Classifications

• • 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
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • 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
  • A61K31/28—Compounds containing heavy metals
  • A61K31/282—Platinum compounds
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • 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
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • 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
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], 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 [IG], 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], 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 [IG], 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
  • C07K16/3023—Lung
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
• • 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
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention generally relates to methods for treating extensive- stage SCLC patients based on use of a combination of durvalumab and platinum-etoposide.
• Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths. Lung cancer is broadly split into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), the latter of which accounts for 13- 17% of all diagnosed lung cancers and is characterized by rapid proliferation, high growth fraction, and early development of widespread metastases (Oronsky et al. What's new in SCLC? A review. Neoplasia 2017;19(10):842-847; Wang et al. Survival changes in patients with small cell lung cancer and disparities between different sexes, socioeconomic statuses and ages. Sci Rep 2017; 7:1339).
• NSCLC non-small-cell lung cancer
• SCLC small-cell lung cancer
• durvalumab both as monotherapy and in combination with the anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody, tremelimumab, showed durable clinical activity and a manageable safety profile in patients with pretreated ES-SCLC, including those with relapsed or refractory disease (Cho et al. Safety and Clinical Activity of Durvalumab in Combination with Tremelimumab in Extensive Disease Small-Cell Lung Cancer. J Clin Oncol 2018; 36(15_suppl; abstr 8517; Goldman et al. Safety and Antitumor Activity of Durvalumab Monotherapy in Patients with Pretreated Extensive Disease Small-Cell Lung Cancer.
• CTL-4 cytotoxic T lymphocyte-associated antigen-4
• this disclosure provides methods comprising administration of durvalumab, with or without tremelimumab, in combination with EP for the first-line treatment of patients with ES-SCLC. As disclosed herein, the methods provide a significant and unexpected advance to the first-line treatment of patients with ES-SCLC.
• the present disclosure generally relates to methods for treating extensive stage small cell lung cancer (ES-SCLC) in patients as a first-line therapy, wherein the methods comprises administration of an antibody that inhibits PD1/PD-L1 activity in combination with etoposide and a platinum-based therapeutic agent, and optionally, an antibody that inhibits CTLA-4.
• ES-SCLC extensive stage small cell lung cancer
• the present disclosure provides a method of extending progression- free survival (PFS) in a patient with extensive- stage small cell lung cancer (ES-SCLC), comprising treating the patient with a) a human anti-PD-Ll antibody and b) etoposide and a platinum-based therapeutic agent (EP).
• the platinum-based therapeutic agent comprises cisplatin and/or carboplatin.
• 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 a VH CDR1 having the amino acid sequence of SEQ ID NO: 3; and a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and a VH CDR3 having the amino acid sequence of SEQ ID NO: 5; and a VL CDR1 having the amino acid sequence of SEQ ID NO: 6; and a VL CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having the amino acid sequence of SEQ ID NO: 8.
• the human anti-PD-Ll antibody is durvalumab, avelumab, or atezolizumab.
• the human anti-PD-Ll antibody is administered as a fixed dose of 1500 mg, intravenously, Q3W. In another embodiment of the first aspect, the human anti-PD-Ll antibody is administered as a dose of 20 mg/kg, intravenously, Q3W. In another embodiment of the first aspect, the method comprises 4 cycles of administration of the human anti-PD-Ll antibody. In embodiment according of the first aspect, the EP is administered as a dose comprising 80-100 mg/m 2 etoposide and carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m 2 , intravenously, per dose of human anti-PD-Ll antibody.
• the method further comprises administration of 1500 mg human anti-PD-Ll antibody, intravenously, Q4W after completion of 4 cycles of Q3W.
• the method further comprises administration of a human anti-CTLA-4 antibody, intravenously, Q3W.
• the human anti-CTLA- 4 antibody is tremelimumab.
• the tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg/kg.
• the method further comprises administration of prophylactic cranial irradiation to the patient.
• the method further comprises treating the patient with a human anti-PD-1 antibody.
• the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA ® ) or nivolumab (OPDIVO ® ).
• PLS is increased by at least about five months versus treatment with EP alone.
• the present disclosure provides a method of extending overall survival (OS) in a patient with extensive-stage small cell lung cancer (ES-SCLC), comprising treating the patient with a) a human anti-PD-Ll antibody and b) etoposide and a platinum-based therapeutic agent (EP).
• the platinum-based therapeutic agent comprises cisplatin and/or carboplatin.
• 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 a VH CDR1 having the amino acid sequence of SEQ ID NO: 3; and a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and a VH CDR3 having the amino acid sequence of SEQ ID NO: 5; and a VL CDR1 having the amino acid sequence of SEQ ID NO: 6; and a VL CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having the amino acid sequence of SEQ ID NO: 8.
• the human anti-PD-Ll antibody is durvalumab, avelumab, or atezolizumab.
• the human anti-PD-Ll antibody is administered as a fixed dose of 1500 mg, intravenously, Q3W. In another embodiment of the second aspect, the human anti-PD-Ll antibody is administered as a dose of 20 mg/kg, intravenously, Q3W. In another embodiment of the second aspect, the method comprises 4 cycles of administration of the human anti-PD-Ll antibody.
• the EP is administered as a dose comprising 80-100 mg/m 2 etoposide and carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m 2 , intravenously, per dose of human anti-PD-Ll antibody.
• the method further comprises administration of 1500 mg human anti-PD-Ll antibody, intravenously, Q4W after completion of 4 cycles of Q3W.
• the method further comprises administration of a human anti-CTLA-4 antibody, intravenously, Q3W.
• the human anti- CTLA-4 antibody is tremelimumab.
• the tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg/kg.
• the method further comprises administration of prophylactic cranial irradiation to the patient.
• the method further comprises treating the patient with a human anti-PD-1 antibody.
• the human anti-PD- 1 antibody comprises pembrolizumab (KEYTRUDA ® ) or nivolumab (OPDIVO ® ).
• OS is extended by at least about three months versus treatment with EP alone.
• the present disclosure provides a method of improving overall response rate (ORR) in a patient with extensive-stage small cell lung cancer (ES-SCLC), comprising treating the patient with a) a human anti-PD-Ll antibody and b) etoposide and a platinum-based therapeutic agent (EP).
• the platinum- based therapeutic agent comprises cisplatin and/or carboplatin.
• 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-L1 antibody comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 3; and a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and a VH CDR3 having the amino acid sequence of SEQ ID NO: 5; and a VL CDR1 having the amino acid sequence of SEQ ID NO: 6; and a VL CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having the amino acid sequence of SEQ ID NO: 8.
• the human anti-PD-Ll antibody is durvalumab, avelumab, or atezolizumab.
• the human anti-PD-Ll antibody is administered as a fixed dose of 1500 mg, intravenously, Q3W. In another embodiment of the third aspect, the human anti-PD-Ll antibody is administered as a dose of 20 mg/kg, intravenously, Q3W. In another embodiment of the third aspect, the method comprises 4 cycles of administration of the human anti-PD-Ll antibody. In embodiment according of the third aspect, the EP is administered as a dose comprising 80-100 mg/m 2 etoposide and carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m 2 , intravenously, per dose of human anti-PD-Ll antibody.
• the method further comprises administration of 1500 mg human anti-PD-Ll antibody, intravenously, Q4W after completion of 4 cycles of Q3W.
• the method further comprises administration of a human anti-CTLA-4 antibody, intravenously, Q3W.
• the human anti- CTLA-4 antibody is tremelimumab.
• the tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg/kg.
• the method further comprises administration of prophylactic cranial irradiation to the patient.
• the method further comprises treating the patient with a human anti-PD-1 antibody.
• the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA ® ) or nivolumab (OPDIVO ® ).
• ORR is increased by at least 10% versus treatment with EP alone.
• the present disclosure provides a method of treating ES-SCLC in a patient in need thereof, comprising administering to the patient durvalumab and EP, wherein the durvalumab and EP are administered as a first-line treatment, and, optionally, administering to the patient tremelimumab.
• the patient may express genes (i.e., have a phenotype) associated with therapeutic response to a therapy comprising a human anti-PD-1 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.
• FIG. 1 shows the study design of the present disclosure.
• *EP consists of etoposide 80-100 mg/m 2 with either carboplatin AUC 5-6 or cisplatin 75-80 mg/m 2 .
• ⁇ Patients received an additional dose of tremelimumab post-EP.
• ⁇ Patients could receive an additional 2 cycles of EP (up to 6 cycles total) in the control arm, as well as PCI.
• ⁇ Patients continued treatment until confirmed disease progression, unacceptable toxicity, evidence of a new PNS or worsening of an existing PNS, pregnancy or intent to become pregnant, initiation of alternative anticancer therapy including another investigational agent, noncompliance, or withdrawal of consent.
• AUC area under the curve
• CT chemotherapy
• ES-SCLC extensive- stage small-cell lung cancer
• EP platinum-etoposide
• PCI prophylactic cranial irradiation
• PD progressive disease
• PNS paraneoplastic syndrome
• PS performance status
• q3w every 3 weeks
• q4w every 4 weeks
• RECIST Response Evaluation Criteria in Solid Tumors
• WHO World Health Organization
• FIG. 2 shows hierarchical multiple testing procedure with a gatekeeping strategy that was used to control the type I error at a two-sided 5% significance level in the present disclosure.
• the hypotheses were to be tested using a multiple testing procedure with an alpha-exhaustive recycling strategy (Burman el al. A recycling framework for the construction of Bonferroni- based multiple tests. Stat Med 2009;28:739-61). This strategy was used to test the two primary analyses of OS and two secondary analyses of PFS. PFS was therefore only to be tested within the multiple testing procedure if both OS primary analyses achieved significance.
• the overall 5% alpha was split between the primary endpoints: an alpha level of 4% was allocated to the analysis of OS for durvalumab plus EP versus EP, and an alpha level of 1% for the analysis of OS for durvalumab plus tremelimumab plus EP versus EP.
• EP platinum-etoposide
• H hypothesis
• ITT intention-to-treat
• OS overall survival
• PFS progression-free survival.
• FIG. 3 shows Overall survival in the intention-to-treat population.
• FIG. 4 shows Progression-free survival and duration of response in the intention-to- treat population.
• FIG. 5 shows Best percentage change from baseline in target lesion size (5 A) Durvalumab plus tremelimumab plus EP versus EP. (5B) Durvalumab plus EP versus EP. [00033]
• FIG. 6 shows confirmed objective response.
• FIG.6 shows overall response rate per RECIST vl.l.
• FIG. 6B shows duration of response (DoR).
• OR odds ratio.
• the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean.
• the term “about” can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value.
• all numerical values provided herein are modified by the term about.
• variable includes definitions of that variable as any single group or combination of listed groups.
• an aspect for a variable or aspect herein includes that aspect as any single aspect or in combination with any other aspects or portions thereof.
• compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
• Ranges provided herein are understood to be shorthand for all of the values within the range.
• a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50.
• 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.
• durvalumab, avelumab, and atezolizumab is an exemplary PD-L1 antibody. In further aspects, durvalumab is an exemplary PD-L1 antibody.
• durvalumab refers to an antibody that selectively binds PD-L1 and blocks the binding of PD-L1 to the PD-1 and CD80 receptors, as disclosed in U.S. Patent No. 9,493,565 (referred to as “2.14H90PT”), which is incorporated by reference herein 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 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.
• anti-PD-1 antibody is meant an antibody or antigen binding fragment thereof that selectively binds a PD-1 polypeptide.
• nivolumab or pembrolizumab is an exemplary PD-1 antibody.
• Tremelimumab refers to an antibody that selectively binds a CTLA-4 polypeptide, as disclosed in U.S. Patent No. 8,491,895 (referred to as clone 11.2.1), which is incorporated by reference herein in its entirety.
• Tremelimumab is specific for human CTLA-4, with no cross-reactivity to related human proteins.
• Tremelimumab blocks the inhibitory effect of CTLA-4, and therefore enhances T-cell activation.
• Tremelimumab shows minimal specific binding to Fc receptors, does not induce natural killer (NK) antibody-dependent cell-mediated cytotoxicity (ADCC) activity, and does not deliver inhibitory signals following plate-bound aggregation.
• NK natural killer
• ADCC antibody-dependent cell-mediated cytotoxicity
• a “complete response” refers to the disappearance of all lesions, whether measurable or not, and no new lesions. Confirmation can be obtained using a repeat, consecutive assessment no less than four weeks from the date of first documentation. New, non-measurable lesions preclude CR.
• a “partial response” refers to a decrease in tumor burden 250% 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 polypeptide, or fragment thereof has at least about 85%, 95% or 100% sequence identity to NCBI Accession No. NP_001254635, and has PD-1 and CD80 binding activity.
• PD-L1 polypeptide sequence (NCBI Accession No. NPJ301254635; SEQ ID NO: 9):
• a “PD-L1 nucleic acid molecule” comprises a polynucleotide encoding a PD-L1 polypeptide.
• An exemplary PD-L1 nucleic acid molecule sequence is provided at NCBI Accession No. NM_001267706.
• PD-L1 nucleic acid sequence (NCBI Accession No. NM_001267706 mRNA; SEQ ID NO: 10):
• PD-1 Programmed Death- 1
• PD-1 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-1, A Novel Member Of The Immunoglobulin Gene Superfamily, Upon Programmed Cell Death,” EMBO J. 11 :3887-3895).
• PD-1 is expressed on activated T cells, B cells, and monocytes (Agata et al. (1996) “Expression Of The PD-1 Antigen On The Surface Of Stimulated Mouse T And B Lymphocytes,” Int. Immunol. 8(5):765-772; Yamazaki et al.
• PD-1 is a receptor responsible for down-regulation of the immune system following activation by binding of PD-L1 or PD-L2 (Martin- Orozco, N. et al. (2007) “Inhibitory Costimulation and Anti-Tumor Immunity,” Semin. Cancer Biol. 17(4):288-298) and functions as a cell death inducer (Ishida, Y. et al. (1992) “Induced Expression of PD-1, A Novel Member of the Immunoglobulin Gene Superfamily, Upon Programmed Cell Death,” EMBO J. 11: 3887-3895; Subudhi, S.K. et al. (2005) “The Balance Of Immune Responses: Costimulation Verse Coinhibition,” J. Molec. Med.
• PD-1 is a well-validated target for immune mediated therapy in oncology, with positive clinical trials in the treatment of melanoma and non-small cell lung cancers (NSCLC), among others.
• Antagonistic inhibition of the PD-1/PD-L1 interaction increases T cell activation, enhancing recognition and elimination of tumor cells by the host immune system.
• the use of anti-PD- 1 antibodies to treat infections and tumors and up-modulate an adaptive immune response has been proposed.
• 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, e.g., the ability to bind PD-L1 specifically. Typically, such fragments would comprise an antigen-binding domain.
• the terms “antigen-binding domain,” “antigen-binding fragment,” and “binding fragment” refer to a part of an antibody molecule that comprises amino acids responsible for the specific binding between the antibody and the antigen.
• an antigen-binding domain may only bind to a part of the antigen.
• a portion of the antigen molecule that is responsible for specific interactions with the antigen-binding domain is referred to as “epitope” or “antigenic determinant.”
• An antigen-binding domain typically comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH); however, it does not necessarily have to comprise both.
• VL antibody light chain variable region
• VH antibody heavy chain variable region
• Fd antibody fragment consists only of a VH domain, but still retains some antigen-binding function of the intact antibody.
• 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 10 6 M -1 , or more preferably higher than 10 8 M -1 .
• 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, temperature, time allowed for binding, concentration of a blocking agent (e.g., serum albumin, milk casein), etc., may be optimized by a skilled artisan using routine
• 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.
• Durvalumab light chain variable region amino acid sequence is provided as SEQ ID NO: 1.
• Durvalumab heavy chain variable region amino acid sequence is provided as SEQ ID NO: 2.
• 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).
• Durvalumab light chain variable region amino acid sequence of CDR1, CDR2, and CDR3 are provided as SEQ ID NO: 6 (CDR1), SEQ ID NO: 7 (CDR2), and SEQ ID NO: 8 (CDR3).
• the disclosure relates to methods of treating patients who have extensive- stage small cell lung cancer (ES-SCLC), comprising administering to the patient a human anti-PD-Ll antibody in combination with etoposide and a platinum-based therapeutic agent. Further, the method can also include administration of a human anti-CTLA-4 antibody.
• the data derived from the clinical results disclosed herein provide for improved treatment methods and substantially redefine the existing standard of care (first-line treatment) for ES-SCLC.
• the disclosed methods of treatment can provide for substantial improvement in a patient’s overall survival (OS), progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), or time to death.
• the disclosed methods provide new, first-line treatment options for treating a patient with ES-SCLC.
• the present disclosure provides a method of extending progression- free survival (PFS) in a patient with extensive- stage small cell lung cancer (ES-SCLC), comprising treating the patient with a) a human anti-PD-Ll antibody and b) etoposide and a platinum-based therapeutic agent (EP).
• the platinum-based therapeutic agent comprises cisplatin and/or carboplatin.
• 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 a VH CDR1 having the amino acid sequence of SEQ ID NO: 3; and a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and a VH CDR3 having the amino acid sequence of SEQ ID NO: 5; and a VL CDR1 having the amino acid sequence of SEQ ID NO: 6; and a VL CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having the amino acid sequence of SEQ ID NO: 8.
• the human anti-PD-Ll antibody is durvalumab, avelumab, or atezolizumab.
• the human anti-PD-Ll antibody is administered as a fixed dose of 1500 mg, intravenously, Q3W. In another embodiment of the first aspect, the human anti-PD-Ll antibody is administered as a dose of 20 mg/kg, intravenously, Q3W. In another embodiment of the first aspect, the method comprises 4 cycles of administration of the human anti-PD-Ll antibody. In embodiment according of the first aspect, the EP is administered as a dose comprising 80-100 mg/m 2 etoposide and carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m 2 , intravenously, per dose of human anti-PD-Ll antibody.
• the method further comprises administration of 1500 mg human anti-PD-Ll antibody, intravenously, Q4W after completion of 4 cycles of Q3W.
• the method further comprises administration of a human anti-CTLA-4 antibody, intravenously, Q3W.
• the human anti-CTLA- 4 antibody is tremelimumab.
• the tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg/kg.
• the method further comprises administration of prophylactic cranial irradiation to the patient.
• the method further comprises treating the patient with a human anti-PD-1 antibody.
• the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA ® ) or nivolumab (OPDIVO ® ).
• PFS is increased by at least about five months versus treatment with EP alone.
• the present disclosure provides a method of extending overall survival (OS) in a patient with extensive-stage small cell lung cancer (ES-SCLC), comprising treating the patient with a) a human anti-PD-Ll antibody and b) etoposide and a platinum-based therapeutic agent (EP).
• the platinum-based therapeutic agent comprises cisplatin and/or carboplatin.
• 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 a VH CDR1 having the amino acid sequence of SEQ ID NO: 3; and a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and a VH CDR3 having the amino acid sequence of SEQ ID NO: 5; and a VL CDR1 having the amino acid sequence of SEQ ID NO: 6; and a VL CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having the amino acid sequence of SEQ ID NO: 8.
• the human anti-PD-Ll antibody is durvalumab, avelumab, or atezolizumab.
• the human anti-PD-Ll antibody is administered as a fixed dose of 1500 mg, intravenously, Q3W. In another embodiment of the second aspect, the human anti-PD-Ll antibody is administered as a dose of 20 mg/kg, intravenously, Q3W. In another embodiment of the second aspect, the method comprises 4 cycles of administration of the human anti-PD-Ll antibody.
• the EP is administered as a dose comprising 80-100 mg/m 2 etoposide and carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m 2 , intravenously, per dose of human anti-PD-Ll antibody.
• the method further comprises administration of 1500 mg human anti-PD-Ll antibody, intravenously, Q4W after completion of 4 cycles of Q3W.
• the method further comprises administration of a human anti-CTLA-4 antibody, intravenously, Q3W.
• the human anti- CTLA-4 antibody is tremelimumab.
• the tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg/kg.
• the method further comprises administration of prophylactic cranial irradiation to the patient.
• the method further comprises treating the patient with a human anti-PD-1 antibody.
• the human anti-PD- 1 antibody comprises pembrolizumab (KEYTRUDA ® ) or nivolumab (OPDIVO ® ).
• OS is extended by at least about three months versus treatment with EP alone.
• the present disclosure provides a method of improving overall response rate (ORR) in a patient with extensive-stage small cell lung cancer (ES-SCLC), comprising treating the patient with a) a human anti-PD-Ll antibody and b) etoposide and a platinum-based therapeutic agent (EP).
• the platinum- based therapeutic agent comprises cisplatin and/or carboplatin.
• 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 a VH CDR1 having the amino acid sequence of SEQ ID NO: 3; and a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and a VH CDR3 having the amino acid sequence of SEQ ID NO: 5; and a VL CDR1 having the amino acid sequence of SEQ ID NO: 6; and a VL CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VL CDR3 having the amino acid sequence of SEQ ID NO: 8.
• the human anti-PD-Ll antibody is durvalumab, avelumab, or atezolizumab.
• the human anti-PD-Ll antibody is administered as a fixed dose of 1500 mg, intravenously, Q3W. In another embodiment of the third aspect, the human anti-PD-Ll antibody is administered as a dose of 20 mg/kg, intravenously, Q3W. In another embodiment of the third aspect, the method comprises 4 cycles of administration of the human anti-PD-Ll antibody. In embodiment according of the third aspect, the EP is administered as a dose comprising 80-100 mg/m 2 etoposide and carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m 2 , intravenously, per dose of human anti-PD-Ll antibody.
• the method further comprises administration of 1500 mg human anti-PD-Ll antibody, intravenously, Q4W after completion of 4 cycles of Q3W.
• the method further comprises administration of a human anti-CTLA-4 antibody, intravenously, Q3W.
• the human anti- CTLA-4 antibody is tremelimumab.
• the tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg/kg.
• the method further comprises administration of prophylactic cranial irradiation to the patient.
• the method further comprises treating the patient with a human anti-PD-1 antibody.
• the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA ® ) or nivolumab (OPDIVO ® ).
• ORR is increased by at least 10% versus treatment with EP alone.
• the present disclosure provides a method of treating ES-SCLC in a patient in need thereof, comprising administering to the patient durvalumab and EP, wherein the durvalumab and EP are administered as a first-line treatment, and, optionally, administering to the patient tremelimumab.
• the patient may express genes (i.e., have a phenotype) associated with therapeutic response to a therapy comprising a human anti-PD-1 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 treatments disclosed herein can comprise administering an anti-PD-Ll antibody or an antigen-binding fragment thereof intravenously once every 2, 3, or 4 weeks, at a dosage of 10 mg/kg or 20 mg/kg.
• the treatments disclosed herein can comprise administering of an anti-PD-Ll antibody or an antigen-binding fragment thereof intravenously once every 2, 3, or 4 weeks at a fixed dose of 200, 250, 500, 1000, or 1500 mg.
• 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 PD-L1 membrane staining.
• a cutoff and scoring algorithm has been previously determined for durvalumab (Study CPI 108; 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.
• the treatments disclosed herein can comprise administering a given dose of therapeutic agents (antibodies and/or chemotherapeutic agents) about every 14 days, or every 3 weeks, or every 4 weeks, for up to 52 weeks or longer.
• 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.
• PFS Progression-Free Survival
• RECIST 1.1 the date of objective disease progression
• 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.
• the disclosed methods comprise administration of an immunotherapeutic agent (e.g., a human anti-PD-Fl antibody or a human anti-PD-1 antibody) in combination with a chemotherapeutic agent (e.g., etoposide and a platinum-based therapeutic agent, such as, for example, cisplatin and/or carboplatin).
• an immunotherapeutic agent e.g., a human anti-PD-Fl antibody or a human anti-PD-1 antibody
• a chemotherapeutic agent e.g., etoposide and a platinum-based therapeutic agent, such as, for example, cisplatin and/or carboplatin.
• the methods treat patients with ES- SCLC.
• cancer staging can be performed using any tests that are generally known and accepted in the art.
• cancer staging can comprise the American Joint Committee on Cancer’s (AJCC’s) TNM system.
• AJCC American Joint Committee on Cancer
• 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.
• the TNM system can be used for both SCLC and NSCLC, but SCLC is typically staged using a different system.
• SCLC has 2 stages: “limited- stage” and “extensive-stage.”
• Limited-stage SCLC indicates that the cancer is only on one side of the chest and can be treated with a single radiation field.
• limited-stage SCLC includes cancers that are in only one lung, and that might have reached lymph nodes on the same side of the chest.
• An exception would be SCLC with tumors that are spread throughout a single lung such that the cancer is not confined to an area small enough to be treated with radiation therapy in one “port.”
• Such cancers are considered to be extensive-stage even though they are only on one side.
• the second stage of SCLC or “extensive-stage” SCLC are those SCLC cancers with tumor spread beyond a radiation therapy treatment area of one port, such as cancers that have spread widely throughout a single lung, to the opposite lung, to lymph nodes on the other side of the chest, to other parts of the body, or to the fluid around the lung.
• 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-1 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-1, such as, for example the human anti-PD- Ll antibodies avelumab and atezolizumab, or the human anti-PD-1 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 ES-SCLC can be administered therapeutic agents such as, an anti-PD-1 antibody, and/or an antigen-binding fragment thereof, and/or an anti-PD- L1 antibody, such as durvalumab, and/or an antigen-binding fragment thereof, along with EP, and optionally an anti-CTLA-4 antibody, and/or an antigen-binding fragment thereof, to treat ES-SCLC.
• therapeutic agents such as, an anti-PD-1 antibody, and/or an antigen-binding fragment thereof, and/or an anti-PD- L1 antibody, such as durvalumab, and/or an antigen-binding fragment thereof, along with EP, and optionally an anti-CTLA-4 antibody, and/or an antigen-binding fragment thereof, to treat ES-SCLC.
• Some or all of these therapeutic agents can be administered once in a cycle that lasts two, three, four, or six weeks (or shorter or longer) and each cycle repeated for as long as the treatment provides benefit to the patient.
• the patient can be administered additional follow-on doses after completion of one or more cycles containing some or all of these therapeutic agents with a subset of therapeutic agents (e.g., only a single therapeutic agent).
• 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.
• 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 follow on dosing period and/or maintenance phase).
• 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 1500 mg of durvalumab every four weeks.
• administering is administered in a fixed dose of 1500 mg and tremelimumab is administered as a fixed dose of 75 mg.
• administering is administered in a weight-based dose of 20 mg/kg and tremelimumab is administered as a weight- based dose of 1 mg/kg.
• a patient is administered intravenously a 1500 mg dose of durvalumab, optionally, a 75 mg dose of tremelimumab, a 80-100 mg/mL dose of etoposide, and either a carboplatin AUC dose of 5-6 mg/mL/min or a 75-80 mg/m 2 dose of cisplatin, Q3W.
• administration of therapeutic agents disclosed herein is via parenteral administration.
• durvalumab or an antigen-binding fragment thereof and EP 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 and EP are 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, Bevacizumab, Erlotinib, or Pemetrexed, or other chemotherapeutic agents, as well radiation or any other anti-cancer treatments.
• the methods provided herein may provide for additional clinical benefits beyond those specifically identified and illustrated by the data including, for example, decreased tumor size, retardation of tumor growth, or maintenance of 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 with etoposide and cisplatin and/or carboplatin 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.
• an anti-PD-Ll antibody for example, durvalumab or an antigen-binding fragment thereof
• 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 ⁇ 1-g/mL.
• the administration can produce a maximum observed concentration (Cmax) of about 15 to about 350 1-g/mL.
• 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.
• Example 1 Clinical assessment of durvalumab, with or without tremelimumab, in combination with EP for the first-line treatment of patients with ES-SCLC
• Most patients with SCLC have extensive-stage (ES) disease at diagnosis, with poor prognosis.
• ES-SCLC extensive-stage disease at diagnosis, with poor prognosis.
• immunotherapy has demonstrated clinical activity in ES-SCLC.
• This example provides results from a phase 3, randomized, open-label, sponsor-blind trial (CASPIAN, ClinicalTrials.gov number NCT03043872) evaluating the efficacy and safety of durvalumab, with or without tremelimumab, in combination with EP for the first-line treatment of patients with ES-SCLC.
• Eligible patients included adults with histologically or cytologically documented ES- SCLC and were treatment naive. Patients also had a World Health Organization (WHO) performance- status score of 0 or 1, measurable disease according to RECIST vl.l, and a life expectancy of >12 weeks from the study start. Patients with brain metastases were eligible provided they were asymptomatic or treated and stable off steroids and anticonvulsants for at least 1 month prior to study entry.
• WHO World Health Organization
• durvalumab + tremelimumab combination dose could be given post chemotherapy to ensure that up to 5 combination doses were administered in Arm 1.
• EP could be given for an additional 2 cycles q3w on Weeks 12 and 15 (i.e., total 6 cycles post-randomization) if clinically indicated before patients enter Follow-up.
• PCI can also be given. This does not alter the planned scan schedule q8w starting at Week 12 for patients in Arm 3.
• Durvalumab dose will be 1500 mg during chemotherapy and post-chemotherapy; tremelimumab dose will be 75mg during and post chemotherapy.
• Efficacy data were analyzed on an intention-to-treat basis including all randomized patients, regardless of whether the treatment was actually received. All patients who received at least one dose of study treatment were included in safety analyses.
• OS and PFS were analyzed using a stratified log-rank test adjusting for planned platinum agent (carboplatin or cisplatin), with HRs and 95% confidence intervals (Cl) estimated using a Cox proportional hazards model. The Kaplan-Meier method was used to estimate survival curves for OS and PFS.
• Sensitivity analyses for OS included examination of censoring patterns to rule out attrition bias.
• Sensitivity analyses for PFS included assessment of attrition bias and evaluation-time bias. Odds ratios and 95% CIs for comparing ORR between treatment arms were calculated using a logistic regression model, adjusted for planned platinum agent.
• the median (IQR) total duration of treatment with durvalumab was 23.1 (14.1-38.3) weeks in the D+T+EP group and 28.0 (20.0-43.9) weeks in the D+EP group.
• the median (IQR) number of durvalumab doses was 6 (4-10) in the D+T+EP group and 7 (6-11) in the D+EP group. 161 (61%) of 266 treated patients in the D+T+EP group received the planned five doses of tremelimumab (Table 4).
• ORR per RECIST vl .1 is defined as the number (%) of patients with at least one visit response of complete response or partial response. Data included is for confirmed responses. ⁇ Odds ratios and 95% CIs for comparing ORR between treatment arms were calculated using a logistic regression model, adjusted for planned platinum agent (carboplatin or cisplatin).
• the median (IQR) best reduction from baseline in target lesion size was -59.3% (-73.6, -40.0) in the D+T+EP group compared with -55.9% (-71.3, -35.8) in the EP group.
• the depth of response is shown in FIG. 5A.
• the median duration of response was similar in the D+T+EP (5.2 months [95% Cl 4.9-5.6]) and EP (5.1 months [4.8-5- 3]) groups (FIG. 4C).
• EP etoposide plus either cisplatin or carboplatin.
• ⁇ N patients with measurable disease at baseline fOdds ratios and 95% CIs were calculated using a logistic regression model adjusted for planned platinum ( carboplatin or cisplatin ); an odds ratio >1 favours immunotherapy. ⁇ Includes one patient with an unconfirmed response ( not evaluable due to no further assessments ). f Estimated using the Kaplan-Meier method.
• EP etoposide plus either cisplatin or carboplatin.
• Treatment-related adverse events leading to death were death, febrile neutropenia, and pulmonary embolism in two patients each, and enterocolitis, general physical health deterioration/multiple organ dysfunction syndrome, pneumonia, pneumonitis/hepatitis, respiratory failure, and sudden death in one patient each in the durvalumab plus tremelimumab plus EP group; cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis in one patient each in the durvalumab plus EP group; and pancytopenia and thrombocytopenia/hemorrhage in one patient each in the EP group.
• CASPIAN is the first pivotal trial to demonstrate a significant survival benefit with PD-1/PD-L1 blockade in combination with etoposide and a choice of carboplatin or cisplatin chemotherapy. This represents an important therapeutic advance given that in recent years (2014-2016) cisplatin-containing chemotherapy was used for 27-42% of patients in the first-line treatment of ES-SCLC in different regions globally (DiBonaventura MD, Shah-Manek B, Higginbottom K, Penrod JR, Yuan Y. Adherence to recommended clinical guidelines in extensive disease small-cell lung cancer across the US, Europe, and Japan. Ther Clin Risk Manag 2019; 15: 355-66).
• D+EP met the primary endpoint of improved survival compared with EP alone at the planned interim analysis (Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum- etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019; 394: 1929- 39).
• SEQ ID NO: 3 VH CDR1 - GFTFSRYWMS
• SEQ ID NO: 4 VH CDR2 - NIKQDGSEKYYVDSVKG
• SEQ ID NO: 5 VH CDR3 - EGGWFGELAFDY
• SEQ ID NO: 6 VL CDR1 - RASQRVSSSYLA
• SEQ ID NO: 7 VL CDR2 - DASSRAT

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Immunology (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Organic Chemistry (AREA)
• Epidemiology (AREA)
• Molecular Biology (AREA)
• Genetics & Genomics (AREA)
• Biophysics (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Biochemistry (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Oncology (AREA)
• Mycology (AREA)
• Microbiology (AREA)
• Inorganic Chemistry (AREA)
• Cell Biology (AREA)
• Biomedical Technology (AREA)
• Endocrinology (AREA)
• Dermatology (AREA)
• Pulmonology (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Peptides Or Proteins (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=72521575

Family Applications (1)

Country Status (10)

Families Citing this family (2)

Citations (2)

Family Cites Families (6)

• 2020
  • 2020-09-04 US US17/012,643 patent/US12012453B2/en active Active
  • 2020-09-04 AU AU2020342713A patent/AU2020342713A1/en not_active Abandoned
  • 2020-09-04 KR KR1020227011152A patent/KR20220058601A/ko active Pending
  • 2020-09-04 CN CN202080062489.9A patent/CN114340673A/zh active Pending
  • 2020-09-04 CA CA3151838A patent/CA3151838A1/en active Pending
  • 2020-09-04 TW TW109130442A patent/TWI907357B/zh active
  • 2020-09-04 EP EP20772218.2A patent/EP4025249A1/en active Pending
  • 2020-09-04 JP JP2022514608A patent/JP2022547061A/ja active Pending
  • 2020-09-04 WO PCT/EP2020/074714 patent/WO2021043955A1/en not_active Ceased
• 2022
  • 2022-02-23 IL IL290834A patent/IL290834A/en unknown
• 2024
  • 2024-05-07 US US18/657,210 patent/US20240376206A1/en active Pending
• 2025
  • 2025-04-17 AU AU2025202735A patent/AU2025202735A1/en active Pending
  • 2025-06-11 JP JP2025097923A patent/JP2025148350A/ja active Pending

Patent Citations (3)

Non-Patent Citations (41)

Also Published As

Similar Documents

Legal Events