WO2019172909A1 - Compositions and methods for treating late stage lung cancer - Google Patents
Compositions and methods for treating late stage lung cancer Download PDFInfo
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- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
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- 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
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- 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
- C07K16/2827—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 B7 molecules, e.g. CD80, CD86
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- C07K2317/00—Immunoglobulins specific features
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- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- NSCLC non-small-cell lung cancer
- PS good performance status
- cCRT concurrent chemoradiation therapy
- PD-L1 Programmed cell death ligand- 1
- PD-l1 Programmed cell death ligand- 1
- Durvalumab is a selective, high-affinity, human IgGl monoclonal antibody that blocks PD-L1 binding to PD-l and CD80, allowing T cells to recognize and kill tumor cells.
- Durvalumab has demonstrated encouraging antitumor activity in an early-phase clinical study across multiple advanced solid tumors, and has been approved for post-platinum, locally advanced or metastatic urothelial carcinoma.
- the disclosure provides methods comprising administration of durvalumab to patients with late stage, locally advanced, unresectable NSCLC, and whose disease had not progressed following chemoradiation therapy (cCRT).
- cCRT chemoradiation therapy
- the disclosure generally relates to methods for treating late stage (e.g., clinical stage III or IV), unresectable non- small-cell lung cancer (NSCLC) with an antibody that inhibits PD1/PD-L1 activity in a patient identified as having not progressed following definitive chemoradiation therapy.
- NSCLC non-small-cell lung cancer
- the disclosure provides a method of extending progression-free survival (PFS) in a patient with, unresectable non-small-cell lung cancer (NSCLC), the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- the method provides an increase in PFS of at least five months relative to placebo. In further aspects, the method provides an increase in PFS of at least 13 months relative to placebo.
- the disclosure provides a method of increasing the overall response rate (ORR) in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- ORR overall response rate
- the method provides an increase in ORR of at 12% relative to placebo.
- the disclosure provides a method of increasing the time to death or metastasis (TTDM) in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- TTDM time to death or metastasis
- the disclosure provides a method of lowering incidences of metastasis in a patient with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- the lower incidence of metastasis may be in lymph nodes, brain, lung, liver, adrenal gland, bone, abdomen, biliary tract, breast, chest, kidney, ovary, pancreas, pericardium, peritoneal fluid, peritoneum,
- the lower incidence of metastasis may be in lymph nodes, brain, lung, liver, adrenal gland, and/or bone.
- the disclosure provides a method of lowering incidences of brain metastasis in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- the method provides lowered incidence of metastasis or lowered incidence of metastasis of at least about 20% to about 50% relative to placebo.
- the method provides a decrease in the incidences of metastasis or of brain metastasis by at least five months versus placebo.
- the chemoradiation therapy comprises a platinum-based therapeutic agent.
- the platinum-based therapeutic agent may be selected from cisplatin or carboplatin, or a combination of cisplatin and carboplatin.
- the human anti-PD-Ll antibody comprises durvalumab (IMFINZI®), avelumab (BAVENCIO®), or atezolizumab
- the human anti-PD-Ll antibody comprises heavy and light chain variable region CDRs sequences, wherein the VH CDR1 has the amino acid sequence of SEQ ID NO: 3; the VH CDR2 has the amino acid sequence of SEQ ID NO: 4; the VH CDR3 has the amino acid sequence of SEQ ID NO: 5; the VL CDR1 has the amino acid sequence of SEQ ID NO: 6; the VL CDR2 has the amino acid sequence of SEQ ID NO: 7; and the VL CDR3 has the amino acid sequence of SEQ ID NO: 8.
- the treatment comprises administering the human anti-PD-Ll antibody intravenously once every 2 weeks, at a dosage of 10 mg/kg.
- the patient may express genes (i.e., have a phenotype) associated with therapeutic response to a therapy comprising a human anti-PD-Ll antibody.
- the patient is PD-L1 (+). In other aspects, the patient is PD-L1 (-).
- the patient is EGFR mutation (+). In other aspects, the patient is EGFR mutation (-) or wild type. In some aspects, the patient may express any combination of PD-L1 and EGFR mutation phenotypes.
- the disclosure provides a method of extending progression-free survival (PFS) in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-l antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- PFS progression-free survival
- the chemoradiation therapy comprises a platinum-based therapeutic agent.
- the platinum-based therapeutic agent may be selected from cisplatin or carboplatin, or a combination of cisplatin and carboplatin.
- the human anti-PDl antibody comprises nivolumab (OPDIVO®) or pembrolizumab (KEYTRUDA®).
- the method provides an increase in PFS of at least five months relative to placebo. In some aspects, the method provides an increase in PFS of at least thirteen months relative to placebo.
- the patient may express genes (i.e., have a phenotype) associated with therapeutic response to a therapy comprising a human anti-PD-l antibody.
- the patient is PD-L1 (+).
- the patient is PD-L1 (-).
- the patient is EGFR mutation (+).
- the patient is EGFR mutation (-) or wild type.
- the patient may express any combination of PD-L1 and EGFR mutation phenotypes.
- the disclosure provides a method of lowering incidences of metastasis in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-l antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- the lower incidence of metastasis may be in lymph nodes, brain, lung, liver, adrenal gland, bone, abdomen, biliary tract, breast, chest, kidney, ovary, pancreas, pericardium, peritoneal fluid, peritoneum,
- the lower incidence of metastasis may be in lymph nodes, brain, lung, liver, adrenal gland, and/or bone.
- the disclosure provides a method of lowering incidences of brain metastasis in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-l antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- the method provides lowered incidence of metastasis or lowered incidence of metastasis of at least about 20% to about 50% relative to placebo. In some aspects the method provides a decrease in the incidences of metastasis or of brain metastasis by at least five months versus placebo.
- the patient may express genes (i.e., have a phenotype) associated with therapeutic response to a therapy comprising a human anti-PD-Ll antibody.
- the patient is PD-L1 (+). In other aspects, the patient is PD-L1 (-).
- the patient is EGFR mutation (+). In other aspects, the patient is EGFR mutation (-) or wild type. In some aspects, the patient may express any combination of PD-L1 and EGFR mutation phenotypes.
- treatment may comprise administration of at least about 10 mg/kg durvalumab, or an antigen-binding fragment thereof. In some aspects, the administration is repeated about every 14 days, for up to 52 weeks.
- anti-PD-Ll antibody is meant an antibody or antigen binding fragment thereof that selectively binds a PD-L1 polypeptide.
- Exemplary anti-PD-Ll antibodies are described for example at U.S. Patent Nos. 8,779,108 and 9,493,565, which are herein incorporated by reference.
- durvalumab, avelumab, or atezolizumab durvalumab is an exemplary PD-L1 antibody.
- durvalumab is an exemplary PD-L1 antibody.
- a "partial response" refers to a decrease in tumor burden > 50% relative to baseline. Confirmation can be obtained using a consecutive repeat assessment at least 4 weeks from the date of first documentation.
- PD Progressive disease
- SD stable disease
- PD-L1 may refer to polypeptide or polynucleotide sequences, or fragments thereof, having at least about 85%, 95% or 100% sequence identity to PD-L1 sequences.
- PD-L1 is also referred to in the art as B7-H1.
- the PD-L1 is also referred to in the art as B7-H1.
- PD-l is an approximately 31 kD type I membrane protein member of the extended CD28/CTLA4 family of T cell regulators (see, Ishida, Y. et al. (1992) Induced Expression Of PD-l, A Novel Member Of The Immunoglobulin Gene Superfamily, Upon Programmed Cell Death," EMBO J. 11 :3887-3895.
- PD-l is expressed on activated T cells, B cells, and monocytes (Agata, Y. et al.
- PD-l is a receptor responsible for down- regulation of the immune system following activation by binding of PDL-l or PDL-2 (Martin- Orozco, N.
- antibody refers to an immunoglobulin or a fragment or a derivative thereof, and encompasses any polypeptide comprising an antigen binding site, regardless whether it is produced in vitro or in vivo.
- the term includes, but is not limited to, polyclonal, monoclonal, monospecific, polyspecific, non-specific, humanized, single chain, chimeric, synthetic, recombinant, hybrid, mutated, and grafted antibodies.
- the term“antibody” also includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen-binding function, i.e., the ability to bind PD-L1 specifically. Typically, such fragments would comprise an antigen-binding domain.
- Binding fragments of an antibody are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies.
- An antibody other than a "bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as "Fab” fragments, and a "Fc” fragment, having no antigen-binding activity but having the ability to crystallize.
- Fv when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites.
- Fab when used herein refers to a fragment of an antibody that comprises the constant domain of the light chain and the CHI domain of the heavy chain.
- mAb refers to monoclonal antibody.
- Antibodies of the invention comprise without limitation whole native antibodies, bispecific antibodies; chimeric antibodies; Fab, Fab', single chain V region fragments (scFv), fusion polypeptides, and unconventional antibodies.
- isolated refers to material that is free to varying degrees from components which normally accompany it as found in its native state.
- Isolate denotes a degree of separation from original source or surroundings.
- Purify denotes a degree of separation that is higher than isolation.
- a “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences.
- binding is meant a compound (e.g ., antibody) that recognizes and binds a molecule (e.g., polypeptide), but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample.
- a molecule e.g., polypeptide
- two molecules that specifically bind form a complex that is relatively stable under physiologic conditions.
- Specific binding is characterized by a high affinity and a low to moderate capacity as distinguished from nonspecific binding which usually has a low affinity with a moderate to high capacity.
- binding is considered specific when the affinity constant K A is higher than l0 6 M _1 , or more preferably higher than 10 8 M _1 . If necessary, non-specific binding can be reduced without substantially affecting specific binding by varying the binding conditions.
- the appropriate binding conditions such as concentration of antibodies, ionic strength of the solution,
- concentration of a blocking agent e.g., serum albumin, milk casein, etc.
- concentration of a blocking agent e.g., serum albumin, milk casein
- the terms“treat,” treating,”“treatment,” and the like refer to reducing, ameliorating, or slowing the progression of a disorder or disease and/or symptoms associated with a disorder or disease. It will be appreciated that, although not precluded, treating a disorder, disease, or condition does not require that the disorder, disease, or condition or associated symptoms be completely eliminated. In particular aspects and aspects relating to NSCLC,“treat,” treating,”“treatment,” can refer to achieving any one or combination of primary or secondary clinical endpoints. BRIEF DESCRIPTION OF THE DRAWINGS
- the total number of events/total number of patients are 214/476 (durvalumab) and 157/237 (placebo); median PFS in months 16.8 (13.0-18.1, 95% Cl (durvalumab)) and 5.6 (4.6-7.8, 95% Cl (placebo)); l2-month PFS rate 55.9% (51.0-60.4%, 95% Cl (durvalumab)) and 44.2% (37.7-50.5%, 95% Cl
- FIGURE 2 depicts PFS (defined by RECIST v.l.l) subgroup analysis of prognostic factors in the intention-to-treat population (assessed by BICR). Hazard ratio and 95% Cl is not calculated if the subgroup level had less than 20 events.
- CR is complete response;
- EGFR is epidermal growth factor receptor;
- PD-L1 is programmed cell death ligand- 1;
- PR is partial response; SD is stable disease; WHO is World Health Organization.
- FIGURE 3 depicts a CONSORT flow diagram of the data obtained in the clinical trial.
- ⁇ Patients who completed 12 months of treatment reported the maximum cycle of immunotherapy reached on the electronic case report form (eCRF).
- eCRF electronic case report form
- FIGURE 5 depicts incidence of new lesions by BICR (ITT), can include more than one new lesion site. Other includes lesions in: abdominal wall, biliary tract, breast, chest wall, kidney, ovary, pancreas, pericardium, peritoneal fluid, peritoneum, retroperitoneum, skin, spleen, uterus and other (unspecified).
- FIGURE 6 depicts statistical analysis of time to death or distant metastasis (TDDM) in the intention-to-treat population. The probability of death or distant metastasis is associated with a median TDDM of 23.2 months (23.2-NR, 95% Cl) for durvalumab and 14.6 months (10.6-18.6, 95% Cl) for placebo. The calculated Hazard ratio is 0.52 (95% Cl, 0.39-0.69).
- Durvalumab heavy chain variable region amino acid sequence of CDR1, CDR2, and CDR3 are provided as SEQ ID NO: 3 (CDR1), SEQ ID NO: 4 (CDR2), and SEQ ID NO: 5 (CDR3).
- the disclosure relates to methods of treating patients who have unresectable, late stage non-small-cell lung cancer (NSCLC) who have not progressed following definitive chemoradiation therapy, comprising administering to the patient a human anti-PD-Ll antibody.
- NSCLC non-small-cell lung cancer
- the disclosure provides a method of extending progression-free survival (PFS) in a patient with, unresectable non-small-cell lung cancer (NSCLC), the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- PFS progression-free survival
- NSCLC unresectable non-small-cell lung cancer
- the disclosure provides a method of increasing the overall response rate (ORR) in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- ORR overall response rate
- the disclosure provides a method of lowering incidences of metastasis in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- the disclosure provides a method of lowering incidences of brain metastasis in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- the disclosure provides a method treating a patient with stage III locally advanced, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-Ll antibody, wherein the patient has not progressed following definitive chemoradiation therapy.
- the disclosure provides a method of extending progression-free survival (PFS) in a patient with, unresectable NSCLC, the method comprising treating the patient with a human anti-PD-l antibody, wherein the patient is at a stage III patient who has not progressed following definitive chemoradiation therapy.
- PFS progression-free survival
- the lower incidence of metastasis may be in lymph nodes, brain, lung, liver, adrenal gland, bone, abdomen, biliary tract, breast, chest, kidney, ovary, pancreas, pericardium, peritoneal fluid, peritoneum, retroperitoneum, skin, spleen, and/or uterus.
- the lower incidence of metastasis may be in lymph nodes, brain, lung, liver, adrenal gland, and/or bone.
- the human anti-PD-Ll antibody comprises durvalumab (IMFINZI®), avelumab (BAVENCIO®), or atezolizumab (TECENTRIQ®).
- the human anti-PD-Ll antibody comprises durvalumab.
- the human anti-PD-Ll antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2.
- the human anti-PD-Ll antibody comprises heavy and light chain variable region CDRs sequences, wherein the VH CDR1 has the amino acid sequence of SEQ ID NO: 3; the VH CDR2 has the amino acid sequence of SEQ ID NO: 4; the VH CDR3 has the amino acid sequence of SEQ ID NO: 5; the VL CDR1 has the amino acid sequence of SEQ ID NO: 6; the VL CDR2 has the amino acid sequence of SEQ ID NO: 7; and the VL CDR3 has the amino acid sequence of SEQ ID NO: 8.
- the method provides an increase in ORR of at 12% relative to placebo.
- the human anti- PD 1 antibody comprises nivolumab (OPDIVO®) or pembrolizumab (KEYTRUDA®).
- the patient is administered one or more doses of an anti-PD-l antibody, wherein the dose is a fixed dose of 200 mg.
- the patient is administered one or more doses of an anti-PD-l antibody, wherein the dose is a fixed dose of 480 mg.
- an anti-PD-l antibody or an antigen-binding fragment thereof is administered every two weeks.
- an anti-PD-l antibody or an antigen-binding fragment thereof is administered every four weeks.
- the patient may express genes (i.e., have a phenotype) associated with therapeutic response to a therapy comprising a human anti-PD-Ll antibody.
- the patient is PD-L1 (+).
- the patient is PD-L1 (-).
- a sample was determined to be“PD-L1 positive” if the sample contained 25% or more tumor cells with PDL1 membrane staining.
- a cutoff and scoring algorithm has been previously determined for durvalumab (Study CP1108; ClinicalTrials.gov number NCT01693562).
- the patient is EGFR mutation (+). In other aspects, the patient is EGFR mutation (-) or wild type. In some aspects, the patient may express any combination of PD-L1 and EGFR mutation phenotypes.
- treatment may comprise administration of at least about 10 mg/kg durvalumab, or an antigen-binding fragment thereof. In some aspects, the administration is repeated about every 14 days, for up to 52 weeks.
- OS Overall Survival
- OS relates to the time period beginning on the date of treatment until death due to any cause.
- OS may refer to overall survival within a period of time such as, for example, 12 months, 18 months, 24 months, and the like.
- Such periods of time can be identified, for example, as“OS24” which refers to the number (%) of patients who are alive at 24 months after treatment onset per the Kaplan-Meier estimate of overall survival at 24 months.
- Progression-Free Survival relates to the time period beginning on the date of treatment until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression).
- the methods provide for increase in PFS.
- the methods provide for PFS of at least 9 months to at least about 24 months (e.g., at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more months, and up to about 5 years).
- Duration of Response refers to the time from the date for first documented response of Complete Response (CR) or Partial Response (PR) until the first documented response of progression per RECIST 1.1 or death in the absence of progression.
- the methods provide for an increase in DoR of at least about 9 months to at least about 36 months.
- Objective Response Rate refers to the number (%) of patients with at least one visit response of Complete Response (CR) or partial response (PR) per RECIST 1.1.
- the methods provide for an increase in DoR of at least about 9 months to at least about 36 months.
- Proportion of patients alive and progression free refers to the number (%) of patients who are alive and progression free per RECIST 1.1.
- APF may refer to a period of time such as, for example, 12 months, 18 months, 24 months, and the like. Such periods of time can be identified, for example, as at APF12 identifying the number of patients alive and progression free at 12 months after treatment onset per Kaplan-Meier estimate of progression free survival at 12 months.
- Time to death or distant metastasis refers to any new lesion that is outside of the radiation field.
- the methods provide for increase in TTDM.
- the methods provide for TTDM of at least 9 months to at least about 24 months (e.g., at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more months, and up to about 5 years).
- the methods are administered to a patient who has not progressed following definitive, concurrent chemoradiation therapy.
- the concurrent chemoradiation therapy comprises any accepted standard first-line treatments for patients with advanced NSCLC.
- standard first-line treatments may include chemotherapy, radiation therapy, or both (chemoradiation therapy).
- the therapy can comprise one or more platinum-based chemotherapeutic agents.
- the one or more platinum-based chemotherapeutic agents can be selected from carboplatin, cisplatin, oxaliplatin, or combinations thereof.
- the platinum-based therapy can comprise singlet or doublet regimens such as, for example, administering cisplatin or carboplatin with another anticancer agent such as paclitaxel, docetaxel, etoposide, gemcitabine, vinorelbine, and the like.
- another anticancer agent such as paclitaxel, docetaxel, etoposide, gemcitabine, vinorelbine, and the like.
- the disclosed methods comprise administration of a therapeutic (e.g., a human anti- PD-L1 antibody or a human andi-PD-l antibody) following a prior therapeutic regimen that failed to achieve one or more clinical endpoints.
- a therapeutic e.g., a human anti- PD-L1 antibody or a human andi-PD-l antibody
- the method is performed following definitive chemoradiation therapy that comprises a platinum-based drug as discussed above.
- the methods is performed following 1, 2, or more rounds of definitive chemoradiation therapy that comprises a platinum-based drug, and which do not inhibit progression of the NSCLC.
- administration of the human anti-PD-Ll antibody or a human andi-PD-l antibody can begin once a determination that the NSCLC was not responsive to the prior therapeutic regimen.
- the patient may be treated within 1 to about 42 days (e.g., 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, or 42 days or more) after the patient had received chemoradiation therapy.
- an“unresectable” cancer includes cancer that cannot be removed completely through surgery for at least one of several medical reasons.
- Reasons why a cancer may be unresectable include, for example, tumor size (e.g., too large to safely remove and/or may require extensive removal of a part of an essential organ), tumor location (e.g., tumor physically intertwined vital structures such as blood vessels or nerves), tumor metastasis where removal of the tumor will not be effective to control all of the cancer, or other medical conditions that heighten risk of surgery to an unacceptable level (e.g., heart disease, lung disease, diabetes).
- an unresectable NSCLC may not be permanently unresectable after aggressive treatment that may be effective to reduce the size of a tumor to a degree that allows for possible surgical resection.
- unresectable NSCLC can also refer to NSCLC (or remote metastases) that will not be completely removed by surgery, but which may be partially removed by one or more surgical procedures. Examples include debulking surgery and surgery that removes parts of the lung cancer as well as parts of metastatic lesions.
- the methods disclosed herein can be used on“resectable” cancers.
- the methods treat patients with late- stage (e.g., Stage III) locally advanced, unresectable NSCLC and who have not progressed following definitive chemoradiation therapy.
- Cancer staging can be performed using any tests that are generally known and accepted in the art.
- the cancer staging can comprise the American Joint Committee on Cancer’s (AJCC’s) TNM system.
- AJCC American Joint Committee on Cancer
- the TNM system provides results from various tests and scans in order to determine the size and location of the primary tumor (Tumor, T); whether the cancer has spread to the lymph nodes, and if it has, the location and number of the affected lymph nodes (Node, N); and whether the cancer has spread to other parts of the body, and if it has, the extent and location of the remote cancer (Metastasis, M). While each type of cancer may have its own specific system, the TNM staging system generally uses scaled scoring for each letter.
- Tumor is associated with a number (e.g., 0 to 4) to describe the general tumor size, location, and whether it intrudes into nearby tissues. Larger or more intrusive tumors are given a higher number and, depending on the cancer, a lowercase letter, such as“a,”“b,” or "m” (for multiple), may be added to provide more detail.
- N is associated with a number (e.g., 0 to 3) to describe whether cancer has been found in the lymph nodes, and can also indicate the number of lymph nodes containing cancer. Larger numbers are assigned when more lymph nodes are involved with cancer.
- M indicates whether or not the cancer has spread to other parts of the body and is labeled M0 for no spread, or Ml if it has spread.
- stage of cancer typically one of four stages: stages I (one) to IV (four). Some cancers also have a stage 0 (zero). Stage 0 describes cancer in situ, remaining local to the original tissue without any spread to nearby tissues. This stage of cancer is often highly curable, usually by removing the entire tumor with surgery. Stage I or early-stage cancer, is typically used to describe a small cancer or tumor that has not grown deeply into nearby tissues, and has not spread to the lymph nodes or other parts of the body. Stage II and III describe larger cancers or tumors that have grown more deeply into nearby tissue, and that may have also spread to lymph nodes but not metastasized to other tissues. Stage IV describes a cancer that has spread to other organs or parts of the body and often identified as advanced or metastatic cancer.
- Staging may include optional analysis of prognostic factors to provide chances of recovery and a recommended therapy.
- Prognostic factors may include grading the cancer based on appearance of the cancer cells; analysis of tumor marker expression; and analysis of tumor genetics.
- a cancer may be restaged using the same initial system in order to determine efficacy of a treatment or obtain more information about a recurrent cancer.
- NSCLC has 5 stages: a stage 0 (zero) and stages I through IV (1 through 4). Stage 0 NSCLC indicates that the cancer has not grown into nearby tissues or spread outside the lung.
- Stage I NSCLC indicates that the cancer is a small tumor that has not spread to any lymph nodes. Stage I is divided into 2 sub-stages based on the size of the tumor: Stage IA tumors are less than 3 centimeters (cm) wide, and Stage IB tumors are more than 3 cm but less than 5 cm wide. Stage I NSCLC may allow for complete surgical removal of the cancer.
- Stage III includes sub-stages IIIA or TUB. Surgery is difficult or impossible in many stage IIIA cancers and nearly all stage MB, because of the spread of the cancer to the lymph nodes or because of its growth into nearby structures in the lung. Surgery in either situation typically requires the partial removal of the cancer.
- Stage IV NSCLC is associated with its spread to more than one area in the other lung, the fluid surrounding the lung or the heart, or distant metastasis in the body. NSCLC is more likely to spread to the brain, bones, liver, and adrenal glands. Stage IV NSCLC includes substages IVA (spread within the chest) and IVB (spread outside of the chest). Surgery is rarely successful for most stage III or IV NSCLC and may be impossible to remove if it has spread to the lymph nodes above the collarbone, or to vital structures within the chest (e.g., heart, large blood vessels, or the main pulmonary structures). In certain aspects, a patient disclosed herein is a stage IV NSCLC patient.
- Antibodies that specifically bind and inhibit PD-L1 activity are useful in the methods disclosed herein.
- Durvalumab is an exemplary anti-PD-Ll antibody that is selective for PD-L1 and blocks the binding of PD-L1 to the PD-l and CD80 receptors.
- Durvalumab can relieve PD-L1- mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism.
- Other agents that are useful in the disclosed methods include agents that inhibit PD-L1 and/or PD-l, such as, for example the human anti-PD- Ll antibodies avelumab and atezolizumab, or the human anti-PD-l antibodies nivolumab and pembrolizumab.
- an antibody that is used in the methods disclosed herein is any agent that disrupts the PD-1/PD-L1 axis.
- Durvalumab (or fragments thereof) for use in the methods provided herein can be found in U.S. Patent Nos. 8,779,108 and 9,493,565, the disclosures of which are incorporated herein by reference in its entirety.
- the fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgGl heavy chain that reduces binding to the complement component Clq and the Fey receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC).
- Durvalumab and antigen-binding fragments thereof for use in the methods provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region.
- durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2.
- durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat- defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8.
- the heavy chain variable region comprises the Kabat- defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5
- the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8.
- durvalumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H90PT antibody as disclosed in U.S. Patent Nos. 8,779,108 and 9,493,565, which are herein incorporated by reference in their entirety.
- Patients with late stage (III or IV) locally advanced, unresectable NSCLC, who have not progressed following definitive chemoradiation therapy are administered an anti-PD-l or anti-PD-Ll antibody, such as durvalumab, or an antigen-binding fragment thereof.
- Durvalumab or an antigen-binding fragment thereof can be administered once every two weeks while providing benefit to the patient.
- the patient is administered additional follow- on doses.
- Follow-on doses can be administered at various time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and/or other factors, including the judgment of the attending physician.
- multiple doses of durvalumab or an antigen-binding fragment thereof are administered to the patient.
- at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least fifteen doses, or at least twenty six doses (i.e., a full year of treatment) or more can be administered to the patient.
- durvalumab or an antigen-binding fragment thereof is administered every two weeks, over a two week period, over a four-week treatment period, over a six-week treatment period, over an eight-week treatment period, over a twelve- week treatment period, over a twenty-four-week treatment period, or over a one-year or more treatment period.
- the interval between doses can be every three weeks. In certain aspects, the interval between doses can be every four weeks. In further aspects, the intervals between doses can be every two months (e.g., during a maintenance phase).
- the dosing intervals can also be about every 14 days or about every 21 days.
- "about" every 14 days or “about” every 21 days indicates 14 days +/- 2 days or 21 days +/- 2 days.
- administration of durvalumab is about every 14 to 21 days.
- the patient is administered one or more doses of an anti-PD-Ll antibody, wherein the dose is a fixed dose of 1200 mg.
- the amount of durvalumab or an antigen-binding fragment thereof to be administered to the patient may be adjusted and can depend on various parameters, such as the patient's age, weight, clinical assessment, tumor burden and/or other factors, including the judgment of the attending physician.
- the dose is a fixed dose.
- the patient is administered one or more doses of durvalumab wherein the dose is about 1 mg/kg. In certain aspects the patient is administered one or more doses of durvalumab wherein the dose is about 3 mg/kg. In certain aspects the patient is administered one or more doses of durvalumab wherein the dose is about 10 mg/kg. In certain aspects the patient is administered one or more doses of durvalumab wherein the dose is about 15 mg/kg. In certain aspects the patient is administered one or more doses of durvalumab wherein the dose is about 20 mg/kg.
- the patient is administered one or more doses of durvalumab wherein the dose is a fixed dose of 1500 mg.
- the patient is administered at least two doses of durvalumab or an antigen-binding fragment thereof, once every two weeks, wherein the dose is about 10 mg/kg. In further aspects, the patient is administered a 10 mg/kg dose of durvalumab every two weeks for up to year or more.
- the patient is administered 1500 mg of durvalumab every four weeks.
- administration of durvalumab or an antigen-binding fragment thereof according to the methods provided herein is through parenteral administration.
- durvalumab or an antigen-binding fragment thereof can be administered by intravenous infusion or by subcutaneous injection. In some aspects, the administration is by intravenous infusion.
- durvalumab or an antigen-binding fragment thereof is administered according to the methods provided herein in combination or in conjunction with additional cancer therapies.
- Such therapies include, without limitation, chemotherapeutic agents such as Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin, Bevacizumab, Erlotinib, or
- the methods provided herein may provide for additional clinical benefits beyond those specifically identified and illustrated by the data including, for example, decrease tumor size, retard tumor growth or maintain a steady state.
- the reduction in tumor size can be significant based on appropriate statistical analyses.
- a reduction in tumor size can be measured by comparison to the size of patient's tumor at baseline, against an expected tumor size, against an expected tumor size based on a large patient population, or against the tumor size of a control population.
- the administration of durvalumab can reduce a tumor size by at least 25%, at least 50%, or at least 75%.
- the methods provided herein can decrease or retard tumor growth.
- the reduction or retardation can be statistically significant.
- a reduction in tumor growth can be measured by comparison to the growth of patient's tumor at baseline, against an expected tumor growth, against an expected tumor growth based on a large patient population, or against the tumor growth of a control population.
- AUC area under the curve
- AUC (tau) refers to AUC until the end of the dosing period
- AUC (inf) refers to the AUC until infinite time.
- the administration can produce AUC (tau) of about 100 to about 2,500 d-pg/mL.
- the administration can produce a maximum observed concentration (Cmax) of about 15 to about 350 pg/mL.
- Cmax maximum observed concentration
- the half-life of the durvalumab or the antigen-binding fragment thereof can be about 5 to about 25 days.
- the clearance of the durvalumab or the antigen-binding fragment thereof can be about 1-10 ml/day/kg.
- durvalumab or an antigen-binding fragment thereof can also decrease free PD-L1 levels.
- Free PD-L1 refers to PD-L1 that is not bound (e.g., by durvalumab).
- PD-L1 levels are reduced by at least 80%.
- PD-L1 levels are reduced by at least 90%.
- PD-L1 levels are reduced by at least 95%.
- PD-L1 levels are reduced by at least 99%.
- PD-L1 levels are eliminated following administration of durvalumab or an antigen-binding fragment thereof.
- administration of durvalumab or an antigen-binding fragment thereof reduces the rate of increase of PD-L1 levels as compared, e.g., to the rate of increase of PD-L1 levels prior to the administration of durvalumab or an antigen-binding fragment thereof.
- the practice of the methods disclosed herein employs, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the purview of the skilled artisan.
- Example 1 Clinical assessment of durvalumab in the treatment of locally advanced, Stage III, unresectable NSCLC
- This example provides results from an interim analysis of the randomized, double blind, international, phase 3 PACIFIC study (ClinicalTrials.gov number NCT02125461) comparing durvalumab versus placebo as consolidation therapy in patients with stage III, locally advanced, unresectable NSCLC, whose disease had not progressed following platinum-based cCRT. This is the first randomized phase 3 study to evaluate immune checkpoint blockade in this setting.
- paclitaxel or docetaxel [paclitaxel or docetaxel], or pemetrexed) concurrently with definitive radiation therapy (54 Gy to 66 Gy), in which the mean lung dose must have been ⁇ 20 Gy and/or V20 must have been ⁇ 35%, and had not progressed following this treatment.
- Patients were aged >18 years, had a World Health Organization (WHO) PS 0 or 1, an estimated life expectancy >12 weeks, and had completed the last dose of radiation within 1 to 14 days before randomization (changed to 1 to 42 days, following a protocol amendment).
- WHO World Health Organization
- Key exclusion criteria include prior exposure to anti-PD-l or anti-PD-Ll antibodies; receipt of immunotherapy or investigational drug within 4 weeks before the first dose (6 weeks in the case of monoclonal antibodies); active or prior autoimmune disease (within the past 2 years) or history of primary immunodeficiency; evidence of uncontrolled, concurrent illness; evidence of ongoing or active infections; unresolved toxicity from previous CRT > grade 2 (based on Common Terminology Criteria for Adverse Event [CTCAE]); > grade 2 pneumonitis from prior CRT.
- CTCAE Common Terminology Criteria for Adverse Event
- PFS (according to Response Evaluation Criteria In Solid Tumors [RECIST] vl.l, as assessed by Blinded Independent Central Review [BICR]), and overall survival (OS).
- PFS was defined as the time from randomization to the date of the first documented event of tumor progression or death in the absence of progression, and OS was defined as the time from randomization until death (any cause). PFS was assessed by
- Secondary endpoints were the proportion of patients alive and progression-free at 12 and 18 months, objective response rate (ORR), duration of response (DoR), and time to death or distant metastasis (TTDM), all per BICR, and OS at 24 months, safety and tolerability (graded using CTCAE v4.03), health-related quality of life, pharmacokinetics and immunogenicity. Efficacy was assessed every 8 weeks for the first 12 months and every 12 weeks thereafter. All reported efficacy endpoints are for treatment with durvalumab or placebo only, i.e. they were not aggregate endpoints that included prior cCRT therapy.
- Patients provided an optional archived tumor tissue sample for PD-L1 testing;
- IMC independent data monitoring committee
- WHO World Health Organization
- PS performance status
- chemotherapies were also well balanced; 55.9% and 54.4% of patients in the durvalumab and placebo groups, respectively, had previously received a cisplatin-based definitive regimen, and 41.8% and 43.0% had received a carboplatin-based regimen (Table 2). In addition, 25.8% and 28.7% had received induction chemotherapy prior to definitive cCRT.
- EGFR mutations were observed in 6.0% of patients (6.1% in the durvalumab group and 5.9% in the placebo group), whereas 67.3% of patient’s tumors were EGFR negative or wild-type (66.2% in the durvalumab group and 69.6% in the placebo group); EGFR mutation status was unknown in 27.7% and 24.5%, respectively (Table 3). There were no statistically significant (P ⁇ 0.05) between-group differences in either PD-L1 expression or EGFR mutation status.
- TC >25%, >25% PD-L1 expression on tumor cells; TC ⁇ 25%, ⁇ 25% PD-L1 expression on tumor cells.
- Percentages are calculated based on the number of patients who received treatment.
- PFS benefit with durvalumab was consistently observed across all pre-specified subgroups, as defined by patient demographics, baseline clinicopathologic features, and response to prior treatment (Fig, 2; additional non-prognostic factors presented in Fig, 4). Notably, PFS benefit with durvalumab was observed irrespective of pre-cCRT PD-L1 expression (HR, 0.59; 95% Cl, 0.43-0.82 for TC ⁇ 25%, and HR, 0.41, 95% Cl: 0.26-0.65 for TC >25%). PFS benefit was also evident in non-smokers and patients with EGFR mutations.
- a patient may have had more than one new lesion site.
- BICR Blinded Independent Central Review
- RECIST Response Evaluation Criteria In Solid Tumors.
- pneumonitis was assessed by investigators with subsequent review and adjudication by the study sponsor.
- pneumonitis is a grouped term, which includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis.
- AESIs any-grade AEs of special interest
- durvalumab and placebo groups were reported in 66.1% and 48.7% of patients in the durvalumab and placebo groups, respectively. The majority were grade 1/2, with grade >3 incidences infrequent ( ⁇ 10%) in both treatment groups. The most frequent any-grade AESIs with durvalumab versus placebo were diarrhea (18.3% vs 18.8%), pneumonitis (12.6% vs. 7.7%), rash (12.2% vs 7.3%) and pruritus (12.2% vs. 4.7%).
- AESIs requiring concomitant treatment were reported in 42.1% and 17.1% of patients, respectively; treatments for AESIs included steroids (15.2% vs 6.8%), high dose steroids (8.8% vs 5.1%), endocrine therapy (11.6% vs 1.3%) and other immunosuppressants (0.4% of both groups).
- Durvalumab also had a favorable impact on the frequency of new metastases, including a lower incidence of new brain metastases.
- Durvalumab had a favorable safety profile in this population, which was consistent with other immunotherapies and its known safety profile as monotherapy in patients with more severe disease (stage IIIB/IV NSCLC). Although the incidences of some all-causality AEs, including pneumonitis/radiation pneumonitis, were higher with both durvalumab and placebo in this study, this was not unexpected in this post-definitive-dose cCRT setting. In addition, pneumonitis/radiation pneumonitis with durvalumab was mostly low grade with the incidences of clinically important grade 3/4 events well balanced between the two treatment groups (3.4% vs 2.6%) and lower than that reported in other studies in the same setting. The favorable safety profile of durvalumab following cCRT shown here may have implications in other disease settings.
- tumors may be more sensitive to anti-PD-Ll therapy after cCRT.
- the disclosure herein suggests that efficacy with durvalumab was observed irrespective of pre-cCRT PD-L1 expression status or type of platinum-doublet.
- Dovedi et al. have suggested that concomitant but not sequential administration of anti-PD-Ll treatment with fractionated radiotherapy may improve survival.
- the data disclosed herein clearly demonstrate a clinical benefit for sequential administration of durvalumab within 42 days following cCRT.
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