CDK4/6 inhibitor dosed daily, including longer acting CDK4/6 inhibitors, in combination with an immune checkpoint inhibitor.
  • the chemotherapeutic agent to be administered can be a chemotherapeutic agent generally administered as part of the standard of care for the stage of the cancer being treated.
  • chemotherapeutic agents for example, but not limited to, protein synthesis inhibiting or DNA- damaging chemotherapeutic agents, tend to be non-specific and toxic to normal, rapidly dividing cells, including immune effector cells, and hematological toxicities such as myelosuppression are a common side effect of chemotherapeutic treatment.
  • Immune effector cells generally require the activity of CDK4/6 for proliferation, i.e., they are CDK4/6-replication dependent (see Roberts et al. Multiple Roles of Cyclin-Dependent Kinase 4/6 Inhibitors in Cancer Therapy. JNCI 2012;104(6):476-487).
  • an additional immune checkpoint inhibitor into the therapeutic protocol, the development of resistance to the effects of immune checkpoint inhibitors due to long-term use and tumor microenvironment immune changes or tumor cell immune effector signal downregulation can be reversed or significantly delayed, providing for long-term efficacy of the therapeutic protocol in difficult to treat patient populations.
  • ICD immunogenic cell death
  • CTR calreticulin
  • HMGB1 high mobility group box 1
  • extracellular ATP extracellular ATP
  • type I interferon type I interferon
  • cancer cell- derived nucleic acids e.g., cancer cell- derived nucleic acids
  • Chemotherapy can also enhance tumor antigen presentation by upregulating the expression of tumor antigens themselves, or of the MHC class I molecules to which the antigens bind.
  • chemotherapy may upregulate costimulatory molecules (B7-1) or downregulate coinhibitory molecules (PD-L1/B7-H1 or B7-H4) expressed on the tumor cell surface, enhancing the strength of effector T-cell activity.
  • Chemotherapy may also render tumor cells more sensitive to T cell-mediated lysis through fas-, perforin-, and Granzyme B-dependent mechanisms.
  • PD1 inhibitors for use in the methods described herein include, for example, but are not limited to, nivolumab (OPDIVO®; Bristol Myers Squibb), pembrolizumab (KEYTRUDA®; Merck), cemiplimab (LIBTAYO®; Regeneron), dostarlimab (JEMPERLI®; GlaxoSmithKline), pidilizumab (Medivation), AMP-224 (AstraZeneca/Medimmune), AMP-514 (AstraZeneca), sintilimab (IBI308; InnoventZEli Lilly) sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), retifanlimab (MGA012/INCMGA00012; Incyte Corporation and MacroGenics), tislelizumab (BGB-A317; BeiGene), toripalimab
  • camrelizumab SHR-1210; Jiangsu Hengrui Medicine Company and Incyte Corporation
  • CS1003 Cstone Pharmaceuticals
  • zimberelimab AB122; Arcus Biosciences
  • JTX-4014 Jounce Therapeutics
  • PD-L1 inhibitors for use in the methods described herein include, for example, but are not limited to, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol- Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK-301; Checkpoint Therapeutics), sugemalimab (CS-1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (Aurigene), CA-170 (Aurigene/Curis) and BGB-A333 (BeiGene).
  • LAG-3 inhibitors for use in the methods described herein include, for example, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), MGD013 (Macrogenics), RO7247669 (Hoffman - LaRoche), EMB-02
  • TIM-3 inhibitors for use in the methods described herein include, for example, but are not limited to, cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca), TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.), and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
  • TSR-022 cobolimab
  • Tesaro Tesaro
  • RG7769 Genetech
  • MAS825 Novartis
  • TIGIT (T cell immunoreceptor with Ig and ITIM domains) inhibitors for use in the methods described herein include, for example, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB
  • CD 73 Ecto-5 'nucleotidase; (NT5E) checkpoint inhibitors for use in the methods described herein include, for example, but are not limited to, HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, Astra Zeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS- 986179 (Bristol Myers).
  • Chemotherapeutic agents for use in the present methods include those associated with a standard of care treatment for the specific stage and prior treatment status of the cancer being treated.
  • suitable chemotherapeutic agents for use in the present methods include, but are not limited to: platinum containing drugs, for example carboplatin, cisplatin, and oxaliplatin; a taxane, for example paclitaxel, docetaxel, or paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel); a topoisomerase inhibitor, for example topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, and teniposide; cyclophosphamide; vinblastine; gemcitabine; 5-fluoruracil (5-FU); eribulin; pemetrexed; mitomycin; sacituzumab govite
  • the chemotherapeutic agent for use in the present methods is a chemotherapeutic agent capable of inducing an immune-mediated response.
  • Chemotherapies capable of inducing an immune-mediated responses are generally known in the art and include, but are not limited to, alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, and oxaliplatin; antimetabolites such as methotrexate, mitoxantrone, gemcitabine, and 5 -fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin and anthracyclines, including doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin; taxanes, such as paclitaxel, cabazitaxel, and docetaxel; topoisomerase inhibitors such as topotecan, irinotecan, and etopo
  • the chemotherapy is selected from idarubicin, epirubicin, doxorubicin, mitoxantrone, oxaliplatin, bortezomib, gemcitabine, and cyclophosphamide, or the pharmaceutically acceptable salts or any thereof, and combinations of any thereof.
  • trilaciclib is administered each day during a cycle that a chemotherapeutic agent is administered, the PD-1 or PD-L1 inhibitor is administered at least on day 1 of each cycle, and the additional immune checkpoint inhibitor selected from a TIGIT inhibitor, TIM-3 inhibitor, LAG-3 inhibitor, or CD73 inhibitor is administered concomitantly with the PD-1 or PD-L1 inhibitor.
  • the PD-1 or PD-L1 inhibitor is not administered concomitantly with the additional checkpoint inhibitor.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks, wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks, and wherein the duration of the first cycle is different than the duration of the second cycle.
  • trilaciclib is further administered alone once a week during the cycle.
  • trilaciclib, the chemotherapeutic agent, the PD-1 or PD-L1 inhibitor, and the additional checkpoint inhibitor are administered on day 1 of a 14-day cycle.
  • trilaciclib is administered again on day 7 of each 14-day cycle.
  • trilaciclib and the chemotherapeutic agent are administered on day 1 of a 21 -day cycle, and the PD-1 or PD- L1 inhibitor and additional immune checkpoint inhibitor are administered on day 1 of the 21 -day cycle.
  • trilaciclib is further administered alone on day 7 and day 14 of the 21 -day cycle.
  • trilaciclib and the chemotherapeutic agent are administered on day 1-3 of a 21 -day cycle, and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor is administered on day 1 of the 21-day cycle. In some embodiments, trilaciclib is further administered alone on day 7 and day 14 of the 21-day cycle. In some embodiments, trilaciclib and the chemotherapeutic agent are administered on days 1, 8, and 15 of a 28-day cycle, and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor is administered on day 1 of the 28- day cycle.
  • trilaciclib, the chemotherapeutic agent, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 28- day cycle. In some embodiments, trilaciclib is again administered on day 7, day 14, and day 21 of each 28-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, the patient is administered 2 or more treatment cycles, for example, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, or more.
  • the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein the trilaciclib, PD-1 or PD- L1 inhibitor, and additional immune checkpoint inhibitor are administered concomitantly once a week, once every two weeks, once every three weeks, once every 4 weeks, or once every six weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks. In some embodiments, the PD-1 or PD-L1 inhibitor is not administered concomitantly with the additional checkpoint inhibitor.
  • the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks, wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks, and wherein the duration of the first cycle is different than the duration of the second cycle.
  • the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein trilaciclib is administered once a week and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor are administered concomitantly once a week, once every two weeks, once every three weeks, once every 4 weeks, or once every six weeks.
  • the patient is administered trilaciclib, a PD- 1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein trilaciclib is administered once a week, wherein the PD-1 or PD-L1 inhibitor is administered once over a duration of a first cycle, wherein the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is different than the duration of the second cycle.
  • NSCLC Non-Small Cell Luns Cancer
  • the treatment protocols described herein are administered to a patient having metastatic or locally advanced non-small cell lung cancer (NSCLC).
  • NSCLC metastatic or locally advanced non-small cell lung cancer
  • the patient has metastatic or locally advanced squamous cell NSCLC.
  • the patient has metastatic or locally advanced non-squamous cell NSCLC.
  • the patient is not eligible for therapy targeted to a driver NSCLC mutation.
  • the patient has NSCLC with a driver mutation but the patient is not eligible to receive therapy targeted to the driver NSCLC mutation.
  • the patient has NSCLC whose driver mutation status is unknown.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by a USFDA-approved, or CE mark test.
  • the patient has a tumor expressing PD-L1 as determined by a tumor proportion score (TPS), which is the number of PD-L1 -positive tumor cells divided by the total number of PD-L1 -positive plus PD-L1 -negative tumor cells, multiplied by 100, as determined by an FDA-approved, or CE Mark test.
  • TPS tumor proportion score
  • the patient > 1%.
  • the patient has a tumor expressing PD-L1 as determined by stained immune cells (%IC).
  • the IC is > 10%.
  • the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%.
  • the chemotherapeutic agent is nab-paclitaxel and carboplatin. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
  • the patient has a tumor expressing PD-L1 with a TC > 1%.
  • the chemotherapeutic agent administered is a standard of care chemotherapeutic agent.
  • the chemotherapeutic agent is selected from docetaxel, gemcitabine, vinorelbine, or a combination thereof.
  • the chemotherapeutic agent is docetaxel.
  • the chemotherapeutic agent is gemcitabine.
  • the chemotherapeutic agent is vinorelbine.
  • the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression.
  • the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor.
  • the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a first line or second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus.
  • the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus.
  • the oncolytic virus is paleorep.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD- L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%.
  • the patient is also administered a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
  • a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, aPD-1 orPD-Ll inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent.
  • the chemotherapeutic agent is a combination of chemotherapeutic agents selected from pemetrexed, gemcitabine, paclitaxel, nab-paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin.
  • the chemotherapeutic agent is gemcitabine and carboplatin or cisplatin.
  • the chemotherapeutic agent is paclitaxel and carboplatin.
  • the chemotherapeutic agent is nab-paclitaxel and carboplatin.
  • the chemotherapeutic agent is docetaxel.
  • the chemotherapeutic agent is pemetrexed and carboplatin, cisplatin, or oxaliplatin.
  • the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression.
  • the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, aPD-1 orPD-Ll inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%.
  • the chemotherapeutic agent administered is a standard of care chemotherapeutic agent.
  • the chemotherapeutic agent is selected from docetaxel, gemcitabine, vinorelbine, or a combination thereof.
  • the chemotherapeutic agent is docetaxel.
  • the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression.
  • the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor.
  • the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first line or second- line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus.
  • the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus.
  • the oncolytic virus is paleorep.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD- L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%.
  • the patient is also administered a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
  • a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
  • the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or metastatic triple negative breast cancer (TNBC) in a first-line advanced/metastatic setting, and whose tumor expresses PD-L1, and wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD- L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with an IC of >5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent.
  • the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer.
  • TMB-H tumor mutational burden-high
  • the patient has a tumor which expresses PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of > 5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 50%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%.
  • the administration of a treatment protocol described herein to the patient subgroups described herein may provide enhanced anti-tumor efficacy in patients.
  • the administration of a treatment protocol described herein in the particular patient subgroups described above provides improved progression free survival (PFS) and/or overall survival (OS).
  • PFS progression free survival
  • OS overall survival
  • an improvement in PFS is based on per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).
  • the administration of a treatment protocol described herein to the patient subgroups described above provides improved myelopreservation of hematopoietic stem and progenitor cells (HSPCs) and immune effector cells such as lymphocytes including T- lymphocytes.
  • HSPCs hematopoietic stem and progenitor cells
  • immune effector cells such as lymphocytes including T- lymphocytes.
  • the administration of a treatment protocol described herein provides a reduction in all-cause dose reductions or cycle delays and relative dose intensity for chemotherapy.
  • the administration of a treatment protocol described herein provides a reduction in i) hospitalizations, including but not limited to those due to all causes, febrile neutropenia/neutropenia, anemia/RBC transfusion, thrombocytopenia/bleeding and infections) or ii) antibiotic use, including but not limited to intravenous (IV), oral, and oral and IV administered antibiotics.
  • the administration of a treatment protocol described herein provides an improvement to one or more of: Functional Assessment of Cancer Therapy-General (FACT- G) domain scores (physical, social/family, emotional, and functional well-being); Functional Assessment of Cancer Therapy -Anemia (FACT-An); 5-level EQ-5D (EQ-5D-5L); Patient Global Impression of Change (PGIC) fatigue item; or Patient Global Impression of Severity (PGIS) fatigue item.
  • FACT- G Functional Assessment of Cancer Therapy-General
  • FACT-An Functional Assessment of Cancer Therapy-Anemia
  • EQ-5D-5L 5-level EQ-5D
  • PGIC Patient Global Impression of Change
  • PGIS Patient Global Impression of Severity
  • FIG. 6 shows the proportion of Tregs in total tumor treated with vehicle, oxaliplatin/PD-Ll, or trilaciclib/oxaliplatin/PD-Ll on days 5 and 9.
  • the x-axis is the results on Day 5 and Day 9 and the y-axis is the % Tregs of CD4+ T cells in the tumor measured as a percentage.
  • FIG. 10A is a bar graph illustrating the quantification of IL-2 cytokine production produced by MC38 tumor infiltrating T lymphocytes.
  • mice were sacrificed and TILs were isolated from the tumor for cytokine analysis for IL-2 from CD4+ T cells (*p ⁇ 0.001).
  • the x-axis is the treatment groups and the y-axis is the percentage of IL-2 from CD4 + cells.
  • FIG. 10B is a bar graph illustrating the quantification of IFNy cytokine production produced by MC38 tumor infiltrating T lymphocytes.
  • mice were sacrificed and TILs were isolated from the tumor for cytokine analysis for IFNy from CD8 + T cells (*p ⁇ 0.001).
  • the x-axis is the treatment groups and the y-axis is the percentage of IFNy from CD8 + T cells.
  • FIG. 11B shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination.
  • MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
  • FIG. 11D shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with citrate buffer (negative control).
  • the mice were treated with citrate buffer (negative control) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. HE shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib only.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 11H shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with anti-PD-1 inhibitor (5 mg/kg, two times per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 11 J shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 1 IK shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib, an anti-PDl inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration.
  • the x- axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration.
  • the x- axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
  • FIG. 12C shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with or without trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) and with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration. Drug dosing was terminated on day 63.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 12D shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control).
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12E shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor only.
  • the mice were treated with anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor only.
  • the mice were treated with anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with anti-PD-1 inhibitor (5 mg/kg, two times per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 121 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination.
  • the mice were treated with trilaciclib (lOOmg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12J shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12K shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13 A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell administration.
  • the x- axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
  • FIG. 13B shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with or without trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) and with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell administration. Drug dosing was terminated on day 63.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 13C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control).
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13D shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13E shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor only.
  • the mice were treated with anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 14A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor.
  • the x- axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 14B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 14C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the x-axis is days post treatment measured in days and the y- axis is tumor volume measured in mm 3 .
  • FIG. 15A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor and/or anti-TIM3 inhibitor alone or in combination.
  • the x-axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
  • FIG. 15B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor alone or in combination.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-LAG3 inhibitor (10 mg/kg, 2 times a week).
  • the x-axis is days of treatment measured in days and the y- axis is tumor growth (fold change).
  • FIG. 15C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIM3 inhibitor alone or in combination.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIM3 inhibitor (10 mg/kg, 2 times a week).
  • the x-axis is days of treatment measured in days and the y- axis is tumor growth (fold change).
  • FIG. 15D shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor alone or in combination.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 15E shows Overall Survival of Balb/C mice implanted with mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIM3 inhibitor alone or in combination.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIM3 inhibitor (10 mg/kg, 2 times a week) from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 15F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control).
  • the mice were treated with citrate buffer as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only.
  • the mice were treated with CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor only.
  • the mice were treated with anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 151 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-LAG3 inhibitor only.
  • the mice were treated with anti-LAG3 inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15J shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIM3 inhibitor only.
  • the mice were treated with anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15L shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIM3 inhibitor in combination.
  • the mice were treated with anti-PD-1 inhibitor (5mg/kg, two times per week) and anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15M shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15N shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-LAG3 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-LAG3 inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 150 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIM3 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15P shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-LAG3 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-LAG3 inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15Q shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIM3 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIM3 inhibitor (5 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 16A shows tumor growth curves of Balb/C mice implanted with CT26 colorectal cancer (CRC) murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • CT-26 murine colorectal cancer cells were injected subcutaneously into Balb/c mice. The mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell implantation.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 16B shows Overall Survival of Balb/C mice implanted with CT26 colorectal cancer (CRC) murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination.
  • CT-26 murine colorectal carcinoma cells were injected subcutaneously into Balb/C mice. The mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 17A shows tumor growth curves of C57BL/6 mice implanted with AT3-OVA murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • AT3-OVA murine breast carcinoma cells were injected subcutaneously into C57BL/6 mice.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell implantation.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 17B shows Overall Survival of Balb/C mice implanted with AT3-OVA breast cancer (BC) murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination.
  • AT3-OVA murine breast carcinoma cells were injected subcutaneously into Balb/C mice.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 18 shows tumor growth curves of Balb/C mice implanted with S2WTP3 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • S2WTP3 murine breast carcinoma cells were injected subcutaneously into Balb/c mice.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti- TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • Figure 19 shows a visual depiction of the effect of adenosinergic molecules on the tumor and surrounding stroma.
  • FIG 20A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-CD73 inhibitor alone or in combination.
  • CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice.
  • the mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-CD73 inhibitor (5 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell implantation. Treatment continued for six weeks.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 20B shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • the compound may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or isomer, such as a rotamer, as if each is specifically described unless specifically excluded by context.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric
  • the term "prodrug” means a compound which when administered to a host in vivo is converted into the parent drug.
  • parent drug means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human.
  • Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent.
  • Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
  • Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
  • carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, and neither biologically nor otherwise inappropriate for administration to a host, typically a human.
  • trilaciclib can be used in a form that has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes that can be incorporated into trilaciclib for use in the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 3 IP, 32P, 35S, 36CI, and 1251 respectively.
  • isotopically labelled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
  • isotopes of carbon e.g., 13 C and 14 C
  • isotopes of carbon e.g., 13 C and 14 C
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest.
  • deuterium is 90, 95 or 99% enriched at a desired location.
  • the CDK4/6 inhibitors, chemotherapy, or checkpoint inhibitors can be used in a form that has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • Trilaciclib or another CDK4/6 inhibitor described herein for use in the present invention may form a solvate with solvents (including water). Therefore, in one non-limiting embodiment, the invention includes the use of a solvated form of the compound.
  • solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound of the invention and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g., D2O, de-acetone, de-DMSO.
  • a solvate can be in a liquid or solid form.
  • hematopoietic stem and progenitor cell includes, but are not limited to, long term hematopoietic stem cells (LT-HSCs), short term hematopoietic stem cells (ST-HSCs), hematopoietic progenitor cells (HPCs), multipotent progenitors (MPPs), oligodendrocyte pre-progenitors (OPPs), monocyte progenitors, granulocyte progenitors, common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-monocyte progenitors (GMPs), granulocyte progenitors, monocyte progenitors, and megakaryocyte-erythroid progenitors (MEPs), megakaryocyte progenitors, erythroid progenitors, HSC/MPPs (CD45dim/CD34+/CD38-), OPPs (LT-HSCs), short term hematopoi
  • Immune effector cell generally refers to an immune cell that performs one or more specific functions.
  • Immune effector cells are known in the art and include for example, but are not limited to, T-cells, including Naive T-cells, Memory T-cells, Activated T-cells (T helper (CD4+) and Cytotoxic T cells (CD8+)), TH1 activated T-cells, TH2 activated T-cells, TH17 activated T-cells, Naive B cells, Memory B cells, plasmablasts, dendritic cells, monocytes, and natural killer (NK) cells.
  • T-cells including Naive T-cells, Memory T-cells, Activated T-cells (T helper (CD4+) and Cytotoxic T cells (CD8+)
  • T helper CD4+
  • CD8+ Cytotoxic T cells
  • TH1 activated T-cells TH2 activated T-cells
  • TH17 activated T-cells
  • Naive B cells
  • patient typically a human patient, although it is to be understood the methods described herein are effective with respect to other animals, such as mammals. More particularly, the term patient can include animals used in assays such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.
  • animals used in assays such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.
  • CDK4/6-replication independent cancer refers to a cancer that does not significantly require the activity of CDK4/6 for replication. Cancers of such type are often, but not always, characterized by (e.g., that has cells that exhibit) an increased level of CDK2 activity or by reduced expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s), such as, but not limited to pl07 and pl30.
  • the increased level of CDK2 activity or reduced or deficient expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s) can be increased or reduced, for example, compared to normal cells.
  • CDK4/6-replication dependent cancer refers to a cancer that requires the activity of CDK4/6 for replication or proliferation, or which may be growth inhibited through the activity of a selective CDK4/6 inhibitor.
  • Cancers and disorders of such type may be characterized by (e.g., that has cells that exhibit) the presence of a functional Retinoblastoma (Rb) protein.
  • Rb Retinoblastoma
  • Such cancers and disorders are classified as being Rb-positive.
  • Rb- positive abnormal cellular proliferation disorders, and variations of this term as used herein, refer to disorders or diseases caused by uncontrolled or abnormal cellular division which are characterized by the presence of a functional Retinoblastoma protein, which can include cancers.
  • the non-small cell lung cancer NSCLC
  • triple negative breast cancer TNBC
  • colorectal cancer CRC
  • metastatic urothelial cancer mUC
  • another solid tumor to be treated is generally PD-L1 positive.
  • the NSCLC, TNBC, colorectal, mUC, or another solid tumor to be treated is PD-L1 negative.
  • PD-L1 is a transmembrane protein that down-regulates immune responses through binding to its two inhibitory receptors, programmed death-1 (PD-1) and B7.1.
  • PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, which is sustained in states of chronic stimulation such as in chronic infection or cancer (Blank, C and Mackensen, A, Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007. 56(5): p. 739-745). Binding of PD-L1 with PD-1 inhibits T cell proliferation, cytokine production and cytolytic activity, leading to the functional inactivation or exhaustion of T cells.
  • B7.1 is a molecule expressed on antigen presenting cells and activated T cells.
  • PD-L1 binding to B7.1 on T cells and antigen presenting cells can mediate down-regulation of immune responses, including inhibition of T-cell activation and cytokine production (see Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007; 27(1): 111-122).
  • PD-L1 expression has been observed in immune cells and tumor cells. See Dong H, Zhu G, Tamada K, Chen L.
  • PD-L1 expression can be determined by methods known in the art.
  • PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, the FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol -Meyers Squibb as a companion test for treatment with pembrolizumab (KEYTRUDA®).
  • IHC in vitro diagnostic immunohistochemistry
  • KYTRUDA® pembrolizumab
  • This scoring method evaluates the number of PD-Ll-staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells.
  • CPS is used to assess PD-L1 expression in: metastatic or unresectable, recurrent HNSCC, advanced esophageal or GEJ carcinoma, metastatic urothelial cancer (mUC), colorectal cancer, advanced cervical cancer and advanced triple-negative breast cancer.
  • Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining. Staining can show PD-L1 expression from 1% to 100%.
  • TPS is used to assess PD-L1 expression in advanced NSCLC, metastatic urothelial cancer (mUC), colorectal cancer and other solid tumors.
  • PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, the FDA- approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with nivolumab (OPDIVO®).
  • IHC in vitro diagnostic immunohistochemistry
  • OPDIVO® nivolumab
  • This qualitative assay uses the Monoclonal rabbit anti-PD-Ll, Clone 28-8 and the EnVision FLEX visualization system on the Autostainer Link 48 platform to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissue.
  • FFPE paraffin-embedded
  • Determination of PD-L1 status is indication-specific, and evaluation is based on either the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity or the percentage of PD-L1 expressing tumor cells (% TC) of any intensity.
  • the cutoff for mUC is >5% IC
  • the cutoff for TNBC is >1% IC
  • the cutoff for NSCLC is >50% TC or 10% IC.
  • the NSCLC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive NSCLC.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive NSCLC of >10% PD-L1 staining tumor-infiltrating immune cells (IC) or >50% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the TNBC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive TNBC.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive TNBC of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) or >1% of PD-L1 staining tumor-infiltrating immune cells (IC). as confirmed by an in vitro diagnostic (IVD) assay, for example, the Dako PD-L1-22C3 pharmDx kit or the Ventana SP-142 assay or another suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status TNBC with >10% PD-L1 staining of tumor cells as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second- line therapeutic protocol has a documented PD-L1 status TNBC with >1% PD-L1 staining of immune cells as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status negative TNBC.
  • the colorectal cancer (CRC) patient being treated in the first-line or second-line therapeutic protocol described herein has a documented tumor shown by an FDA- approved or CE Mark test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • the CRC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive CRC.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive CRC of >1% PD-L1 staining tumor-infiltrating immune cells (IC) or >1% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status CRC with >1% PD-L1 staining of tumor cells (TC) as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status negative CRC.
  • the mUC patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive mUC.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive mUC of >5% PD-L1 staining tumor-infiltrating immune cells (IC) or >50% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP- 142 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >25% PD-L1 staining of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-263 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >5% PD-L1 staining of immune cells (IC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >1% PD-L1 staining of tumor cells (%TC) as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second- line therapeutic protocol has a documented PD-L1 status mUC with >1% PD-L1 staining of immune cells (%IC) as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status positive mUC of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-263 assay or another suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >1% viable tumor cells showing partial or complete membrane staining (TPS) at any intensity as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status negative mUC.
  • the solid tumor patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer.
  • TMB-H tumor mutational burden-high
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive squamous cell carcinoma of the head and neck (SCCHN) of >1% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS).
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive cervical cancer of >1% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as determined by an FDA- approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive esophageal cancer of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status gastroesophageal junction cancer with >1% viable tumor cells showing partial or complete membrane staining (TPS) at any intensity as determined by an FDA-approved or CE Mark test.
  • the NSCLC, TNBC, CRC, mUC, or another solid tumor to be treated is CDK4/6 -negative.
  • the NSCLC, TNBC, CRC, mUC or another solid tumor to be treated is CDK4/6-positive.
  • the NSCLC, TNBC, CRC, mUC or another solid tumor is CDK4/6 indeterminate.
  • CDK4/6 replication independent cancers generally have a retinoblastoma gene (Rbl) aberration.
  • the gene product of Rbl — Rb-protein — is a downstream target of CDK4/6.
  • RBI is commonly dysregulated in cancer cells through deletion, mutation or epigenetic modification resulting in loss of RB expression, as well as by aberrant CDK kinase activity leading to excessive phosphorylation and inactivation of RB function (Chen et al. Novel RBI -Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types. Clin Cancer Res. 2019; 25(14); Sherr, C.J., and McCormick, F. The RB and p53 pathways in cancer. Cancer Cell, 2002; 2: 103 12.).
  • CCNE1/2 cyclin E
  • CCNE1/2 is part of a parallel pathway that provides functional redundancy with CDK4/6 and helps to transition cells from the G1 to S phase.
  • CDK 4/6 replication dependent TNBCs generally have an intact and functional Rb pathway and/ increased expression of CDK4/6 activators (cyclin D), and/or a d-type cyclin activating features (DCAF) — including CCND1 translocation, CCND1-3 3’UTR loss, and amplification of CCND2 or CCND3 (see Gong et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017; 32(6): 761-76). Tumors that are wildtype for RB and CCNE1/2 as well as have one of the DCAF described above are generally classified as “CDK4/6 dependent”.
  • CDK4/6-replication dependent or CDK4/6- replication independent are generally classified as “CDK4/6 indeterminate” since they cannot be confirmed as CDK4/6 dependent or independent.
  • the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6-replication dependent. In some embodiments, the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6-replication independent. In some embodiments, the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6 indeterminate.
  • an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIM- 3 T-cell immunoglobulin mucin-3
  • LAG-3 Lymphocyte-activation gene 3
  • CD73 Cluster of Differentiation 73
  • Retinoblastoma protein 1 (Rbl) loss which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)).
  • an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
  • TTIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIM- 3 T-cell immunoglobulin mucin-3
  • LAG-3 Lymphocyte-activation gene 3
  • CD73 Cluster of Differentiation 73
  • Rb 1 loss which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained));
  • 3) has at least one of the following D-cyclin activating features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD 1-3 3’ UTR loss defined as a homozygous or heterozygous deletion of any of these UTRs.
  • an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIM- 3 T-cell immunoglobulin mucin-3
  • LAG-3 Lymphocyte-activation gene 3
  • CD73 Cluster of Differentiation 73
  • Retinoblastoma protein 1 (Rbl) loss which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)).
  • the solid tumor patient being treated in a specifically timed protocol has a documented CDK4/6 independent solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer.
  • TMB-H tumor mutational burden-high
  • the solid tumor patient being treated in a specifically timed protocol has a documented CDK4/6 dependent solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer.
  • TMB-H tumor mutational burden-high
  • NSCLC advanced/metastatic non-small cell lung cancer
  • TNBC advanced/metastatic triple negative breast cancer
  • CRC advanced/metastatic and unresectable colorectal cancer
  • mUC advanced/metastatic urothelial carcinoma
  • an advanced/metastatic other solid tumor for example, squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer (GEJ), an esoph
  • Example of immune checkpoint inhibitors and immune modulating agents include, but are not limited to, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, CD73 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, TIGIT inhibitor, Siglec-15 inhibitor, B7-H3 (CD272) inhibitor, BTLA inhibitor (CD272), small molecule, peptide, nucleotide, or another inhibitor.
  • the immune modulator is an antibody, such as a monoclonal antibody.
  • PD-L1 inhibitors for use in the methods described herein include, for example, but are not limited to, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK- 301; Checkpoint Therapeutics), sugemalimab (CS-1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (Aurigene), CA-170 (Aurigene/Curi
  • the patient has previously been administered a dual PD-L1/PD-1 inhibitor. In some embodiments, the patient has previously been administered a PD-L1/VISTA inhibitor.
  • PD-L1-VISTA inhibitors include, but are not limited to, CA-170 (Curis Inc.).
  • the immune checkpoint inhibitor is a VISTA immune checkpoint inhibitor.
  • VISTA inhibitors include, but are not limited to, JNJ-61610588 (Johnson & Johnson).
  • LAG-3 inhibitors for use in the methods described herein include, for example, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR- 033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIGIT (T cell immunoreceptor with Ig and ITIM domains) inhibitors for use in the methods described herein include, for example, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab /OMP- 313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/P
  • the patient has previously been administered an immune checkpoint inhibitor including, for example, but not limited to, a B7-H3/CD276 immune checkpoint inhibitor such as enoblituzumab (MGA217, Macrogenics) MGD009 (Macrogenics), 13 lI-8H9/omburtamab (Y-mabs), and I-8H9/omburtamab (Y-mabs), an indoleamine 2,3-dioxygenase (IDO) immune checkpoint inhibitor such as Indoximod and INCB024360, a killer immunoglobulin-like receptors (KIRs) immune checkpoint inhibitor such as Lirilumab (BMS-986015), a carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitor (e.g., CEACAM-1, -3 and/or -5).
  • a B7-H3/CD276 immune checkpoint inhibitor such as enoblituzumab (MGA217, Macrogenics) M
  • anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 and WO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552.
  • the anti-CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 September 2; 5(9). pii: el2529 (DOI: 10: 1371/joumal. pone.0021146), or crossreacts with CEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US 2014/0271618.
  • the patient has previously been administered an immune checkpoint inhibitor directed to CD39, including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secama)
  • an immune checkpoint inhibitor directed to CD39 including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secama)
  • the patient has previously been administered an immune checkpoint inhibitor directed to B and T lymphocyte attenuator molecule (BTLA), for example as described in Zhang et al., Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1): 77-87, and TAB004/JS004 (Junshi Biosciences).
  • BTLA B and T lymphocyte attenuator molecule
  • the patient has previously been administered a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (an anti- Siglec-15 mAb).
  • Siglec-15 sialic acid-binding immunoglobulin-like lectin 15
  • a chemotherapeutic agent is also administered as part of the therapeutic protocol.
  • the administration of the selective CDK4/6 inhibitor trilaciclib in conjunction with a PD-1 or PD-L1 inhibitor and an additional ICI as described herein increases the efficacy of immune checkpoint inhibition, including overcoming the development of resistance to previously administered PD-1 or PD-L1 inhibitors and/or reducing or delaying the onset of resistance, resulting in the extended efficacy of the anti -cancer protocol.
  • the administration of the selective CDK4/6 inhibitor trilaciclib in conjunction with a PD-1 or PD- L1 inhibitor and an additional ICI as described herein provides for improved survival outcomes, including overall survival (OS) and/or progression free survival (PFS) and reduced or delayed resistance to ICI therapy for these difficult to treat patients.
  • OS overall survival
  • PFS progression free survival
  • Trilaciclib (2'-((5-(4-methylpiperazin-l-yl) pyridin-2-yl) amino)-7',8'-dihydro-6'H-spiro (cyclohexane- l,9'-pyrazino (l',2':l,5) pyrrolo(2,3-d) pyrimidin)-6'-one) is a highly selective
  • CDK4/6 inhibitor having the structure:
  • Trilaciclib or its pharmaceutically acceptable salt, composition, isotopic analog, or prodrug thereof is administered in a suitable carrier.
  • Trilaciclib is available commercially as COSELA® (G1 Therapeutics, Inc.). Trilaciclib is described in US 2013-0237544, incorporated herein by reference in its entirety. Trilaciclib can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety. Trilaciclib can be administered in any manner that achieves the desired outcome, including systemically, parenterally, intravenously, intramuscularly, subcutaneously, or intradermally.
  • Trilaciclib can be administered intravenously as described herein.
  • trilaciclib is in the form of a dihydrochloride optionally as a hydrate.
  • trilaciclib can be used in the present invention as a dihydrochloride, dihydrate or as a pharmaceutical composition formed from trilaciclib dihydrochloride, dihydrate.
  • trilaciclib is administered at between about 180 mg/m 2 and 300 mg/m 2 .
  • trilaciclib is administered at about 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, or about 280 mg/m 2 .
  • trilaciclib is administered at least 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, or 240 mg/m 2 .
  • trilaciclib is administered at about 240 mg/m 2 , prior to administration of the chemotherapeutic agent prior to about 4 hours or less, for example about 4 hours or less, 3 hours or less, 2 hours or less, about 1 hour or less, or about 30 minutes prior to administration of the chemotherapeutic, or first chemotherapeutic to be administered in a combination protocol, respectively.
  • trilaciclib is administered intravenously over a period of about 30 minutes. In some embodiments, trilaciclib is completely administered prior to administration.
  • a different CDK4/6 inhibitor is administered.
  • the CDK4/6 inhibitor used instead of trilaciclib in the protocols described herein is ribociclib (Novartis), palbociclib (Pfizer), or abemaciclib (Eli Lilly), or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is lerociclib, which has the structure: or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in US 2013-0237544, incorporated herein by reference in its entirety, and can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety.
  • lerociclib is administered as a pharmaceutically acceptable salt, for example, the dihydrocloride salt.
  • the CDK4/6 inhibitor has the structure: or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in US 2013-0237544, incorporated herein by reference in its entirety, and can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety.
  • a CDK4/6 inhibitor selected from Palbociclib, ribociclib, or abemaciclib is used instead of trilaciclib.
  • the first immune checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibits immune suppression.
  • the immune checkpoint inhibitor is a PD-1 immune checkpoint inhibitor selected from nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®; Regeneron), dostarlimab (JEMPERLI®), pidilizumab (Medivation), AMP -224 (AstraZeneca/Medimmune), AMP-514 (AstraZeneca), sintilimab (IB 1308; Innovent/Eli Lilly) sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), retifanlimab (MGA012/INCMGA00012); Incyte Corporation and MacroGenics
  • the PD-1 inhibitor is nivolumab (OPDIVO®) administered in an effective amount for the treatment of unresectable or metastatic melanoma, early-stage and metastatic non-small cell lung cancer (NSCLC), intermediate or poor risk advanced renal cell carcinoma (RCC), relapsed or progressed classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), locally advanced or metastatic urothelial carcinoma (mUC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC), hepatocellular carcinoma, unresectable malignant pleural mesothelioma, adjuvant or metastatic esophageal carcinoma, gastroesophageal junction (GEJ) cancer and gastric cancer.
  • nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks for NSCLC,
  • the PD-1 inhibitor is cemiplimab (LIBTAYO®) administered in an effective amount for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC), locally advanced or metastatic non-small cell lung cancer (NSCLC), locally advanced or metastatic basal cell carcinoma, metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial carcinoma (mUC).
  • cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks until disease progression.
  • cemiplimab is administered prior to chemotherapy.
  • the first immune checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression.
  • PD-L1 inhibitors include, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK-301; Checkpoint Therapeutics), sugemalimab (CS- 1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (A
  • the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab (TECENTRIQ®) administered in an effective amount for the treatment of locally advanced or metastatic urothelial carcinoma (mUC), unresectable or metastatic melanoma, metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC), metastatic non-small cell lung cancer (NSCLC), unresectable or metastatic hepatocellular carcinoma or metastatic small cell lung cancer (SCLC).
  • atezolizumab is administered at 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.
  • atezolizumab is administered prior to chemotherapy.
  • the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor avelumab (BAVENCIO®) administered in an effective amount for the treatment of Merkel cell carcinoma, metastatic urothelial carcinoma (mUC), renal cell carcinoma (RCC), metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial carcinoma (mUC).
  • avelumab is administered at 800 mg every 2 weeks. In one embodiment, avelumab is administered prior to chemotherapy.
  • T cell immunoreceptor with immunoglobulin and HIM domain (TIGIT) Inhibitors T cell immunoreceptor with immunoglobulin and HIM domain (TIGIT) Inhibitors
  • TIGIT also called WUCAM, Vstm3, VSIG9
  • WUCAM WUCAM
  • Vstm3 a receptor of the Ig superfamily, which plays a critical role in limiting adaptive and innate immunity
  • TIGIT participates in a complex regulatory network involving multiple inhibitory receptors (e.g., CD96/TACTILE, CD112R/PVRIG), one competing costimulatory receptor (DNAM-1/CD226), and multiple ligands (e.g., CD155 (PVR/NECL-5), CD112 (Nectin- 2/PVRL2) (Levin et al., Vstm3 is a member of the CD28 family and an important modulator of T- cell function.
  • multiple inhibitory receptors e.g., CD96/TACTILE, CD112R/PVRIG
  • DNAM-1/CD226 competing costimulatory receptor
  • multiple ligands e.g., CD155 (PVR/NECL-5), CD112 (Nectin- 2/PVRL2) (Levin et al., Vstm3 is a member of the CD28 family and an important modulator of T- cell function.
  • TIGIT is co-expressed with PD-1 on tumor antigen-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) in mice and humans
  • TILs tumor-infiltrating lymphocytes
  • TIGIT and PD-1 impair tumor antigen-specific CD8 + T cells in melanoma patients. J Clin Invest 2015; 125: 2046-58; Johnston et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26 :923-37).
  • TIGIT is highly expressed by T re gs in peripheral blood mononuclear cells of healthy donors and patients with cancer and further upregulated in the TME (Joller et al., Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Thl and Thl7 cell responses. Immunity 2014; 40: 569-81; Zhang et al., Genome-Wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells. Blood 2013; 122: 2823-36).
  • the additional immune checkpoint inhibitor is a TIGIT inhibitor that blocks the interaction of TIGIT and CD 155 by binding to the TIGIT receptor, and in turn inhibits immune suppression.
  • TIGIT inhibitors include, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB-154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (M
  • the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression. In one embodiment, the TIGIT inhibitor blocks the interaction between TIGIT and CD155 to inhibit immune suppression.
  • the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, TIGIT inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIGIT inhibitor.
  • the CDK4/6 inhibitor, the PD-1 or PD-L1 inhibitor and the TIGIT inhibitor is used without chemotherapy.
  • the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD- L1 inhibitor is avelumab. In one embodiment, the PD-L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression.
  • the TIGIT inhibitor blocks the interaction between TIGIT and CD 155 to inhibit immune suppression.
  • the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, TIGIT inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIGIT inhibitor.
  • the CDK4/6 inhibitor, the PD-L1 inhibitor and the TIGIT inhibitor is used without chemotherapy.
  • T-cell immunoglobulin and mucin domain 3 (TIMS) inhibitors T-cell immunoglobulin and mucin domain 3 (TIMS) inhibitors
  • T-cell immunoglobulin and mucin domain 3 (encoded by Haver ) is an immunoglobulin (Ig) and mucin domain-containing cell surface molecule that was originally discovered as a cell surface marker specific to interferon (IFN-y) producing CD4 + T helper 1 (Thl) and CD8 + T cytotoxic 1 (Tel) cell (Monney et al., Thl-specific cell surface protein TIM-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415: 536- 41).
  • IFN-y interferon
  • Thl T helper 1
  • Tel T cytotoxic 1
  • Tim-3 is coregulated and co-expressed along with other immune checkpoint receptors (PD- 1, Lag-3, and TIGIT) on CD4 + and CD8 + T cells (Chihara et al., Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 2018; 558: 454-9; DeLong et al., 11-27 and TCR stimulation promote T cell expression of multiple inhibitory receptors. Immuno Horizons 2019; 3: 13-25).
  • TIM-3 expression specifically marks the most dysfunctional or terminally exhausted subset of CD8 + T cells (Fourcade et al., Upregulation of TIM-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.
  • the additional immune checkpoint inhibitor is a TIM-3 inhibitor that blocks the interaction of TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 by binding to the TIM-3 receptor, and in turn inhibits immune suppression.
  • PtdSer phosphatidylserine
  • HMGB1 high-mobility group protein Bl
  • CEACAM-1 CEACAM-1
  • TIM-3 inhibitors include, but are not limited to, Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the TIM-3 and PD-1 bispecific RO7121661 (Roche).
  • the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression.
  • the TIM- 3 inhibitor blocks the interaction between TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 to inhibit immune suppression.
  • PtdSer phosphatidylserine
  • HMGB1 high-mobility group protein Bl
  • CEACAM-1 CEACAM-1 to inhibit immune suppression.
  • the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, TIM-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIM-3 inhibitor.
  • the CDK4/6 inhibitor, the PD-1 inhibitor and the TIM-3 inhibitor is used without chemotherapy.
  • the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD- L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor is avelumab. In one embodiment, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression.
  • the TIM-3 inhibitor blocks the interaction between TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 to inhibit immune suppression.
  • PtdSer phosphatidylserine
  • HMGB1 high-mobility group protein Bl
  • CEACAM-1 CEACAM-1
  • the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, TIM-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIM-3 inhibitor.
  • the CDK4/6 inhibitor, the PD-L1 inhibitor and the TIM-3 inhibitor is used without chemotherapy.
  • LAG-3 (CD223) is encoded by the LAG-3 gene.
  • LAG-3 is a member of the immunoglobulin superfamily (IgSF) and exerts a wide variety of biologic impacts on T cell function (Triebel et al., LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171 : 1393-405).
  • LAG-3 is expressed on cell membranes of natural killer cells (NK), B cells, tumor-infiltrating lymphocytes (TIL), a subset of T cells, and dendritic cells (DC) (Triebel et al., LAG-3, a novel lymphocyte activation gene closely related to CD4.
  • NK natural killer cells
  • TIL tumor-infiltrating lymphocytes
  • DC dendritic cells
  • lymphocyte activation gene 3 (LAG-3)
  • LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
  • LAG-3 protein binds a nonholomorphic region of major histocompatibility complex 2 (MHC class II) with greater affinity than CD 4 (Baixeras et al., Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med 1992; 176: 327- 37).
  • MHC class II major histocompatibility complex 2
  • LAG-3 is one of the various immune-checkpoint receptors that are coordinately upregulated on both regulatory T cells (Tregs) and anergic T cells, and the simultaneous blockade of these receptors can result in an enhanced reversal of this anergic state relative to the blockade of one receptor alone (Grosso et al., Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol 2009; 182: 6659-69).
  • the LAG-3/MHC class II molecule interaction leads to the downregulation of CD4+ Ag-specific T cell clone proliferation and cytokine secretion (Huard et al., T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding. Eur J Immunol 1996; 26: 1180-6).
  • the additional immune checkpoint inhibitor is a LAG-3 inhibitor that blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression.
  • LAG-3 inhibitors include, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), bootszelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR- 033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen, LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologie
  • the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the LAG-3 inhibitor is relatlimab.
  • the PD-1 inhibitor blocks the interaction between PD-1 and PD- L1 to inhibit immune suppression.
  • the LAG-3 inhibitor blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression.
  • MHC class II major histocompatibility complex 2
  • the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, LAG-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and LAG-3 inhibitor.
  • the CDK4/6 inhibitor, the PD-1 inhibitor and the LAG-3 inhibitor is used without chemotherapy.
  • the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD-L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor is avelumab. In one embodiment, the LAG-3 inhibitor is relatlimab.
  • the PD- L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression.
  • the LAG-3 inhibitor blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression.
  • MHC class II major histocompatibility complex 2
  • the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, LAG-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and LAG-3 inhibitor.
  • the CDK4/6 inhibitor, the PD-L1 inhibitor and the LAG-3 inhibitor is used without chemotherapy.
  • CD73 commonly serves to convert AMP to adenosine (Allard et al., "Chapter Fifteen - Measurement of CD73 enzymatic activity using luminescence-based and colorimetric assays", Methods in Enzymology, Tumor Immunology and Immunotherapy - Molecular Methods, Academic Press, 629: 269-289).
  • CD73 is a membrane-bound extracellular enzyme overexpressed in several types of cancer. Its expression has been linked to poor prognosis in melanoma, colorectal, gastric, triple negative breast cancer, and to a pro-metastatic phenotype in prostate cancer (Stagg J et al., CD73- deficient mice are resistant to carcinogenesis. Cancer Res.
  • CD39 adenosine triphosphate (ATP) into adenosine.
  • ATP adenosine triphosphate
  • CD73 is active on the last step of the degradation pathway, where it is the enzyme that degrades AMP into adenosine. The CD73 blockade promotes anti-tumor immunity by reducing adenosine accumulation.
  • anti-CD73 mAbs stimulate antitumor immunity and reduce tumor metastasis in mouse tumor models and could enhance the efficacy of treatment with anti-PDl or anti-CTLA4 antibodies (Allard et al., Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res. 2013 Oct 15; 19(20):5626-35).
  • Figure 19 shows a visual depiction of the effect of adenosinergic molecules on the tumor and surrounding stroma (Vijay an D et al., Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer. 2017 Dec;17(12):709-724).
  • Adenosine is a well-described immunosuppressive agent which attenuates the effector functions of various immune cell populations, including T cells, and enhances the suppressive functions of T regs.
  • Adenosine accumulation favors tumor growth and metastasis through effects on tumor cells and stroma.
  • activation of CD73 on tumor cells favors cell adhesion potentially through epidermal growth factor receptor (EGFR) signaling (indicated by dashed arrow) and inhibits tumor apoptosis.
  • EGFR epidermal growth factor receptor
  • CD73 activation also releases matrix metalloproteinases (MMPs) that facilitate breakdown of extracellular matrix (ECM), thus enabling tumor cells to invade and migrate to distant organs.
  • MMPs matrix metalloproteinases
  • A2BR activation on tumor cells promotes proliferation and angiogenesis through secretion of vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • CAFs cancer-associated fibroblasts
  • FGF2 fibroblast growth factor 2
  • FAP fibroblast activation protein
  • A2BR activation leads to elevated release of CXCL12 by these FAP+ fibroblasts, thus increasing the number of CD31+ endothelial cells within the tumor.
  • A2BR can engage the G protein-coupled receptor Gq-protein kinase C (PKC) signaling pathway to activate interleukin-6 (IL-6), which in turn mediates epithelial-to-mesenchymal transition (EMT).
  • GPC G protein-coupled receptor Gq-protein kinase C
  • tumor exosomes co-express CD39 and CD73, which might be associated with tumor dissemination to distant organs (Vijayan, D., Young, A., Teng, M. W. L., & Smyth, M. J. (2017). Targeting immunosuppressive adenosine in cancer. Nature Reviews Cancer, 17(12), 709-724).
  • the additional immune checkpoint inhibitor is a CD73 inhibitor that specifically binds to CD73 and blocks its extracellular 5'-nucleotidase activity.
  • the CD73 inhibitor can relieve the inhibitory effect of adenosine on the proliferation and tumor-killing activity of CD8+ T cells, and weaken the stimulation of adenosine on immunosuppressive cells, so as to modulate the tumor microenvironment and enhance the antitumor immune response.
  • CD73 inhibitors include, but are not limited to, HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, Astra Zeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS- 986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti-CD73-TGFP- Trap Bifunctional Antibody dalutrafusp alf
  • the CD73 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression.
  • the CD73 inhibitor specifically binds to CD73 and blocks its extracellular 5'-nucleotidase activity.
  • the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, CD73 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and CD73 inhibitor.
  • the CDK4/6 inhibitor, the PD-1 inhibitor and the CD73 inhibitor is used without chemotherapy.
  • the CD73 inhibitor specifically binds to CD73 and blocks its extracellular 5 '-nucleotidase activity.
  • the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, CD73 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and CD73 inhibitor.
  • the CDK4/6 inhibitor, the PD-L1 inhibitor and the CD73 inhibitor is used without chemotherapy. Additional Immune Checkpoint Inhibitors
  • the alternative immune checkpoint inhibitor is an inhibitor directed to CD39, including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secama)
  • the alternative immune checkpoint inhibitor is a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (an anti- Siglec-15 mAb).
  • Siglec-15 sialic acid-binding immunoglobulin-like lectin 15
  • the chemotherapeutic agent is toxic to immune effector cells. In one embodiment the chemotherapeutic agent inhibits cell growth. In one embodiment, the cytotoxic chemotherapeutic agent administered is a DNA damaging chemotherapeutic agent. In one embodiment, the chemotherapeutic agent is a protein synthesis inhibitor, a DNA-damaging chemotherapeutic, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, DNA polymerase inhibitor, an anticancer enzyme, RAC1 inhibitor, thymidylate synthase inhibitor, oxazophosphorine compound, integrin inhibitor such as cilengitide, camptothecin or homocamptothecin, antifolate or a folate antimetabolite. Cytotoxic Chemotherapeutic Agents
  • Cytotoxic, DNA-damaging chemotherapeutic agents tend to be non-specific and, particularly at high doses, toxic to normal, rapidly dividing cells such as HSPC and immune effector cells.
  • DNA-damaging chemotherapy or chemotherapeutic agent refers to treatment with a cytostatic or cytotoxic agent (i.e., a compound) to reduce or eliminate the growth or proliferation of undesirable cells, for example cancer cells, wherein the cytotoxic effect of the agent can be the result of one or more of nucleic acid intercalation or binding, DNA or RNA alkylation, inhibition of RNA or DNA synthesis, the inhibition of another nucleic acid-related activity (e.g., protein synthesis), or any other cytotoxic effect.
  • a cytostatic or cytotoxic agent i.e., a compound
  • alkylating agents include alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as a benzodizepa, carboquone, meturedepa, and uredepa; ethylenimines and methylmelamines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylol melamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichine, phenesterine, prednimustine, trofosfamide, and uracil mustard; and nitroso ureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine.
  • aziridines such as
  • DNA-damaging chemotherapeutic agents include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozocin.
  • Chemotherapeutic antimetabolites include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine P-l-D-arabinoside, amethopterin, aminopterin, 2-aminopurine, aphi dicolin, 8- azaguanine, azaserine, 6-azauracil, 2'-azido-2'-deoxynucleosides, 5-bromodeoxycytidine, cytosine P-l-D-arabinoside, diazooxynorleucine, dideoxynucle
  • Chemotherapeutic protein synthesis inhibitors include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin, ethionine, fluoride, 5 -fluorotryptophan, fusidic acid, guanylyl methylene diphosphonate and guanylyl imidodiphosphate, kanamycin, kasugamycin, kirromycin, and O-methyl threonine.
  • Additional protein synthesis inhibitors include modeccin, neomycin, norvaline, pactamycin, paromomycine, puromycin, ricin, shiga toxin, showdomycin, sparsomycin, spectinomycin, streptomycin, tetracycline, thiostrepton, and trimethoprim.
  • Inhibitors of DNA synthesis include alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards; intercalating agents, such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, propidium diiodide-intertwining; and other agents, such as distamycin and netropsin.
  • alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards
  • intercalating agents such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, propidium diiodide-intertwining
  • other agents such as distamycin and netropsin.
  • Topoisomerase inhibitors such as irinotecan, teniposide, coumermycin, nalidixic acid, novobiocin, and oxolinic acid; inhibitors of cell division, including colcemide, mitoxantrone, colchicine, vinblastine, and vincristine; and RNA synthesis inhibitors including actinomycin D, a-amanitine and other fungal amatoxins, cordycepin (3 '-deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine, streptovaricin, and streptolydigin also can be used as the DNA damaging compound.
  • RNA synthesis inhibitors including actinomycin D, a-amanitine and other fungal amatoxins, cordycepin (3 '-deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine, streptovaricin, and streptolydig
  • the chemotherapeutic agent is a DNA complex binder such as camptothecin, or etoposide; a thiolate alkylating agent such as nitrosourea, BCNU, CCNU, ACNU, or fotesmustine; a guanine alkylating agent such as temozolomide, a tubulin binder such as vinblastine, vincristine, vinorelbine, vinflunine, cryptophycin 52, halichondrins, such as halichondrin B, dolastatins, such as dolastatin 10 and dolastatin 15, hemiasterlins, such as hemiasterlin A and hemiasterlin B, colchicine, combrestatins, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, discodermolide; a DNA polymerase inhibitor such as cytarabine; an anticancer enzyme such as asparaginas, 5-
  • the topoisomerase inhibitor is a type I inhibitor. In another embodiment the topoisomerase inhibitor is a type II inhibitor.
  • DNA-damaging chemotherapeutic agents whose toxic effects can be mitigated by the presently disclosed selective CDK4/6 inhibitors include, but are not limited to, cisplatin, hydrogen peroxide, carboplatin, procarbazine, ifosfamide, bleomycin, plicamycin, taxol, transplatinum, thiotepa, oxaliplatin, and the like, and similar acting-type agents.
  • the DNA damaging chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, camptothecin, and etoposide.
  • chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds.
  • General anticancer pharmaceutical agents include: Vincristine (ONCOVIN®), liposomal vincristine (MARQIBO®), doxorubicin (ADRIAMYCIN®), Cytarabine (cytosine arabinoside, ara-C, or CYTOSAR®), L-asparaginase (ELSPAR®) or PEG-L- asparaginase (pegaspargase or ONCASPAR®), Etoposide (VP- 16), Teniposide (VUMON®), 6- mercaptopurine (6-MP or PURINETHOL®), Prednisone, and Dexamethasone (DECADRON®).
  • chemotherapeutic agents include but are not limited to 5- fluorouracil, dacarbazine, alkylating agents, anthramycin (AMC)), anti-mitotic agents, cisdichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), bleomycin sulfate, calicheamicin, cytochalasin B, dactinomycin (formerly actinomycin), daunorubicin HC1, daunorubicin citrate, denileukin diftitox, dihydroxy anthracin dione, Docetaxel, doxorubicin HC1, E.
  • coli L-asparaginase Erwinia L-asparaginase, etoposide citrovorum factor, etoposide phosphate, gemcitabine HC1, idarubicin HC1, interferon a-2b, irinotecan HC1, maytansinoid, mechlorethamine HC1, melphalan HC1, mithramycin, mitomycin C, mitotane, paclitaxel, polifeprosan 20 with carmustine implant, procarbazine HC1, streptozotocin, teniposide, thiotepa, topotecan HC1, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.
  • cytotoxic chemotherapeutic agents for use with the present invention include: epirubicin, abraxane, taxotere, epothilone, tafluposide, vismodegib, azacytidine, doxifluridine, vindesine, and vinorelbine.
  • the chemotherapeutic agent is a DNA complex binder. In one embodiment the chemotherapeutic agent is a tubulin binder. In one embodiment the chemotherapeutic agent is an alkylating agent. In one embodiment the chemotherapeutic agent is a thiolate alkylating agent. Additional Chemotherapeutic Agents
  • Chemotherapeutic agents useful in the present invention include, but are not limited to, Trastuzumab (HERCEPTIN®), Pertuzumab (PERJETA®), Lapatinib (TYKERB®), Gefitinib (IRES SA®), Erlotinib (TARCEVA®), Cetuximab (ERBITUX®), Panitumumab (VECTIBIX®), Vandetanib (CAPRELSA®), Vemurafenib (ZELBORAF®), Vorinostat (ZOLINZA®), Romidepsin (ISTODAX®), Bexarotene (TARGRETIN®), Alitretinoin (PANRETIN®), Tretinoin (VESANOID®), Carfilzomib (KYPROLIS®), Pralatrexate (FOLOTYN®), Bevacizumab (AVASTIN®), Ziv-aflibercept (ZALTRAP®), Sorafenib (NEXAVAR
  • Additional chemotherapeutic agents may include an estrogen inhibitor including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist.
  • Partial anti -estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
  • fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.
  • the chemotherapeutic agent may include a kinase inhibitor, including but not limited to a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’ s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
  • PI3K phosphoinositide 3-kinase
  • BTK Bruton’ s tyrosine kinase
  • Syk spleen tyrosine kinase
  • BTK inhibitors are well known.
  • BTK inhibitors include ibrutinib (also known as PCI-32765)(ImbruvicaTM) (l-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin- 4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6- (4-(2-hydroxyethyl)piperaz
  • Syk inhibitors are well known, and include, for example, Cerdulatinib (4- (cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-l-yl)phenyl)amino)pyrimidine-5- carboxamide), entospletinib (6-(lH-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[l,2- a]pyrazin-8-amine), fostamatinib ([6-( ⁇ 5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4- pyrimidinyl ⁇ amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][l,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib di sodium salt (sodium (6-((5-
  • the chemotherapeutic agent can also be a B-cell lymphoma 2 (Bcl-2) protein inhibitor.
  • BCL-2 inhibitors are known in the art, and include, for example, ABT-199 (4-[4-[[2-(4- Chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4- [[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5- yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-l-yl]-N-[4- [[(2R)-4-(dimethylamino)-l-phenylsulfanylbutan-2-yl
  • Additional chemotherapeutic agents for use in the methods contemplated herein include, but are not limited to, midazolam, MEK inhibitors, RAS inhibitors, ERK inhibitors, ALK inhibitors, HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or a combination thereof), RAF inhibitors, apoptotic compounds, topoisomerase inhibitors, AKT inhibitors, including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, or FLT-3 inhibitors, including but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof.
  • Examples of MEK inhibitors include but are not limited to trametinib /GSK1120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl ⁇ phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5- carboxamide), pimasertib/AS703026/MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l-(
  • RAS inhibitors include but are not limited to Reolysin and siG12D LODER.
  • ALK inhibitors include but are not limited to Crizotinib, AP26113, and LDK378.
  • HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.
  • ERK inhibitors include SCH772984 (Merck/Schering-Plough), VTX-1 le (Vertex), DEL-22379, Ulixertinib (BVD-523, VRT752271), GDC-0994, FR 180204, XMD8-92, and ERK5-IN-1.
  • Raf inhibitors are well known, and include, for example, Vemurafinib (N-[3-[[5-(4- Chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-l- propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-
  • topoisomerase I inhibitors useful in the present invention include (S)-10- [(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinoline- 3,14(4H,12H)-dione monohydrochloride (topotecan), (S)-4-ethyl-4-hydroxy-lH- pyrano[3',4':6,7]indolizino[l,2-b]quinoline-3,14-(4H,12H)-dione (camptothecin), (1S,9S)-1- Amino-9-ethyl-5-fluoro-l,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- benzo(de)pyrano(3 ' ,4' : 6,7)indolizino(l ,2-b)quinoline- 10,13 -d
  • the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycle), and trilaciclib is administered again on day 7 of each 14-day cycle.
  • the co-formulation of immune checkpoint inhibitors comprises a PD-L1 or PD-1 immune checkpoint inhibitor and an additional immune checkpoint inhibitor selected from the group consisting of a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the PD-L1 or PD- 1 immune checkpoint inhibitor and the additional immune checkpoint inhibitor are dosed at different amounts.
  • the PD-L1 or PD-1 immune checkpoint inhibitor and the additional immune checkpoint inhibitor are dosed at the same amounts.
  • the additional immune checkpoint inhibitor is a TIGIT inhibitor.
  • the additional immune checkpoint inhibitor is a TIM-3 inhibitor.
  • the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
  • the trilaciclib is administered once a week.
  • nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks.
  • nivolumab and relatlimab are administered once every two weeks.
  • nivolumab and relatlimab are administered once every three weeks.
  • nivolumab and relatlimab are administered once every four weeks.
  • nivolumab and relatlimab are administered once every six weeks.
  • the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • the melanoma is unresectable or metastatic melanoma.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a TIGIT immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a CD73 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above.
  • the cancer is a non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial cancer (mUC).
  • NSCLC non-small cell lung cancer
  • TNBC triple negative breast cancer
  • CRC metastatic colorectal cancer
  • mUC metastatic urothelial cancer
  • the patient has second-line metastatic non-squamous or squamous NSCLC.
  • the patient has second-line metastatic triple negative breast cancer.
  • the patient has second-line metastatic colorectal cancer (CRC).
  • the patient has second-line locally advanced or metastatic urothelial carcinoma (mUC).
  • the additional immune checkpoint inhibitor administered in combination with trilaciclib and a PD-1 or PD-L1 inhibitor is selected from an inhibitor of program death-ligand 2 (PD-L2), CTLA-4, and V-domain Ig suppressor of T-cell activation (VISTA), B7-H3/CD276, indoleamine 2,3 -dioxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEACAM-3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), and B and T lymphocyte attenuator (BTLA) protein.
  • PD-L2 program death-ligand 2
  • CTLA-4 CTLA-4
  • IDO indoleamine 2,3 -dioxygenase
  • KIRs killer immunoglobulin-like receptors
  • an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above.
  • the cancer is a non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial cancer (mUC).
  • NSCLC non-small cell lung cancer
  • TNBC triple negative breast cancer
  • CRC metastatic colorectal cancer
  • mUC metastatic urothelial cancer
  • the patient has second-line metastatic non-squamous or squamous NSCLC.
  • the patient has second-line metastatic triple negative breast cancer.
  • the patient has second-line metastatic colorectal cancer (CRC).
  • the patient has second-line locally advanced or metastatic urothelial carcinoma (mUC).
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a PD-L2 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a CTLA-4 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • the CTLA-4 immune checkpoint inhibitor is ipilimumab.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a KIR immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a CEACAM immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a BTLA immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycle), and trilaciclib is administered again on day 7 of each 14-day cycle.
  • trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD- L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21 -day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 28-day cycle, and trilaciclib is administered again on day 7, day 14, and day 21 of each 28-day cycle. In some embodiments, trilaciclib is administered one or more times per week.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 42-day cycle, and trilaciclib is administered again on day 7, day 14, day 21, day 28, and day 35 of each 42-day cycle.
  • trilaciclib is administered one or more times per week.
  • trilaciclib is administered once a week during treatment, and the PD-1 or PD-L1 and additional immune checkpoint inhibitor are administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor.
  • the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib.
  • the patient has a tumor expressing PD-L1.
  • the patient has a tumor expressing PD-L1 as determined by an FDA-approved, or CE Mark test.
  • Non-limiting examples of combination chemotherapy regimens for the first-line treatment of locally advanced or metastatic squamous cell NSCLC include cisplatin 75 mg/m 2 IV on day 1 plus paclitaxel 175 mg/m 2 IV on day 1 every 21 days, cisplatin 100 mg/m 2 IV on day 1 plus gemcitabine 1000 mg/m 2 IV on days 1, 8, and 15 every 28 days, cisplatin 60 mg/m 2 IV on day 1 plus gemcitabine 1000 mg/m 2 IV on days 1 and 8 every 21 days, cisplatin 75 mg/m 2 IV on day 1 plus docetaxel 75 mg/m 2 IV on day 1 every 21 days, carboplatin AUC 6 IV on day 1 plus paclitaxel 175-225 mg/m 2 IV on day 1 every 21 days, carboplatin AUC 6 IV on day 1 plus paclitaxel 90 mg/m 2 IV on days 1, 8, and 15 every 28 days, protein-bound paclitaxel 100 mg/m 2 IV on days 1, 8, and 15 of every 21 days plus
  • the CDK4/6 inhibitor is trilaciclib.
  • trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m 2 . In some embodiments, the trilaciclib is administered at about 240 mg/m 2 .
  • the immune checkpoint inhibitor is a PD-1 inhibitor.
  • the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®).
  • the PD-1 inhibitor is nivolumab.
  • nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles.
  • nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks.
  • the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes. In one embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is selected from a group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®).
  • the PD-LI inhibitor is atezolizumab.
  • atezolizumab is administered at as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year.
  • the PD-LI inhibitor is avelumab.
  • avelumab is administered at 800 mg every 2 weeks as an intravenous infusion over 60 minutes.
  • the PD-LI inhibitor is durvalumab.
  • durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
  • the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor.
  • the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154;
  • the additional checkpoint inhibitor is a TIM-3 checkpoint inhibitor.
  • the TIM-3 checkpoint inhibitor is selected from a group consisting of Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS- 986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the TIM-3 inhibitor are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21-day cycle.
  • the PD-1 or PD-L1 inhibitor comprises PD-1 inhibitor dostarlimab.
  • the TIM-3 inhibitor comprises cobolimab.
  • trilaciclib, dostarlimab, and cobolimab are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21-day cycle.
  • the 21-day cycle is repeated in the absence of disease progression or unacceptable toxicity.
  • dostarlimab and cobolimab are administered intravenously over 30 minutes. In some embodiments, dostarlimab is administered at a dose of about 500 mg. In some embodiments, cobolimab is administered at a dose of about 300 mg.
  • the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor.
  • the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), bootszelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics
  • the additional checkpoint inhibitor is a CD73 checkpoint inhibitor.
  • the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1.
  • the CDK4/6 inhibitor is trilaciclib.
  • trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen.
  • trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen.
  • trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m 2 .
  • the trilaciclib is administered at about 240 mg/m 2 .
  • the immune checkpoint inhibitor is a PD-1 inhibitor.
  • the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®).
  • the PD-1 inhibitor is nivolumab.
  • nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles.
  • nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks.
  • the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes.
  • the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448;
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic triple negative breast cancer (TNBC) in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • TNBC triple negative breast cancer
  • the patient has a tumor expressing PD-L1.
  • a CDK4/6 inhibitor in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor
  • TTIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIM-3 T-cell immunoglobulin mucin-3
  • LAG-3 Lymphocyte-activation gene 3
  • CD73 Cluster of Differentiation 73
  • Non-limiting examples of first-line adjuvant therapy for metastatic TNBC include: Capecitabine 1,000-1,250 mg/m 2 orally twice daily on days 1-14, repeat cycle every 3 weeks; Carboplatin AUC 6 IV over 30 minutes on day 1, repeat cycle every 3 or 4 weeks; Cisplatin 75 mg/m 2 IV over 60 minutes on day 1, repeat cycle every 3 weeks; Doxorubicin 60-75 mg/m 2 IV push on day 1, repeat cycle every 3 weeks or Doxorubicin 20 mg/m 2 IV push on day 1, repeat cycle weekly; Eribulin 1.4 mg/m 2 IV push on days 1 and 8, repeat cycle every 3 weeks; Gemcitabine 800-1,200 mg/m 2 IV over 30 minutes on days 1, 8, and 15, repeat cycle every 4 weeks; Liposomal Doxorubicin 40-50 mg/m 2 IV on day 1, repeat cycle every 4 weeks; Paclitaxel 175 mg/m 2 IV over 3 hours on day 1, repeat cycle every 3 weeks or Paclitaxel 80 mg/m 2 IV over 60 minutes on day 1, repeat cycle weekly; Vinor
  • the CDK4/6 inhibitor is trilaciclib.
  • trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m 2 . In some embodiments, the trilaciclib is administered at about 240 mg/m 2 .
  • the PD-LI inhibitor is durvalumab.
  • durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
  • the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor.
  • the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154;
  • the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor.
  • the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (Opdualag®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), bootszelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenic
  • the additional checkpoint inhibitor is a CD73 checkpoint inhibitor.
  • the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1.
  • the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • a CDK4/6 inhibitor in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor
  • T cell immunoreceptor with Ig and ITIM domains T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor
  • a metastatic urothelial carcinoma treatment protocol such as, but not limited to: postoperative adjuvant intravesical chemotherapy for metastatic urothelial carcinoma, first-line chemotherapy for metastatic urothelial carcinoma, and second-line chemotherapy for metastatic
  • the additional checkpoint inhibitor is a CD73 checkpoint inhibitor.
  • the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.
  • Additional embodiments provided herein include liposomal formulations of the active compounds disclosed herein.
  • the technology for forming liposomal suspensions is well known in the art.
  • the compound is an aqueous-soluble salt, using conventional liposome technology, the same can be incorporated into lipid vesicles.
  • the active compound due to the water solubility of the active compound, the active compound can be substantially entrained within the hydrophilic center or core of the liposomes.
  • the lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free.
  • the active compound of interest is water-insoluble, again employing conventional liposome formation technology, the salt can be substantially entrained within the hydrophobic lipid bilayer that forms the structure of the liposome.
  • pharmaceutically acceptable salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with hosts (e.g., human hosts) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the presently disclosed host matter.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the presently disclosed compounds. These salts can be prepared during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Basic compounds are capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents.
  • Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-m ethylglucamine, and procaine.
  • the base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.
  • Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like.
  • Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
  • an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
  • TIGIT T cell immunoreceptor with immunoglobulin and ITIM domain
  • TIM-3 T-cell immunoglobulin and mucin domain 3
  • LAG-3 lymphocyte activation gene-3
  • CD73 Cluster of Differentiation 73
  • embodiment 1 or 2 wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma. 4. The use of any of embodiments 1-3, wherein the solid cancer is small cell lung cancer.
  • PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
  • PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, bootszelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
  • TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
  • TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223, or HB0036.
  • CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
  • any of embodiments 1-30 wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitax
  • a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.
  • PD- 1 programmed cell death protein-1
  • PD-L1 programmed death-ligand- 1
  • embodiment 41 or 42 wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
  • embodiment 58 wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, caba
  • a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a lymphocyte activation gene-3 (LAG- 3) inhibitor.
  • PD- 1 programmed cell death protein-1
  • PD-L1 programmed death-ligand- 1
  • embodiment 72 or 73 wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • embodiment 86 wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
  • embodiment 88 wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
  • the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelima
  • PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • any of embodiments 72-95 wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the LAG-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, caba
  • a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having melanoma, wherein the melanoma is unresectable or metastatic melanoma, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of nivolumab; and, c. administering to the human an effective amount of relatlimab.
  • CDK4/6 cyclin dependent kinase 4/6
  • embodiment 106 wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
  • embodiment 109 wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
  • nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks.
  • nivolumab and relatlimab are administered once every four weeks.
  • 114. The use of any of embodiments 106-111, wherein nivolumab is administered once over a duration of a first cycle and relatlimab is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, herein the duration of the first cycle is different than the duration of the second cycle.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, bootszelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213 or SNA-03.
  • embodiment 221, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent. 223.
  • the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • embodiment 226, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent. 228.
  • the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, or head and neck squamous cell carcinoma.
  • CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
  • any of embodiments 226-237 wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the CD73 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, caba
  • a composition for use for the treatment of a human patient with cancer wherein the cancer is an advanced or metastatic solid cancer, and wherein the composition for use comprises a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; and, wherein the treatment comprises: a. administering to the patient an effective amount of trilaciclib, b. administering to the patient an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c.
  • PD- 1 programmed cell death protein-1
  • PD-L1 programmed death-ligand- 1
  • an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
  • TAGIT T cell immunoreceptor with immunoglobulin and ITIM domain
  • TIM-3 T-cell immunoglobulin and mucin domain 3
  • LAG-3 lymphocyte activation gene-3
  • CD73 Cluster of Differentiation 73
  • composition of embodiment 248, wherein the treatment further comprises administering to the patient an effective amount of a chemotherapeutic agent.
  • composition of embodiment 248 or 249, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • composition of embodiment 252 wherein the patient has previously received a PD- 1 or PD-L1 inhibitor and has experienced disease progression. 254. The composition of any of embodiments 248-253, wherein the patient is administered an effective amount of a PD-1 inhibitor.
  • composition of embodiment 254, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP-224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
  • the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP-224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab
  • composition of embodiment 255, wherein the PD-1 inhibitor is nivolumab.
  • composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
  • composition of embodiment 259, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, bootszelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213 or SNA-03.
  • composition of embodiment 260, wherein the LAG-3 inhibitor is relatlimab.
  • composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
  • composition of embodiment 262, wherein the TIM-3 inhibitor is selected from cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425 or RO7121661.
  • composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
  • composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
  • composition of embodiment 275 or 276, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • a method of treating a human having cancer wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c.
  • CDK4/6 cyclin dependent kinase 4/6
  • PD- 1 programmed cell death protein-1
  • PD-L1 programmed death-ligand- 1
  • an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
  • TIGIT T cell immunoreceptor with immunoglobulin and ITIM domain
  • TIM-3 T-cell immunoglobulin and mucin domain 3
  • LAG-3 lymphocyte activation gene-3
  • CD73 Cluster of Differentiation 73
  • invention 280 or 282 wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
  • PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223, or HB0036.
  • CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, caba
  • a method of treating a human having cancer wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD-
  • TIM-3 T-cell immunoglobulin and mucin domain 3
  • embodiment 320 or 322 wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine de méthodes thérapeutiques améliorées pour traiter des cancers localement avancés et/ou métastatiques chez des patients dont le cancer a progressé malgré un traitement par un inhibiteur de point de contrôle immunitaire en raison du développement d'une résistance aux effets inhibiteurs de l'inhibiteur de point de contrôle immunitaire, ou dont le cancer est en risque de développement une résistance aux effets d'un inhibiteur de point de contrôle immunitaire. Les méthodes de la présente invention sont particulièrement appropriés pour un groupe sélectionné de patients difficiles à traiter atteints d'un cancer du sein triple négatif avancé/métastasique (TNBC), d'un cancer du poumon non à petites cellules récurrent ou métastasique (NSCLC), d'un cancer colorectal avancé ou métastatique et non résécable et d'un carcinome urothélial avancé ou métastatique localement avancé, et permet une survie prolongée sans progression (PFS) et/ou une survie globale accrue (OS) dans ces populations de patients.
PCT/US2022/042088 2021-08-30 2022-08-30 Traitements améliorés contre des cancers avancés/métastatiques avec une résistance aux inhibiteurs de points de contrôle ou une susceptibilité à une telle résistance WO2023034336A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202163238739P 2021-08-30 2021-08-30
US63/238,739 2021-08-30
US202263399977P 2022-08-22 2022-08-22
US63/399,977 2022-08-22

Publications (2)

Publication Number Publication Date
WO2023034336A2 true WO2023034336A2 (fr) 2023-03-09
WO2023034336A3 WO2023034336A3 (fr) 2023-05-19

Family

ID=85413190

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/042088 WO2023034336A2 (fr) 2021-08-30 2022-08-30 Traitements améliorés contre des cancers avancés/métastatiques avec une résistance aux inhibiteurs de points de contrôle ou une susceptibilité à une telle résistance

Country Status (2)

Country Link
TW (1) TW202327610A (fr)
WO (1) WO2023034336A2 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI760751B (zh) * 2019-05-29 2022-04-11 美商美國禮來大藥廠 Tigit及pd-1/tigit-結合分子
WO2022125829A1 (fr) * 2020-12-09 2022-06-16 G1 Therapeutics, Inc. Traitements contre le cancer du sein triple négatif avancé et/ou métastatique

Also Published As

Publication number Publication date
TW202327610A (zh) 2023-07-16
WO2023034336A3 (fr) 2023-05-19

Similar Documents

Publication Publication Date Title
US11529352B2 (en) Preservation of immune response during chemotherapy regimens
ES2878188T3 (es) Terapias de combinación que comprenden moléculas de anticuerpos contra LAG-3
AU2015214390B2 (en) Combination of a PD-1 antagonist and a VEGFR inhibitor for treating cancer
JP2022180567A (ja) Ｐｄ－１に対する抗体分子およびその使用
JP2020121975A (ja) 抗ｃｄ１９キメラ抗原受容体を使用する癌の処置
JP2022043060A (ja) 組み合わせ治療
CN110996952A (zh) 用于治疗癌症的方法
JP6764017B2 (ja) がんの処置での使用のためのコビシスタット
TW201642859A (zh) Ｍｄｍ２抑制劑及ｂｔｋ抑制劑之倂用治療法
WO2022271684A1 (fr) Composés modulant les diacylglycérol kinases
WO2023034336A2 (fr) Traitements améliorés contre des cancers avancés/métastatiques avec une résistance aux inhibiteurs de points de contrôle ou une susceptibilité à une telle résistance
RU2779478C2 (ru) Сохранение иммунного ответа во время химиотерапевтических схем
NZ795224A (en) Preservation of immune response during chemotherapy regimens
EA043297B1 (ru) Применение ингибитора cdk4/6 в сохранении иммунного ответа во время химиотерапевтических схем
Wagner Investigation of a novel small molecule TRAIL inducer, ONC201: pre-clinical anti-cancer efficacy, anti-metastasis effects, tumor immunity; and the structure-activity relationships (SAR) and mechanism of action of potential analogues
TW202313033A (zh) 組合療法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22865455

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE