Compositions and methods for treating extensive-stage small cell lung cancer (es-SCLC)

Abstract

To provide a method for extending progression-free survival (PFS) in a patient with extensive-stage small cell lung cancer (ES-SCLC).SOLUTION: This method comprises treating a patient with extensive-stage small cell lung cancer with a) a human anti-PD-L1 antibody and b) etoposide and a platinum-based therapeutic agent (EP).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention generally relates to methods for treating patients with extensive-stage SCLC based on the use of a combination of durvalumab and platinum etoposide. [Background technology]

[0002] Lung cancer is the leading cause of cancer deaths in both men and women, accounting for approximately one-fifth of all cancer deaths. Lung cancer is broadly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The latter accounts for 13-17% of all diagnosed lung cancers and is characterized by rapid growth, a high proliferative fraction, and the early development of extensive metastatic lesions (Non-Patent Document 1; Non-Patent Document 2). Fewer than 7% of SCLC patients survive five years after diagnosis (Non-Patent Document 3; Non-Patent Document 2). Extensive-stage SCLC (ES-SCLC), in which the cancer has spread widely to the lungs or other parts of the body, accounts for approximately two-thirds of all SCLC cases (Non-Patent Document 1). The prognosis is particularly poor, with only 6% of all SCLC patients surviving five years after diagnosis.

[0003] For over 30 years, standard treatment (first-line therapy) for ES-SCLC has consisted of four to six cycles of etoposide plus cisplatin or carboplatin (EP), leaving limited options (Non-Patent Document 4; Non-Patent Document 5; Non-Patent Document 6; Non-Patent Document 7). Despite an initial response rate of up to 78% in patients treated with EP (Non-Patent Document 8; Non-Patent Document 9), the majority of patients relapse within 6 months of completing initial treatment, with a median overall survival (OS) of approximately 10 months (Non-Patent Document 8; Non-Patent Document 10). Outside of Japan, the current standard of care in the second-line setting is topotecan (Non-Patent Document 5; Non-Patent Document 6), which is associated with poor outcomes (a 5% response rate and a 9% 1-year survival rate in patients with platinum-refractory disease) (Non-Patent Document 11), highlighting the significant unmet need for improved first-line therapy.

[0004] In recent years, immunotherapies targeting the programmed cell death 1 (PD-1) pathway and programmed cell death ligand 1 (PD-L1) pathway have demonstrated clinical activity in patients with ES-SCLC, including as first-line therapy (NPL 12). Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody that blocks the binding of PD-L1 to PD-1 and CD80 (NPL 13). It is indicated for the treatment of patients with unresectable stage III non-small cell lung cancer after platinum-based chemoradiotherapy (NPL 14; NPL 15). In early-phase clinical trials, durvalumab, both as monotherapy and in combination with the anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody tremelimumab, demonstrated durable clinical activity and a manageable safety profile in pretreated patients with ES-SCLC, including those with relapsed or refractory disease (NPL 16; NPL 17; NPL 18).

[0005] To address the significant unmet need for improved first-line treatments, the present disclosure provides methods for the first-line treatment of patients with ES-SCLC, comprising administering durvalumab in combination with EP, with or without tremelimumab. As disclosed herein, the methods provide a significant and unexpected advance in the first-line treatment of patients with ES-SCLC. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Oronsky et al.What's new in SCLC?A review.Neoplasia 2017;19(10):842-847 [Non-patent document 2] 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 [Non-patent document 3] Byers et al.Small cell lung cancer:where do we go from here?Cancer 2015 1;121(5):664-72 [Non-patent document 4] Pietanza et al.Small Cell Lung Cancer:Will Recent Progress Lead to Improved Outcomes?Clin Cancer Res 2015;21:2244-55 [Non-Patent Document 5] Frueh et al.Small-cell lung cancer(SCLC):ESMO Clinical Practice Guidelines for Diagnosis,Treatment and Follow-up.Ann Oncol 2013;24(Suppl 6):vi99-105 [Non-patent document 6] Rudin et al.Treatment of small-cell lung cancer:American Society of Clinical Oncology endorsement of the American College of Chest Physicians guideline.J Clin Oncol 2015 8;33(34):4106-11 [Non-Patent Document 7] Japan Lung Cancer Society:Lung cancer practice guidelines 2018 version III.Small cell lung cancer(SCLC) [Non-patent document 8] Farago et al. Current standards for clinical management of small cell lung cancer. Transl Lung Cancer Res 2018;7(1):69-79

Non-patent Document 9

Non-patent Document 10

Non-patent Document 11

Non-patent Document 12

Non-patent Document 13

[0007] The present disclosure generally relates to a method of treating extensive-stage small cell lung cancer (ES-SCLC) in a patient as a first-line treatment, comprising administering 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.

[0008] In a first aspect, the disclosure provides a method of extending progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC), the method comprising treating the patient with a) a human anti-PD-L1 antibody and b) etoposide and a platinum-based therapy (EP). In one embodiment of the first aspect, the platinum-based therapy comprises cisplatin and / or carboplatin. In another embodiment of the first aspect, the human anti-PD-L1 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. In one embodiment of the first aspect, the human anti-PD-L1 antibody comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, 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, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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. In one embodiment of the first aspect, the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. In another embodiment of the first aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a fixed dose of 1500 mg. In another embodiment of the first aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a dose of 20 mg / kg. In another embodiment of the first aspect, the method comprises administering four cycles of the human anti-PD-L1 antibody. In an embodiment according to the first aspect, EP is administered at a dose of 80-100 mg / m per dose of the human anti-PD-L1 antibody. 2 of etoposide, and carboplatin with an area under the curve of 5 to 6 mg / mL / min or 75 to 80 mg / m 2 It is administered intravenously as a dose containing cisplatin.

[0009] In one embodiment of the first aspect, the method further comprises administering 1500 mg of the human anti-PD-L1 antibody intravenously Q4W after completion of the 4 cycles Q3W.

[0010] In one embodiment of the first aspect, the method further comprises administering a human anti-CTLA-4 antibody intravenously Q3W. In one embodiment, the human anti-CTLA-4 antibody is tremelimumab. In another embodiment, tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg / kg.

[0011] In another embodiment of the first aspect or a further embodiment of the first aspect, the method further comprises administering prophylactic cranial irradiation to the patient.

[0012] In another embodiment of the first aspect or other embodiments of the first aspect, the method further comprises treating the patient with a human anti-PD-1 antibody. In one embodiment, the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

[0013] In another embodiment of the first aspect, PFS is increased by at least about 5 months compared to treatment with EP alone.

[0014] In a second aspect, the disclosure provides a method of extending overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC), comprising treating the patient with a) a human anti-PD-L1 antibody and b) etoposide and a platinum-based therapy (EP). In one embodiment of the second aspect, the platinum-based therapy comprises cisplatin and / or carboplatin. In another embodiment of the second aspect, the human anti-PD-L1 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. In one embodiment of the second aspect, the human anti-PD-L1 antibody comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, 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, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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. In one embodiment of the second aspect, the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. In another embodiment of the second aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a fixed dose of 1500 mg. In another embodiment of the second aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a dose of 20 mg / kg. In another embodiment of the second aspect, the method comprises administering four cycles of the human anti-PD-L1 antibody. In an embodiment according to the second aspect, EP is administered at a dose of 80-100 mg / m per dose of the human anti-PD-L1 antibody. 2 of etoposide, and carboplatin with an area under the curve of 5 to 6 mg / mL / min or 75 to 80 mg / m 2 It is administered intravenously as a dose containing cisplatin.

[0015] In one embodiment of the second aspect, the method further comprises administering 1500 mg of the human anti-PD-L1 antibody intravenously Q4W after completion of 4 cycles Q3W.

[0016] In one embodiment of the second aspect, the method further comprises administering a human anti-CTLA-4 antibody intravenously Q3W. In one embodiment, the human anti-CTLA-4 antibody is tremelimumab. In another embodiment, tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg / kg.

[0017] In another embodiment of the second aspect or other embodiments of the second aspect, the method further comprises administering prophylactic cranial irradiation to the patient.

[0018] In another embodiment of the second aspect or other embodiments of the second aspect, the method further comprises treating the patient with a human anti-PD-1 antibody. In one embodiment, the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

[0019] In another embodiment of the second aspect, OS is extended by at least about 3 months compared to treatment with EP alone.

[0020] In a third aspect, the disclosure provides a method of improving overall response rate (ORR) in patients with extensive-stage small cell lung cancer (ES-SCLC), the method comprising treating the patient with a) a human anti-PD-L1 antibody and b) etoposide and a platinum-based therapy (EP). In one embodiment of the third aspect, the platinum-based therapy comprises cisplatin and / or carboplatin. In another embodiment of the third aspect, the human anti-PD-L1 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. In one embodiment of the third aspect, the human anti-PD-L1 antibody comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, 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, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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. In one embodiment of the third aspect, the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. In another embodiment of the third aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a fixed dose of 1500 mg. In another embodiment of the third aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a dose of 20 mg / kg. In another embodiment of the third aspect, the method comprises administering four cycles of the human anti-PD-L1 antibody. In an embodiment according to the third aspect, EP is administered at a dose of 80-100 mg / m per dose of the human anti-PD-L1 antibody. 2 of etoposide, and carboplatin with an area under the curve of 5 to 6 mg / mL / min or 75 to 80 mg / m 2 It is administered intravenously as a dose containing cisplatin.

[0021] In one embodiment of the third aspect, the method further comprises administering 1500 mg of the human anti-PD-L1 antibody intravenously Q4W after completion of 4 cycles Q3W.

[0022] In one embodiment of the third aspect, the method further comprises administering a human anti-CTLA-4 antibody intravenously Q3W. In one embodiment, the human anti-CTLA-4 antibody is tremelimumab. In another embodiment, tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg / kg.

[0023] In another embodiment of the third aspect or other embodiments of the third aspect, the method further comprises administering prophylactic cranial irradiation to the patient.

[0024] In another embodiment of the third aspect or any other embodiment of the third aspect, the method further comprises treating the patient with a human anti-PD-1 antibody. In one embodiment, the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

[0025] In another embodiment of the third aspect, the ORR is increased by at least 10% compared to treatment with EP alone.

[0026] In a fourth aspect, the present disclosure provides a method of treating ES-SCLC in a patient in need thereof, the method comprising administering durvalumab and EP to the patient, wherein durvalumab and EP are administered as first-line treatment, and optionally administering tremelimumab to the patient.

[0027] In some embodiments of any of the above aspects or any of the above aspects, the patient may express a gene (i.e., have a phenotype) associated with a therapeutic response to a therapy comprising a human anti-PD-L1 antibody. In some aspects, the patient is PD-L1(+). In other aspects, the patient is PD-L1(-). In some aspects, the patient is EGFR mutant(+). In other aspects, the patient is EGFR mutant(-) or wild-type. In some aspects, the patient may express any combination of PD-L1 and EGFR mutant phenotypes.

[0028] Other features, aspects, embodiments, and advantages provided by the present disclosure will become apparent from the following detailed description. [Brief explanation of the drawings]

[0029] [Figure 1] Figure 1 shows the study design of this disclosure. *EP consisted of etoposide 80-100 mg / m² and carboplatin AUC 5-6 or cisplatin 75-80 mg / m². †Patients received tremelimumab after EP. ‡Patients could receive two additional cycles of EP (up to a total of six cycles) and PCI in the control arm. §Patients continued treatment until confirmed disease progression, unacceptable toxicity, new PNS signs or worsening of existing PNS, pregnancy or intent to become pregnant, initiation of alternative anticancer therapy, including another investigational drug, noncompliance, or consent withdrawal. Patients in all treatment arms who experienced disease progression (indeterminate and confirmed) by RECIST v1.1, continued benefit from their assigned treatment, and met criteria for treatment in the setting of disease progression could continue to receive their assigned treatment as long as clinical benefit was achieved. This included EP, which was limited to a maximum of four cycles for patients in the immunotherapy arm and a maximum of six cycles for patients in the control arm. 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. [Figure 2]Figure 2 shows the hierarchical multiple testing procedure with a gatekeeping strategy used in this disclosure to control type I error at a two-sided 5% significance level. The hypotheses were tested using a multiple testing procedure with an alpha comprehensive recycling strategy (Burman et al. A recycling framework for the construction of Bonferroni-based multiple tests. Stat Med 2009;28:739-61). Using this strategy, two primary analyses of OS and two secondary analyses of PFS were tested. Therefore, PFS was only tested within the multiple testing procedure if significance was achieved in both primary OS analyses. The overall 5% alpha was divided between the following primary endpoints as follows: an alpha level of 4% was assigned to the analysis of OS for durvalumab plus EP vs. EP, and an alpha level of 1% was assigned to the analysis of OS for durvalumab plus tremelimumab plus EP vs. EP. EP: platinum etoposide; H: hypothesis; ITT: intention to treat; OS: overall survival; PFS: progression-free survival. [Figure 3] Figure 3 shows overall survival in the intention-to-treat population. (3A) Kaplan-Meier graph of durvalumab + tremelimumab + EP vs. EP, (3B) Kaplan-Meier graph of durvalumab + EP vs. EP, (3C) subgroup analysis of durvalumab + EP vs. EP. CI: confidence interval, EP: platinum etoposide, OS: overall survival, PFS: progression-free survival. [Figure 4] Figure 4 shows progression-free survival and duration of response in the intent-to-treat population. (4A) Kaplan-Meier graph of progression-free survival for durvalumab + tremelimumab + EP vs. EP, (4B) Kaplan-Meier graph of progression-free survival for durvalumab + EP vs. EP, (4C) Kaplan-Meier graph of duration of response for durvalumab + tremelimumab + EP vs. EP, (4D) Kaplan-Meier graph of duration of response for durvalumab + EP vs. EP. [Figure 5] Figure 5 shows the best percent change from baseline in target lesion size. (5A) Durvalumab + tremelimumab + EP vs. EP. (5B) Durvalumab + EP vs. EP. [Figure 6]Figure 6 shows confirmed objective responses. Figure 6 shows the overall response rate per RECIST v1.1. Figure 6B shows the duration of response (DoR). OR: odds ratio. D+EP: durvalumab and EP (etoposide and carboplatin or cisplatin). DETAILED DESCRIPTION OF THE INVENTION

[0030] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0031] The following references provide those skilled in the art with general definitions of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0032] In this disclosure, the words "comprises," "comprising," "containing," and "having," etc., can have the meaning ascribed to them in U.S. patent law and can mean "includes," "including," etc. The terms "consisting essentially of" or "consists essentially" likewise have the meaning ascribed to them in U.S. patent law and are open-ended, allowing for the presence of more than what is recited but excluding prior art aspects, so long as the basic or novel characteristics of what is recited are not changed by the presence of more than what is recited.

[0033] As used herein, unless otherwise stated or clear from context, the term "or" is understood to be inclusive. Unless otherwise stated or clear from context, as used herein, the terms "a," "an," and "the" are understood to be singular or plural.

[0034] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within normal tolerances 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 indicated value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term "about."

[0035] The recitation of a list of chemical groups in any definition of a variable herein includes definition of that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable or aspect herein includes any single embodiment or embodiment in combination with any other embodiment or portion thereof.

[0036] Any composition or method provided herein can be combined with any one or more of the other compositions and methods provided herein.

[0037] Ranges provided herein are understood to be shorthand for all values ​​within that range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, and subranges 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, or 50.

[0038] "Anti-PD-L1 antibody" refers to an antibody or antigen-binding fragment thereof that selectively binds to a PD-L1 polypeptide. Exemplary anti-PD-L1 antibodies are described, for example, in U.S. Patent Nos. 8,779,108 and 9,493,565, which are incorporated herein by reference. In some aspects, durvalumab, avelumab, and atezolizumab are exemplary PD-L1 antibodies. In a further aspect, durvalumab is an exemplary PD-L1 antibody.

[0039] The term "durvalumab," as used herein, refers to an antibody (referred to as "2.14H9OPT") that selectively binds to PD-L1 and blocks PD-L1 binding to the PD-1 receptor and CD80 receptor, as disclosed in U.S. Patent No. 9,493,565, which is incorporated herein by reference in its entirety. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation within the constant domain of the IgG1 heavy chain that reduces binding to complement component C1q and Fcγ receptors, which are 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 xenograft models through a T cell-dependent mechanism.

[0040] "Anti-PD-1 antibody" means an antibody or antigen-binding fragment thereof that selectively binds to a PD-1 polypeptide. In some embodiments, nivolumab or pembrolizumab are exemplary PD-1 antibodies.

[0041] The term "tremelimumab," as used herein, refers to an antibody that selectively binds to the CTLA-4 polypeptide (referred to as "clone 11.2.1"), as disclosed in U.S. Pat. No. 8,491,895, which is incorporated herein by reference in its entirety. Tremelimumab is specific for human CTLA-4 and has no cross-reactivity with related human proteins. Tremelimumab blocks the inhibitory effects of CTLA-4, thus enhancing T cell activation. Tremelimumab exhibits minimal specific binding to Fc receptors, does not induce natural killer (NK) antibody-dependent cell-mediated cytotoxicity (ADCC) activity, and does not deliver an inhibitory signal after binding to and agglutinating on a plate.

[0042] A "complete response" (CR) refers to the disappearance of all lesions, measurable or not, and the absence of new lesions. This confirmation can be obtained using repeated serial assessments for ≥4 weeks from the date of initial documentation. New non-measurable lesions preclude a CR.

[0043] A "partial response" (PR) refers to a 2.50% reduction in tumor burden relative to baseline, confirmed using serial repeat assessments at least 4 weeks from the date of initial documentation.

[0044] "Progression" (PD) refers to an increase in tumor burden of 2-25% relative to the nadir. This confirmation can be obtained using serial repeat assessments for at least 4 weeks from the date of initial documentation. New non-measurable lesions do not define PD.

[0045] "Stable disease" (SD) refers to failure to meet the criteria for CR, PR, or PD. SD indicates failure to establish a 50% reduction in tumor burden compared to baseline and a 25% increase compared to nadir.

[0046] As referred to herein, "PD-L1" can refer to a polypeptide or polynucleotide sequence having at least about 85%, 95%, or 100% sequence identity to a PD-L1 sequence, or a fragment thereof. PD-L1 is also referred to in the art as B7-H1. In some embodiments, the PD-L1 polypeptide, or a 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.

[0047] PD-L1 polypeptide sequence (NCBI accession number NP_001254635; SEQ ID NO: 9): [ka]

[0048] In some embodiments, a "PD-L1 nucleic acid molecule" comprises a polynucleotide that encodes a PD-L1 polypeptide. An exemplary PD-L1 nucleic acid molecule sequence is provided in NCBI Accession No. NM_001267706.

[0049] PD-L1 nucleic acid sequence (NCBI accession number NM_001267706mRNA; SEQ ID NO: 10): [ka] [ka] [ka]

[0050] Programmed death-1 ("PD-1") is an approximately 31 kD type I membrane protein member of the extended CD28 / CTLA4 family of T cell regulatory factors (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. (2002) "Expression of Programmed Death 1 Ligands by Murine T Cells and APC,” J. Immunol. 169:5538-5545), and is expressed at low levels in natural killer (NK) T cells (Nishimura, H. et al. (2000) “Facilitation of Beta Selection and Modification of Positive Selection in the Thymus of PD-1-Deficient Mice,” J. Exp. Med. 191:891-898; Martin-Orozco et al. (2007) “Inhibitory Costimulation and Anti-Tumor Immunity,” Semin. J. Biol. 17(4):288-298).PD-1 is a receptor responsible for downregulation of the immune system following activation by binding to 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 Versus Coinhibition," J. Molec. Med. 83:193-202) (Lazar-Molnar, E. et al. (2008) "Crystal Structure of the Complex Between Programmed Death-1 (PD-1) and Its Ligand PD-L2,” Proc. Natl. Acad. Sci. (USA) 105(30):10483-10488). This process is exploited in many tumors through overexpression of PD-L1, resulting in suppression of the immune response.

[0051] 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 cancer (NSCLC), among others. Antagonistic inhibition of the PD-1 / PD-L1 interaction increases T cell activation and improves tumor cell recognition and elimination by the host immune system. The use of anti-PD-1 antibodies has been proposed to treat infections and tumors and to upregulate adaptive immune responses.

[0052] The term "antibody," as used in this disclosure, refers to an immunoglobulin or a fragment or derivative thereof, and encompasses any polypeptide comprising an antigen-binding site, whether produced in vitro or in vivo. This term includes, but is not limited to, polyclonal antibodies, monoclonal antibodies, monospecific antibodies, multispecific antibodies, nonspecific antibodies, humanized antibodies, single-chain antibodies, chimeric antibodies, synthetic antibodies, recombinant antibodies, hybrid antibodies, mutant antibodies, and grafted antibodies. For purposes of this disclosure, unless specifically modified by the term "intact," as in "intact antibody," the term "antibody" also encompasses 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 specifically bind PD-L1. Typically, such fragments will include the antigen-binding domain.

[0053] The terms "antigen-binding domain," "antigen-binding fragment," and "binding fragment" refer to a portion of an antibody molecule containing amino acids involved in the specific binding of the antibody to an antigen. If the antigen is large, the antigen-binding domain may bind only a portion of the antigen. The portion of the antigen molecule responsible for the specific interaction with the antigen-binding domain is called an "epitope" or "antigenic determinant." An antigen-binding domain usually comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH), but does not necessarily comprise both. For example, a so-called Fd antibody fragment consists only of the VH domain but still retains some of the antigen-binding function of an intact antibody.

[0054] Antibody binding fragments can be produced by recombinant DNA technology or by enzymatic or chemical cleavage of intact antibodies. Examples of binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. Antibodies other than "bispecific" or "bifunctional" antibodies are understood to have identical binding sites. Digestion of antibodies with the enzyme papain produces two identical antigen-binding fragments, also known as "Fab" fragments, and an "Fc" fragment, which lacks antigen-binding activity but has the ability to crystallize. Digestion of antibodies with the enzyme pepsin produces an F(ab')2 fragment, in which the two arms of the antibody molecule remain linked and contain two antigen-binding sites. The F(ab')2 fragment has the ability to cross-link antigen. "Fv," as used herein, refers to the minimum fragment of an antibody that retains both the antigen-recognition and antigen-binding sites. "Fab," as used herein, refers to an antibody fragment containing the constant domain of the light chain and the CHI domain of the heavy chain.

[0055] The term "mAb" refers to a monoclonal antibody. Antibodies of the present invention include, but are not limited to, whole native antibodies, bispecific antibodies, chimeric antibodies, Fab, Fab', single chain V region fragments (scFv), fusion polypeptides, and non-conventional antibodies.

[0056] The terms "isolated," "purified," or "biologically pure" refer to material that is free, to varying degrees, from components that normally accompany it as found in its natural state. "Isolated" indicates some degree of separation from the original source or environment. "Purified" indicates a greater degree of separation than isolation. A "purified" or "biologically pure" protein is sufficiently free from other substances so that any impurities do not substantially affect the biological properties of the protein or cause other adverse consequences.

[0057] "Specifically binds" refers to a compound (e.g., an antibody) that recognizes and binds to a molecule (e.g., a polypeptide) in a sample, e.g., a biological sample, but does not substantially recognize or bind to other molecules. For example, two molecules that specifically bind form a complex that is relatively stable under physiological conditions. Specific binding is characterized by high affinity and low to moderate capacity, and is distinguished from nonspecific binding, which usually has low affinity and moderate to high capacity. Generally, binding is determined by an affinity constant, K A is 10 6 M -1 or more preferably 10 8 M -1 If the binding affinity is higher than 0.05, it is considered specific. If necessary, nonspecific binding can be reduced by varying the binding conditions without substantially affecting specific binding. Those skilled in the art can use routine techniques to optimize appropriate binding conditions, such as antibody concentration, ionic strength of the solution, temperature, time allowed for binding, concentration of blocking agent (e.g., serum albumin, milk casein), etc.

[0058] As generally used herein, the terms "treat," "treating," "treatment," and the like refer to inhibiting, ameliorating, or slowing the progression of a disorder or disease and / or symptoms associated with the disorder or disease. It will be recognized, although not excluded, that treating a disorder, disease, or condition does not require the complete elimination of the disorder, disease, or condition, or associated symptoms. In certain embodiments, and in relation to NSCLC, "treat," "treating," or "treatment" can refer to achieving any one or combination of primary or secondary clinical endpoints.

[0059] array The durvalumab light chain variable region amino acid sequence is provided as SEQ ID NO:1.

[0060] The durvalumab heavy chain variable region amino acid sequence is provided as SEQ ID NO:2.

[0061] The durvalumab heavy chain variable region amino acid sequences of CDR1, CDR2, and CDR3 are provided as SEQ ID NO:3 (CDR1), SEQ ID NO:4 (CDR2), and SEQ ID NO:5 (CDR3).

[0062] The durvalumab light chain variable region amino acid sequences of CDR1, CDR2, and CDR3 are provided as SEQ ID NO:6 (CDR1), SEQ ID NO:7 (CDR2), and SEQ ID NO:8 (CDR3).

[0063] The present disclosure relates to a method of treating patients with extensive-stage small cell lung cancer (ES-SCLC), comprising administering to the patient a human anti-PD-L1 antibody in combination with etoposide and a platinum-based therapeutic agent. Additionally, the method may also include administering a human anti-CTLA-4 antibody. In particular, data obtained from the clinical results disclosed herein provide improved treatment methods and substantially redefine the existing standard of care (first-line treatment) for ES-SCLC. The disclosed treatment methods can provide substantial improvements in patient overall survival (OS), progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), or time to death.

[0064] Thus, in various aspects described herein, the disclosed methods provide a new first-line treatment option for treating patients with ES-SCLC.

[0065] In a first aspect, the disclosure provides a method of extending progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC), the method comprising treating the patient with a) a human anti-PD-L1 antibody and b) etoposide and a platinum-based therapy (EP). In one embodiment of the first aspect, the platinum-based therapy comprises cisplatin and / or carboplatin. In another embodiment of the first aspect, the human anti-PD-L1 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. In one embodiment of the first aspect, the human anti-PD-L1 antibody comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, 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, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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. In one embodiment of the first aspect, the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. In another embodiment of the first aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a fixed dose of 1500 mg. In another embodiment of the first aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a dose of 20 mg / kg. In another embodiment of the first aspect, the method comprises administering four cycles of the human anti-PD-L1 antibody. In an embodiment according to the first aspect, EP is administered at a dose of 80-100 mg / m per dose of the human anti-PD-L1 antibody. 2 of etoposide, and carboplatin with an area under the curve of 5 to 6 mg / mL / min or 75 to 80 mg / m 2 It is administered intravenously as a dose containing cisplatin.

[0066] In one embodiment of the first aspect, the method further comprises administering 1500 mg of the human anti-PD-L1 antibody intravenously Q4W after completion of the 4 cycles Q3W.

[0067] In one embodiment of the first aspect, the method further comprises administering a human anti-CTLA-4 antibody intravenously Q3W. In one embodiment, the human anti-CTLA-4 antibody is tremelimumab. In another embodiment, tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg / kg.

[0068] In another embodiment of the first aspect or a further embodiment of the first aspect, the method further comprises administering prophylactic cranial irradiation to the patient.

[0069] In another embodiment of the first aspect or other embodiments of the first aspect, the method further comprises treating the patient with a human anti-PD-1 antibody. In one embodiment, the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

[0070] In another embodiment of the first aspect, PFS is increased by at least about 5 months compared to treatment with EP alone.

[0071] In a second aspect, the disclosure provides a method of extending overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC), comprising treating the patient with a) a human anti-PD-L1 antibody and b) etoposide and a platinum-based therapy (EP). In one embodiment of the second aspect, the platinum-based therapy comprises cisplatin and / or carboplatin. In another embodiment of the second aspect, the human anti-PD-L1 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. In one embodiment of the second aspect, the human anti-PD-L1 antibody comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, 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, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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. In one embodiment of the second aspect, the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. In another embodiment of the second aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a fixed dose of 1500 mg. In another embodiment of the second aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a dose of 20 mg / kg. In another embodiment of the second aspect, the method comprises administering four cycles of the human anti-PD-L1 antibody. In an embodiment according to the second aspect, EP is administered at a dose of 80-100 mg / m per dose of the human anti-PD-L1 antibody. 2 of etoposide, and carboplatin with an area under the curve of 5 to 6 mg / mL / min or 75 to 80 mg / m 2 It is administered intravenously as a dose containing cisplatin.

[0072] In one embodiment of the second aspect, the method further comprises administering 1500 mg of the human anti-PD-L1 antibody intravenously Q4W after completion of 4 cycles Q3W.

[0073] In one embodiment of the second aspect, the method further comprises administering a human anti-CTLA-4 antibody intravenously Q3W. In one embodiment, the human anti-CTLA-4 antibody is tremelimumab. In another embodiment, tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg / kg.

[0074] In another embodiment of the second aspect or other embodiments of the second aspect, the method further comprises administering prophylactic cranial irradiation to the patient.

[0075] In another embodiment of the second aspect or other embodiments of the second aspect, the method further comprises treating the patient with a human anti-PD-1 antibody. In one embodiment, the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

[0076] In another embodiment of the second aspect, OS is extended by at least about 3 months compared to treatment with EP alone.

[0077] In a third aspect, the disclosure provides a method of improving overall response rate (ORR) in patients with extensive-stage small cell lung cancer (ES-SCLC), the method comprising treating the patient with a) a human anti-PD-L1 antibody and b) etoposide and a platinum-based therapy (EP). In one embodiment of the third aspect, the platinum-based therapy comprises cisplatin and / or carboplatin. In another embodiment of the third aspect, the human anti-PD-L1 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. In one embodiment of the third aspect, the human anti-PD-L1 antibody comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, 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, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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. In one embodiment of the third aspect, the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. In another embodiment of the third aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a fixed dose of 1500 mg. In another embodiment of the third aspect, the human anti-PD-L1 antibody is administered intravenously Q3W as a dose of 20 mg / kg. In another embodiment of the third aspect, the method comprises administering four cycles of the human anti-PD-L1 antibody. In an embodiment according to the third aspect, EP is administered at a dose of 80-100 mg / m per dose of the human anti-PD-L1 antibody. 2 of etoposide, and carboplatin with an area under the curve of 5 to 6 mg / mL / min or 75 to 80 mg / m 2 It is administered intravenously as a dose containing cisplatin.

[0078] In one embodiment of the third aspect, the method further comprises administering 1500 mg of the human anti-PD-L1 antibody intravenously Q4W after completion of 4 cycles Q3W.

[0079] In one embodiment of the third aspect, the method further comprises administering a human anti-CTLA-4 antibody intravenously Q3W. In one embodiment, the human anti-CTLA-4 antibody is tremelimumab. In another embodiment, tremelimumab is administered as a fixed dose of 75 mg or as a dose of 1 mg / kg.

[0080] In another embodiment of the third aspect or other embodiments of the third aspect, the method further comprises administering prophylactic cranial irradiation to the patient.

[0081] In another embodiment of the third aspect or any other embodiment of the third aspect, the method further comprises treating the patient with a human anti-PD-1 antibody. In one embodiment, the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

[0082] In another embodiment of the third aspect, the ORR is increased by at least 10% compared to treatment with EP alone.

[0083] In a fourth aspect, the present disclosure provides a method of treating ES-SCLC in a patient in need thereof, the method comprising administering durvalumab and EP to the patient, wherein durvalumab and EP are administered as first-line treatment, and optionally administering tremelimumab to the patient.

[0084] In some embodiments of any of the above aspects or any of the above aspects, the patient may express a gene (i.e., have a phenotype) associated with a therapeutic response to a therapy comprising a human anti-PD-L1 antibody. In some aspects, the patient is PD-L1(+). In other aspects, the patient is PD-L1(-). In some aspects, the patient is EGFR mutant(+). In other aspects, the patient is EGFR mutant(-) or wild-type. In some aspects, the patient may express any combination of PD-L1 and EGFR mutant phenotypes.

[0085] Further to the above aspects, the treatments disclosed herein may comprise administering an anti-PD-L1 antibody or antigen-binding fragment thereof intravenously at a dose of 10 mg / kg or 20 mg / kg once every two, three, or four weeks.

[0086] In addition to the above aspects, the treatments disclosed herein may comprise administering a fixed dose of 200, 250, 500, 1000, or 1500 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof intravenously once every two, three, or four weeks.

[0087] In embodiments of the above embodiments, the patient may express a gene (i.e., have a phenotype) associated with a therapeutic response to a treatment comprising a human anti-PD-L1 antibody. In some embodiments, the patient is PD-L1(+). In other embodiments, the patient is PD-L1(-). A sample was determined to be "PD-L1 positive" if it contained 25% or more tumor cells with PD-L1 membrane staining. The cutoff and scoring algorithm have been previously determined for durvalumab (Study CP1108; ClinicalTrials.gov number NCT01693562).

[0088] In some embodiments, the patient is EGFR mutated (+). In other embodiments, the patient is EGFR mutated (-) or wild-type. In some embodiments, the patient may express any combination of PD-L1 and EGFR mutated phenotypes.

[0089] In addition to the above aspects, the treatments disclosed herein can include administering a dose of a therapeutic agent (antibody and / or chemotherapeutic agent) about every 14 days, or every 3 weeks, or every 4 weeks, for up to 52 weeks or more.

[0090] Overall survival (OS) refers to the time from the date of treatment to death from any cause. OS can refer to overall survival rates within time periods such as 12 months, 18 months, and 24 months. Such periods can be identified, for example, as "OS24," which refers to the percentage of patients alive 24 months after the start of treatment, using the Kaplan-Meier estimate of overall survival at 24 months.

[0091] Progression-free survival (PFS) refers to the time from the date of treatment to the date of objective disease progression (RECIST 1.1) or death (from any cause in the absence of progression). In some embodiments, the methods provide increased PFS. In some embodiments, the methods provide a 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 months or more, up to about 5 years).

[0092] Duration of response (DoR) refers to the time from the date of the first documented response of complete response (CR) or partial response (PR) by RECIST 1.1 to the date of the first documented response of progression or death in the absence of progression. In embodiments, the method provides an increase in DoR of at least about 9 months to at least about 36 months.

[0093] Objective response rate (ORR) refers to the number (%) of patients with at least one visit response of complete response (CR) or partial response (PR) by RECIST 1.1. In embodiments, the method provides an increase in DoR of at least about 9 months to at least about 36 months.

[0094] The disclosed methods involve administering an immunotherapeutic agent (e.g., a human anti-PD-L1 antibody or a human anti-PD-1 antibody) in combination with a chemotherapeutic agent (e.g., etoposide and a platinum-based drug (e.g., cisplatin and / or carboplatin)).

[0095] As described above and exemplified herein, these methods treat patients with ES-SCLC.

[0096] Cancer staging can be performed using any commonly known and art-recognized test. In certain embodiments, cancer staging can include the American Joint Committee on Cancer's (AJCC's) TNM system. Generally, the TNM system provides the results of various tests and scans to determine the size and location of the primary tumor (tumor, T); whether the cancer has spread to lymph nodes, and if so, the location and number of involved lymph nodes (nodes, N); and whether the cancer has spread to other parts of the body, and if so, the extent and location of distant cancer (metastasis, M). While each type of cancer may have its own specific system, the TNM staging system generally uses a scaled scoring system for each letter.

[0097] For tumors, the "T" is associated with a number (e.g., 0-4) that describes the general tumor size, location, and whether it has invaded nearby tissue. Larger or more invasive tumors are given higher numbers, and depending on the cancer, further detail may be provided by adding a lowercase letter such as "a," "b," or "m" (if plural).

[0098] Similarly, for nodes, "N" can be associated with a number (e.g., 0-3) to describe whether cancer was found in a lymph node and can also indicate the number of lymph nodes containing cancer. Higher numbers are assigned if more lymph nodes are involved with the cancer.

[0099] In the case of metastasis, "M" indicates whether the cancer has spread to other parts of the body, and is labeled M0 if it has not spread, or M1 if it has spread.

[0100] The results of T, N, and M are combined to determine the stage of the cancer, typically one of four stages: Stage I (1) to IV (4). Some cancers also have a Stage 0 (zero). Stage 0 describes intraepithelial carcinoma that remains localized in the tissue of origin and has not spread to any nearby tissues. Cancers at this stage often have a very high chance of being cured, usually by removing the entire tumor through surgery. Stage I, or early cancer, is generally used to describe small cancers or tumors that have not grown deeply into nearby tissues and have not spread to lymph nodes or other parts of the body. Stages II and III describe larger cancers or tumors that have grown deeply into nearby tissues and may have spread to lymph nodes, but have not metastasized to other tissues. Stage IV describes cancer that has spread to other organs or parts of the body and is often identified as advanced or metastatic cancer.

[0101] Staging may include analysis of optional prognostic factors to provide chances of recovery and recommended treatments, which may include grading the cancer based on the appearance of the cancer cells, analysis of tumor marker expression, and analysis of tumor genetics.

[0102] The TNM system can be used for both SCLC and NSCLC, although SCLC is generally staged using a different system.

[0103] Staging of SCLC SCLC has two stages: "limited" and "extensive." Limited-stage SCLC indicates that the cancer is present on only one side of the chest and can be treated with one radiation field. Generally, limited-stage SCLC includes cancer that originates in only one lung and may have reached lymph nodes on the same side of the chest. An exception would be SCLC where the tumor has spread throughout one lung and the cancer is not confined to a small enough area to be treated with radiation therapy from one "port." Such cancers are considered extensive, even if they are present on only one side.

[0104] Second-stage SCLC, or "extensive" stage SCLC, is SCLC cancer that has spread beyond the radiation therapy treatment area of ​​one port, such as to the entire lung on one side, the other lung, lymph nodes on the other side of the chest, other parts of the body, or to the fluid around the lung.

[0105] Anti-PD-L1 antibody Antibodies that specifically bind and inhibit PD-L1 activity (e.g., bind to PD-1 and / or CD80) are useful in the methods disclosed herein.

[0106] Durvalumab is an exemplary anti-PD-L1 antibody that is selective for PD-L1 and blocks PD-L1 binding to the PD-1 and CD80 receptors. Durvalumab can attenuate PD-L1-mediated suppression of human T cell activation in vitro and inhibits tumor growth in xenograft models through a T cell-dependent mechanism. Other agents useful in the disclosed methods include agents that inhibit PD-L1 and / or PD-1, such as the human anti-PD-L1 antibodies avelumab and atezolizumab, or the human anti-PD-1 antibodies nivolumab and pembrolizumab.

[0107] In certain embodiments, the antibody used in the methods disclosed herein is any agent that disrupts the PD-1 / PD-L1 axis.

[0108] Information regarding 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 their entireties. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation within the constant domain of the IgG1 heavy chain that reduces binding to complement components C1q and Fcy receptors, which are responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC).

[0109] Durvalumab and antigen-binding fragments thereof used in the methods provided herein comprise a heavy chain and a light chain, or a heavy chain variable region and a light chain variable region. In certain embodiments, durvalumab or antigen-binding fragments thereof used in the methods provided herein comprise 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. In certain embodiments, durvalumab or antigen-binding fragments thereof used in the methods provided herein comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2, and CDR3 sequences defined by Kabat in SEQ ID NOs: 3-5, and the light chain variable region comprises the CDR1, CDR2, and CDR3 sequences defined by Kabat in SEQ ID NOs: 6-8. Those of skill in the art can readily identify Chothia-defined, Abm-defined, or other CDR definitions known to those of skill in the art. In certain aspects, durvalumab or an antigen-binding fragment thereof used in the methods provided herein comprises the CDR sequences of the variable heavy and variable light chains of the 2.14H9OPT antibody disclosed in U.S. Pat. Nos. 8,779,108 and 9,493,565, which are incorporated by reference in their entireties.

[0110] As disclosed herein, patients with ES-SCLC may 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 (e.g., 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, for the treatment of ES-SCLC. Some or all of these therapeutic agents may be administered once in cycles lasting 2, 3, 4, or 6 weeks (or shorter or longer), with each cycle being repeated as long as the treatment benefits the patient. In a further aspect, after completing one or more cycles including some or all of these therapeutic agents, the patient may further receive subsequent doses with a subset of the therapeutic agents (e.g., only a single therapeutic agent). Subsequent doses may be administered at various time intervals depending on the patient's age, weight, clinical evaluation, tumor burden, and / or other factors, including the judgment of the treating physician.

[0111] In certain embodiments, the dosing interval can be every three weeks. In certain embodiments, the dosing interval can be every four weeks. In further embodiments, the dosing interval can be every two months (e.g., during the follow-on dosing period and / or maintenance phase).

[0112] The amount of durvalumab or an antigen-binding fragment thereof administered to a patient may be adjusted according to and depend on various parameters, such as the patient's age, weight, clinical evaluation, tumor burden, and / or other factors, including the judgment of the attending physician. In some embodiments, the dose is a fixed dose.

[0113] In certain embodiments, the patient is administered one or more doses of durvalumab, wherein the dose is about 1 mg / kg. In certain embodiments, the patient is administered one or more doses of durvalumab, wherein the dose is about 3 mg / kg. In certain embodiments, the patient is administered one or more doses of durvalumab, wherein the dose is about 10 mg / kg. In certain embodiments, the patient is administered one or more doses of durvalumab, wherein the dose is about 15 mg / kg. In certain embodiments, the patient is administered one or more doses of durvalumab, wherein the dose is about 20 mg / kg.

[0114] In certain embodiments, the patient receives one or more doses of durvalumab, the dose being a fixed dose of 1500 mg.

[0115] In certain embodiments, patients receive 1500 mg of durvalumab every four weeks.

[0116] In some embodiments, the administration of an anti-PD-L1 antibody such as durvalumab is administered as a fixed dose of 1500 mg and tremelimumab is administered as a fixed dose of 75 mg.

[0117] In some embodiments, administration of an anti-PD-L1 antibody such as durvalumab is administered at a 20 mg / kg body weight-based dose and tremelimumab is administered as a 1 mg / kg body weight-based dose.

[0118] In some embodiments, patients receive durvalumab at a 1500 mg dose, optionally tremelimumab at a 75 mg dose, etoposide at a dose of 80-100 mg / mL, and carboplatin at an AUC dose of 5-6 mg / mL / min or 75-80 mg / mL 2 The dose of cisplatin will be administered intravenously Q3W.

[0119] In certain aspects, administration of the therapeutic agents disclosed herein is by parenteral administration. For example, durvalumab or an antigen-binding fragment thereof and EP can be administered by intravenous infusion or subcutaneous injection. In some aspects, administration is by intravenous infusion.

[0120] In certain aspects, durvalumab or an antigen-binding fragment thereof is administered in accordance with the methods provided herein in combination or conjunction with additional cancer treatments, including, but not limited to, chemotherapeutic agents such as vemurafenib, erlotinib, afatinib, cetuximab, bevacizumab, erlotinib, or pemetrexed, or other chemotherapeutic agents, and radiation or any other anti-cancer treatment.

[0121] The methods provided herein can provide additional clinical benefits beyond those specifically identified and indicated by the data, including, for example, reduction in tumor size, delay in tumor growth, or maintenance of steady state. In certain embodiments, the reduction in tumor size can be significant based on appropriate statistical analysis. The reduction in tumor size can be measured by comparison to the patient's tumor size at baseline, a comparison to an expected tumor size, a comparison to an expected tumor size based on a larger patient population, or a comparison to the tumor size of a control population. In certain embodiments provided herein, administration of durvalumab with etoposide and cisplatin and / or carboplatin can reduce tumor size by at least 25%, at least 50%, or at least 75%.

[0122] The methods provided herein can reduce or slow tumor growth. In some aspects, the reduction or slowing can be statistically significant. The reduction in tumor growth can be measured by comparison to the patient's tumor growth at baseline, by comparison to expected tumor growth, by comparison to expected tumor growth based on a large patient population, or by comparison to tumor growth in a control population.

[0123] According to the methods provided herein, administration of a PD-L1 antibody (e.g., durvalumab) or its antigen-binding fragment can result in desirable pharmacokinetic parameters. Total drug exposure can be estimated using the "area under the curve" (AUC). "AUC(tau)" refers to the AUC to the end of the administration period, while "AUC(inf)" refers to the AUC to infinity. Administration can result in an AUC(tau) of about 100 to about 2,500 dl-g / mL. Administration can result in a maximum observed concentration (Cmax) of about 15 to about 350 dl-g / mL. The half-life of durvalumab or its antigen-binding fragment can be about 5 to about 25 days. Furthermore, the clearance of durvalumab or its antigen-binding fragment can be about 1 to 10 mL / day / kg.

[0124] As provided herein, durvalumab or an antigen-binding fragment thereof can also reduce free PD-L1 levels. Free PD-L1 refers to PD-L1 that is not bound (e.g., by durvalumab). In some embodiments, PD-L1 levels are reduced by at least 80%. In some embodiments, PD-L1 levels are reduced by at least 90%. In some embodiments, PD-L1 levels are reduced by at least 95%. In some embodiments, PD-L1 levels are reduced by at least 99%. In some embodiments, PD-L1 levels are cleared after administration of durvalumab or an antigen-binding fragment thereof. In some embodiments, administration of durvalumab or an antigen-binding fragment thereof reduces the rate of increase in PD-L1 levels, for example, compared to the rate of increase in PD-L1 levels before administration of durvalumab or an antigen-binding fragment thereof.

[0125] 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 skill of one in the art. Such techniques are explained fully in such references as "Molecular Cloning: A Laboratory Manual," second edition (Sambrook, 1989); "Oligonucleotide Synthesis" (Gait, 1984); "Animal Cell Culture" (Freshney, 1987); "Methods in Enzymology" and "Handbook of Experimental Immunology" (Weir, 1996); "Gene Transfer Vectors for Mammalian Cells" (Miller and Calos, 1987); "Current Protocols in Molecular Biology" (Ausubel, 1987); "PCR: The Polymerase Chain Reaction" (Mullis, 1994); and "Current Protocols in Immunology" (Coligan, 1991).

[0126] The following examples provide illustrations of some of the embodiments and aspects described above and are not intended to limit the scope of the invention as claimed. [Example]

[0127] Example 1: Clinical evaluation of durvalumab in combination with EP, with or without tremelimumab, as first-line treatment in patients with ES-SCLC Most patients with SCLC have extensive-stage disease (ES) at diagnosis and have a poor prognosis. Recently, immunotherapy has shown clinical activity in ES-SCLC. This example presents results from a phase 3, randomized, open-label, sponsor-blinded trial (CASPIAN, ClinicalTrials.gov number NCT03043872) evaluating the efficacy and safety of durvalumab in combination with EP, with or without tremelimumab, as first-line treatment for patients with ES-SCLC.

[0128] patient Eligible patients included treatment-naïve adults with histologically or cytologically confirmed ES-SCLC. Patients also had a World Health Organization (WHO) performance status score of 0 or 1, measurable disease per RECIST v1.1, and a life expectancy of 12 weeks or more from study entry. Patients with brain metastases were eligible if they were asymptomatic or stable on steroids and anticonvulsants for at least one month before study enrollment.

[0129] Key exclusion criteria included a history of radiation therapy to the chest or planned consolidative thoracic radiation therapy; active or past autoimmune or inflammatory disease; autoimmune paraneoplastic syndrome requiring systemic treatment; a history of active primary immunodeficiency; and uncontrolled intercurrent illness or active infection.

[0130] Design and Treatment Patients were randomized in a 1:1:1 ratio to receive durvalumab 1500 mg + EP, durvalumab 1500 mg + tremelimumab 75 mg + EP, or EP (Figure 1). In all three study arms, chemotherapy consisted of etoposide 80–100 mg / m 2 (administered on days 1 to 3 of each cycle) and carboplatin or cisplatin 75 to 80 mg / m with an area under the curve of 5 to 6 mg / mL / min 2The randomization consisted of EP plus durvalumab (administered on day 1 of each cycle). Randomization was stratified by the planned platinum agent. Patients in the immunotherapy group received up to four cycles of EP plus durvalumab every three weeks (q3w), followed by a maintenance dose of durvalumab 1500 mg every four weeks (q4w). Patients in the EP group could receive two additional cycles of EP (up to a total of six cycles) and prophylactic cranial irradiation (PCI). Patients continued treatment until disease progression, unacceptable toxicity, or other discontinuation criteria as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), were met. Continuation of study treatment after disease progression was permitted if evidence of clinical benefit was observed (Figure 1). Crossover from the EP group to the immunotherapy plus EP group was not permitted during the study. The general dosing scheme is shown in Table 1.

[0131] [Table 1]

[0132] Endpoints and Evaluation Tumor imaging was performed every 6 weeks for the first 12 weeks, then every 8 weeks until objective disease progression was confirmed. Survival was assessed every 2 months after treatment discontinuation. Adverse events (AEs) were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.03.

[0133] The primary endpoint was OS (time from randomization to death from any cause). Secondary endpoints included progression-free survival (PFS; time from randomization to date of objective disease progression or death from any cause without progression), objective response rate (ORR), OS at 18 and 24 months, PFS at 6 and 12 months, and safety. PFS and ORR were assessed according to RECIST v1.1.

[0134] statistical analysis The study was considered positive if OS was significantly longer with durvalumab plus EP or durvalumab plus tremelimumab plus EP than with EP alone. A hierarchical multiple testing procedure with a gatekeeping strategy was used across the primary OS and secondary PFS analyses to control the type I error to 5% (two-sided) (Figure 2). Alphas of 4% and 1% were assigned to the primary endpoints of OS comparing durvalumab plus EP vs. EP and durvalumab plus tremelimumab + EP vs. EP, respectively. PFS was to be formally tested within the multiple testing procedure only if both primary OS analyses were significant.

[0135] For the final analysis of OS, approximately 795 patients needed to be randomized 1:1:1 to obtain 425 events in the durvalumab + EP group and the EP group overall, and 425 events (80% maturity) in the durvalumab + tremelimumab + EP group and the EP group overall. Sample size assumptions are detailed in Table 2.

[0136] [Table 2]

[0137] Efficacy data were analyzed on an intention-to-treat basis, including all randomized patients, regardless of whether they actually received treatment. Safety analyses included all patients who received at least one dose of study drug. OS and PFS were analyzed using the stratified log-rank test, adjusting for the planned platinum agent (carboplatin or cisplatin), with HRs and 95% confidence intervals (CIs) estimated using a Cox proportional hazards model. Survival curves for OS and PFS were estimated using the Kaplan-Meier method. Sensitivity analyses for OS included consideration of censoring patterns to exclude attrition bias. Sensitivity analyses for PFS included assessment of attrition bias and assessment time bias. Odds ratios and 95% CIs for comparing ORR between treatment groups were calculated using a logistic regression model, adjusting for the planned platinum agent.

[0138] result Patients and Treatment During the study, 972 patients were screened, 167 of whom were excluded, and 805 were randomly assigned to D+T+EP (n = 268), D+EP (n = 268), or EP alone (n = 269). Baseline demographics were generally well balanced between groups (Table 3). Across all groups, the median age was 63 years (IQR 57-68), most patients were male (576 of 805 [72%]), current or former smokers (753 [94%]), and had stage IV disease at diagnosis (735 [91%]). Numerically, the D+T+EP group was more likely to have a baseline WHO performance status score of 0, be male, have brain or CNS metastases, and have liver metastases than the D+EP and EP groups.

[0139] [Table 3]

[0140] Of the 795 patients who received chemotherapy, 618 (78%) received carboplatin and 198 (25%) received cisplatin. The median (IQR) overall chemotherapy treatment duration was 12.3 (12.0-13.5) weeks, 12.1 (12.0-13.1) weeks, and 19.0 (12.6-20.3) weeks in the D+T+EP, D+EP, and EP groups, respectively (Table 4). More than 80% of patients in each treatment group received at least four cycles of chemotherapy. Patients in the D+T+EP group had less exposure to durvalumab compared with those in the D+EP group (Table 4). The median (IQR) overall durvalumab treatment duration 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) weeks in the D+T+EP group and 7 (6-11) weeks in the D+EP group. 161 of 266 treated patients (61%) in the D+T+EP group received the planned 5 doses of tremelimumab (Table 4).

[0141] [Table 4]

[0142] Effectiveness In the interim analysis, the confirmed ORR was higher with durvalumab plus EP than with EP (67.9% vs. 57.6%; odds ratio, 1.56; 95% CI, 1.095-2.218) (Figure 6 and Table 5). Six patients (2.2%) treated with durvalumab plus EP and two patients (0.7%) treated with EP achieved a confirmed complete response. The median duration of response was 5.1 months for both patients treated with durvalumab plus EP and EP. Among responding patients, the proportion of those with ongoing responses at 12 months was higher with durvalumab plus EP than with EP (22.7% vs. 6.3%).

[0143] [Table 5]

[0144] At the time of data cutoff, the median follow-up period for OS among censored patients was 25.1 months (IQR 22.3-27.9). Thirty of 268 patients (11%) in the D+T+EP group and 32 of 268 patients (12%) in the D+EP group continued durvalumab treatment. One hundred seventeen of 268 patients (44%) in the D+T+EP group, 123 of 268 patients (46%) in the D+EP group, and 125 of 269 patients (46%) in the EP group subsequently received at least one systemic anticancer therapy, and nearly all patients received chemotherapy (Table 6). A small number of patients subsequently received immunotherapy: three (1%) in the D+T+EP group, six (2%) in the D+EP group, and 17 (6%) in the EP group. The use of two or more subsequent line systemic anticancer therapies was numerically lower in the D+T+EP group (31 [12%] patients) compared with the D+EP group (51 [19%]) and the EP group (49 [18%]). Twenty-two of 269 patients (8%) in the EP group underwent PCI after chemotherapy. Additionally, PCI use after study drug discontinuation was reported in 7 of 268 patients (3%) in the D+T+EP group.

[0145] [Table 6]

[0146] At the final analysis data cutoff, 438 deaths (81.6% maturity) were observed in the D+T+EP and EP groups: 207 patients (77%) in the D+T+EP group and 231 patients (86%) in the EP group. Based on the number of events observed at the data cutoff, the multiplicity-adjusted two-sided alpha consumed in the final analysis of OS for D+T+EP versus EP was 4.18% (i.e., a p-value of less than 0.0418 was considered statistically significant). A numerical improvement in OS was observed with D+T+EP versus EP; HR 0.82 (95% CI 0.68-1.00; p = 0.0451; Figure 3A). Median OS was 10.4 months (95% CI 9.6-12.0) for D+T+EP compared with 10.5 months (9.3-11.2) for EP; 18-month OS rate was 30.7% (25.2-36.4) for D+T+EP compared with 24.8% (19.7-30.1) for EP; and 24-month OS rate was 23.4% (18.4-28.8) for D+T+EP compared with 14.4% (10.3-19.2) for EP.

[0147] At data cutoff, 229 of 268 patients (85%) in the D+T+EP group and 236 of 269 patients (88%) in the EP group had progressed or died. The HR for PFS for D+T+EP versus EP was 0.84 (95% CI 0 70–1 01; Figure 4A). The median PFS was 4.9 months (95% CI 4.7-5.9) in the D+T+EP group compared with 5.4 months (4.8-6.2) in the EP group; the 12-month PFS rate was 16.9% (12.6-21.7) in the D+T+EP group compared with 5.3% (2.9-8.8) in the EP group; and the 24-month PFS rate was 11.5% (7.9-15.8) in the D+T+EP group compared with 2.9% (1.2-5.8) in the EP group.

[0148] The proportion of patients with an investigator-assessed pending objective response was similar in the D+T+EP group (198 of 267 patients [74%]) and the EP group (190 of 269 patients [71%]); odds ratio [OR] 1.19 (95% CI 0.82-1.75; Table 7). The proportion of patients with a confirmed objective response in the D+T+EP group (post hoc analysis) (156 of 267 patients [58%]) was the same as in the EP group (156 of 269 patients [58%]); OR 1.02 (0.72-1.44). The median (IQR) best reduction in target lesion size from baseline 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 Figure 5A. For patients with confirmed responses, the median duration of response was similar in the D+T+EP (5.2 months [95% CI 4.9-5.6]) and EP (5.1 months [4.8-5.3]) groups (Figure 4C). The estimated proportion of patients with sustained response was higher with D+T+EP than with EP at both 12 months (24.9% [18.4-3.0] vs. 7.3% [3.8-12.4]) and 24 months (17.2% [11.4-24.0] vs. 3.9% [1.4-8.4]).

[0149] At the final analysis data cutoff, 441 deaths (82.1% maturity) were observed in the D+EP and EP groups: 210 patients (78%) in the D+EP group and 231 patients (86%) in the EP group. The OS benefit observed in the interim analysis of D+EP compared with EP persisted with an additional 11 months of follow-up; in this updated analysis, the OS HR was 0.75 (95% CI 0.62-0.91; nominal p=0.0032; Figure 3B). Median OS was 12.9 months (95% CI 11.3-14.7) with D+EP, and the 24-month OS rate was 22.2% (17.3-27.5). As observed in the interim analysis, the OS HR consistently favored D+EP over EP in all prespecified patient subgroups, as well as in the posthoc subgroup defined by baseline liver metastases (Figure 3C).

[0150] At the time of data cutoff, 234 of 268 patients (87%) in the D+EP group had progressed or died. PFS favored D+EP compared with EP, with a HR of 0.80 (95% CI 0.66-0.96; Figure 4B). The median PFS was 5.1 months (95% CI 4.7-6.2) with D+EP, and the 12- and 24-month PFS rates were 17.9% (13.5-22.8) and 11.0% (7.5-15.2), respectively.

[0151] The proportion of patients with confirmed objective responses was higher in the D+EP group (182 of 268 [68%]) than in the EP group (58%); OR 1.53 (95% CI 1.08-2.18; Table 6). The median (IQR) best reduction in target lesion size from baseline was -60.4% (-72.9, -44.3) in the D+EP group. The depth of response is shown in Figure 5B. Among patients with confirmed responses, the median duration of response was similar in the D+EP and EP groups (Figure 4D). The proportion of patients with ongoing responses at 12 and 24 months in the D+EP group (23.2% [95% CI 17.3-29.7] and 13.5% [8.7-19.3]) was higher than in the EP group (7.3% and 3.9%; see above) at both time points.

[0152] [Table 7]

[0153] safety Treatment-related AEs, serious AEs, and AEs leading to discontinuation are listed in Table 8.

[0154] [Table 8]

[0155] [Table 9]

[0156] Consideration CASPIAN is the first pivotal trial to demonstrate a significant survival benefit from PD-1 / PD-L1 blockade in combination with etoposide and chemotherapy with carboplatin or cisplatin. This represents an important therapeutic advance, given that in recent years (2014–2016), cisplatin-containing chemotherapy was used in 27–42% of patients in the first-line treatment of ES-SCLC in various regions of the world. (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).

[0157] D+EP met the primary endpoint of improved survival compared with EP alone at a 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 randomized, controlled, open-label, phase 3 trial. Lancet 2019;394:1929-39). This updated analysis, with a median follow-up of more than 2 years, demonstrated a sustained improvement in OS with D+EP. The proportion of surviving patients was numerically higher with D+EP compared with EP at all landmark time points, with 24-month OS rates of 22.2% with D+EP versus 14.4% with EP, and the separation of Kaplan-Meier curves was maintained until the end of follow-up. The OS benefit of D+EP compared with EP was consistently demonstrated in all patient subgroups, including patients treated with cisplatin at baseline and those with brain metastases. In the updated analysis, PFS was favorable with D+EP compared with EP, with a HR of 0.80 (95% CI 0.66-0.96). PFS rates were numerically higher with D+EP than with EP at 12 months (17.9% vs. 5.3%) and 24 months (11.0% vs. 2.9%). Both the unconfirmed and confirmed objective response rates were approximately 10% higher with D+EP than with EP, consistent with the interim analysis. Furthermore, a higher proportion of patients remained in response with D+EP than with EP at both 12 months (23.2% vs. 7.3%) and 24 months (13.5% vs. 3.9%). Furthermore, after 1 year of follow-up, D+EP continued to demonstrate a manageable safety profile, consistent with the interim analysis and the established safety profiles of the individual agents.

[0158] The Kaplan-Meier tails for OS were similar in both immunotherapy arms, with more than 20% of patients in each arm still alive at 24 months. This suggests that adding durvalumab to EP, followed by maintenance durvalumab with a convenient 4-week dosing schedule, provides consistent and durable benefit in patients with ES-SCLC. The durability of benefit is particularly noteworthy in this aggressive disease, where it has historically been difficult to demonstrate long-term survival benefit. The Kaplan-Meier tails for PFS also showed similarities between the immunotherapy arms. In both durvalumab arms, nearly 20% of patients were progression-free at 12 months (compared to 5% in the EP arm), and the observation that many of these patients remained progression-free at 24 months suggests that a proportion of patients with ES-SCLC may derive long-term clinical benefit from D+EP.

[0159] This is also the first reported phase 3 trial evaluating dual immune checkpoint blockade in combination with chemotherapy in ES-SCLC. Although median OS for D+T+EP was similar to that for EP, the Kaplan-Meier curves for the D+T+EP group began to separate from the EP curve after 10 months. Specifically, the 24-month OS rate was 23.4% in the D+T+EP group compared with 14.4% in the EP group. The HR for PFS was 0.84 for D+T+EP vs. EP, with the associated 95% CI crossing 1 (0.70-1.01). Similar to OS, the Kaplan-Meier curve separation was slow, and the 12- and 24-month PFS rates were numerically higher for D+T+EP vs. EP (16.9% vs. 5.3% and 11.5% vs. 2.9%, respectively). Confirmed objective response rates and median duration of response were similar between the D+T+EP and EP groups. However, the proportion of patients with sustained responses at both 12 and 24 months was higher with D+T+EP than with EP.

[0160] In conclusion, the results of this randomized, open-label, phase 3 trial demonstrated that the addition of durvalumab to EP conferred a durable OS benefit compared with a robust control arm in patients with ES-SCLC. Safety findings across all arms were consistent with the known safety profiles of the individual agents. These results support the use of D+EP as a new standard of care for first-line treatment of ES-SCLC, providing flexibility in platinum agent options and a 4-weekly maintenance dosing schedule that expands treatment options for patients and physicians.

[0161] Other Aspects From the foregoing, it will be apparent that variations and modifications may be made to the invention described herein to adapt it to various uses and conditions, and such embodiments are within the scope of the following claims.

[0162] The recitation of a list of elements in any definition of a variable herein includes definition of the variable as any single element or combination (or subcombination) of the listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0163] All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

[0164] Sequence Listing SEQ ID NO:1- EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK SEQ ID NO:2- [ka] 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 SEQ ID NO:8-VL CDR3-QQYGSLPWT

Claims

1. 1. A method for extending progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC), comprising: a) Human anti-PD-L1 antibody and b) etoposide and platinum-based drugs (EP) treating said patient with

2. 10. The method of claim 1, wherein the platinum-based therapeutic agent comprises cisplatin and / or carboplatin.

3. 2. The method of claim 1, wherein the human anti-PD-L1 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.

4. The human anti-PD-L1 antibody The method of claim 1, comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, a VH CDR2 having the amino acid sequence of SEQ ID NO: 4, a VH CDR3 having the amino acid sequence of SEQ ID NO: 5, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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.

5. 2. The method of claim 1, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.

6. 2. The method of claim 1, wherein the human anti-PD-L1 antibody is administered intravenously as a fixed dose of 1500 mg every three weeks (Q3W).

7. 2. The method of claim 1, wherein the human anti-PD-L1 antibody is administered intravenously Q3W at a dose of 20 mg / kg.

8. The method of claim 6 or 7, comprising administration of four cycles of the human anti-PD-L1 antibody.

9. EP is 80-100 mg / m per dose of human anti-PD-L1 antibody. ２ etoposide, and carboplatin with an area under the curve of 5-6 mg / mL / min or 75-80 mg / m ２ The method of any one of claims 6 to 8, wherein the cisplatin is administered intravenously as a dose containing cisplatin of 0.1 mg / kg or more.

10. 10. The method of any one of claims 6-9, further comprising administering 1500 mg of a human anti-PD-L1 antibody intravenously Q4W after completion of 4 cycles Q3W.

11. The method of any one of claims 6 to 9, further comprising administering a human anti-CTLA-4 antibody intravenously Q3W.

12. The method of claim 11, wherein the human anti-CTLA-4 antibody is tremelimumab.

13. 13. The method of claim 12, wherein tremelimumab is administered as a fixed dose of 75 mg.

14. 13. The method of claim 12, wherein tremelimumab is administered as a dose of 1 mg / kg.

15. The method of any one of claims 1 to 14, further comprising administering prophylactic cranial irradiation to the patient.

16. The method of any one of claims 1 to 15, further comprising treating the patient with a human anti-PD-1 antibody.

17. 17. The method of claim 16, wherein the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

18. 10. The method of claim 1, wherein PFS is increased by at least about 5 months compared to treatment with EP alone.

19. 1. A method of extending overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC), comprising: a) Human anti-PD-L1 antibody and b) etoposide and platinum-based drugs (EP) treating said patient with

20. 20. The method of claim 19, wherein the platinum-based therapeutic agent comprises cisplatin and / or carboplatin.

21. 20. The method of claim 19, wherein the human anti-PD-L1 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.

22. The human anti-PD-L1 antibody 20. The method of claim 19, comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, a VH CDR2 having the amino acid sequence of SEQ ID NO: 4, a VH CDR3 having the amino acid sequence of SEQ ID NO: 5, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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.

23. 20. The method of claim 19, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.

24. 20. The method of claim 19, wherein the human anti-PD-L1 antibody is administered intravenously Q3W as a fixed dose of 1500 mg.

25. 20. The method of claim 19, wherein the human anti-PD-L1 antibody is administered intravenously Q3W at a dose of 20 mg / kg.

26. The method of claim 24 or 25, comprising administration of four cycles of the human anti-PD-L1 antibody.

27. EP is 80-100 mg / m per dose of human anti-PD-L1 antibody. ２ etoposide, and carboplatin with an area under the curve of 5-6 mg / mL / min or 75-80 mg / m ２ 27. The method of any one of claims 24 to 26, wherein the cisplatin is administered intravenously as a dose containing cisplatin of 0.1 mg / kg or more.

28. 28. The method of any one of claims 24-27, further comprising administering 1500 mg of human anti-PD-L1 antibody intravenously Q4W after completion of 4 cycles Q3W.

29. 28. The method of any one of claims 24 to 27, further comprising administering a human anti-CTLA-4 antibody intravenously Q3W.

30. 30. The method of claim 29, wherein the human anti-CTLA-4 antibody is tremelimumab.

31. 31. The method of claim 30, wherein tremelimumab is administered as a fixed dose of 75 mg.

32. 31. The method of claim 30, wherein tremelimumab is administered as a dose of 1 mg / kg.

33. 33. The method of any one of claims 19 to 32, further comprising administering prophylactic cranial irradiation to the patient.

34. The method of any one of claims 19 to 33, further comprising treating the patient with a human anti-PD-1 antibody.

35. 35. The method of claim 34, wherein the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

36. 20. The method of claim 19, wherein OS is extended by at least about 3 months compared to treatment with EP alone.

37. 1. A method for improving overall response rate (ORR) in patients with extensive-stage small cell lung cancer (ES-SCLC), comprising: a) Human anti-PD-L1 antibody and b) etoposide and platinum-based drugs (EP) treating said patient with

38. 38. The method of claim 37, wherein the platinum-based therapeutic agent comprises cisplatin and / or carboplatin.

39. 38. The method of claim 37, wherein the human anti-PD-L1 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.

40. The human anti-PD-L1 antibody 38. The method of claim 37, comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 3, a VH CDR2 having the amino acid sequence of SEQ ID NO: 4, a VH CDR3 having the amino acid sequence of SEQ ID NO: 5, a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, 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.

41. 38. The method of claim 37, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.

42. 38. The method of claim 37, wherein the human anti-PD-L1 antibody is administered intravenously Q3W as a fixed dose of 1500 mg.

43. 38. The method of claim 37, wherein the human anti-PD-L1 antibody is administered intravenously Q3W at a dose of 20 mg / kg.

44. The method of claim 42 or 43, comprising administration of four cycles of the human anti-PD-L1 antibody.

45. EP is 80-100 mg / m per dose of human anti-PD-L1 antibody. ２ etoposide, and carboplatin with an area under the curve of 5-6 mg / mL / min or 75-80 mg / m ２ 45. The method of any one of claims 42 to 44, wherein the cisplatin is administered intravenously as a dose containing cisplatin.

46. 46. ​​The method of any one of claims 42-45, further comprising administering 1500 mg of a human anti-PD-L1 antibody intravenously Q4W after completing four cycles of therapy.

47. 46. ​​The method of any one of claims 42-45, further comprising administering a human anti-CTLA-4 antibody intravenously Q3W.

48. 48. The method of claim 47, wherein the human anti-CTLA-4 antibody is tremelimumab.

49. 49. The method of claim 48, wherein tremelimumab is administered as a fixed dose of 75 mg.

50. 49. The method of claim 48, wherein tremelimumab is administered as a dose of 1 mg / kg.

51. 51. The method of any one of claims 37 to 50, further comprising administering prophylactic cranial irradiation to the patient.

52. The method of any one of claims 37 to 51, further comprising treating the patient with a human anti-PD-1 antibody.

53. 53. The method of claim 52, wherein the human anti-PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®).

54. 38. The method of claim 37, wherein the ORR is increased by at least 10% compared to treatment with EP alone.

55. 1. A method of treating ES-SCLC in a patient in need thereof, comprising administering to said patient durvalumab and EP, wherein said durvalumab and EP are administered as first-line treatment, and optionally administering to said patient tremelimumab.

Images