Compositions and methods for treating late-stage lung cancer

Abstract

To provide compositions for use in methods of increasing the overall survival (OS) of a patient with unresectable non-small-cell lung cancer (NSCLC).SOLUTION: The compositions comprise a human anti-PD-L1 antibody. The methods of increasing the overall survival (OS) comprises: a) treating the patient with a human anti-PD-L1 antibody, where the patient is a stage III patient who has not progressed following definitive chemoradiation therapy; and b) increasing the overall survival (OS) in the patient relative to a placebo.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] Approximately one-third of patients with non-small cell lung cancer (NSCLC) present with locally advanced stage III disease at diagnosis. The standard of care for patients with good performance status (PS) and unresectable stage III NSCLC is platinum-based doublet chemotherapy with concurrent radiation therapy. However, the median progression-free survival (PFS) with concurrent chemoradiotherapy (cCRT) in this population is approximately 8 months, with only 15% of patients surviving at 5 years. Additionally, there have been no major advances in this setting for many years. Thus, there remains a significant unmet need for novel therapeutic approaches that increase patient survival beyond cCRT.

[0002] Programmed death-ligand 1 (PD-L1) on tumor and myeloid cells within the tumor microenvironment binds to and inhibits the activity of the immune checkpoint protein PD-1 on activated T cells. Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody that blocks the binding of PD-L1 to PD-1 and CD80, allowing T cells to recognize and kill tumor cells. Durvalumab has demonstrated potent antitumor activity in early clinical trials across multiple advanced solid tumors and is approved for locally advanced or metastatic post-platinum urothelial carcinoma.

[0003] In addressing the need for improved methods for the clinical management of late-stage cancer, the present disclosure provides methods comprising the administration of durvalumab to patients with late-stage, locally advanced, unresectable NSCLC whose disease has not progressed after chemoradiotherapy (cCRT). As disclosed herein, the methods provide a significant and unexpected advancement over the existing standard of care in patients with late-stage, locally advanced, unresectable NSCLC who have not responded to chemoradiotherapy (cCRT). Summary of the Invention [Means for solving the problem]

[0004] The present disclosure relates generally to methods of treating late-stage (e.g., clinical stage III or IV), unresectable non-small cell lung cancer (NSCLC) in patients identified as not progressing after definitive chemoradiotherapy with antibodies that inhibit PD1 / PD-L1 activity.

[0005] In one aspect, the disclosure provides a method of extending progression-free survival (PFS) in patients with unresectable non-small cell lung cancer (NSCLC), the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

[0006] In another embodiment, the method provides an increase in PFS of at least 5 months compared to placebo. In a further embodiment, the method provides an increase in PFS of at least 13 months compared to placebo.

[0007] In one aspect, the disclosure provides a method of increasing overall response rate (ORR) in a patient with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

[0008] In some embodiments, the method provides an increase in ORR of 12% compared to placebo.

[0009] In another aspect, the disclosure provides a method of increasing time to death or metastasis (TTDM) in a patient with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

[0010] In a further aspect, the disclosure provides methods of reducing the incidence of metastases in patients with unresectable NSCLC, the methods comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy. In some aspects, the lower incidence of metastases can be in the lymph nodes, brain, lungs, liver, adrenal glands, bone, abdomen, biliary tree, breast, chest, kidneys, ovaries, pancreas, pericardium, ascites, peritoneum, retroperitoneum, skin, spleen, and / or intrauterine. In some aspects, the lower incidence of metastases can be in the lymph nodes, brain, lungs, liver, adrenal glands, and / or intrabone.

[0011] In a related aspect, the disclosure provides a method of reducing the incidence of brain metastases in patients with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy.

[0012] In some embodiments, the methods provide a reduction in the incidence of metastases or a reduction in the incidence of metastases of at least about 20% to about 50% compared to placebo, hi some embodiments, the methods provide a reduction in the incidence of metastases or brain metastases of at least 5 months relative to placebo.

[0013] In another aspect, the disclosure provides a method of treating a patient with Stage III locally advanced unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient has not progressed after definitive chemoradiation therapy.

[0014] In certain of the above aspects, the chemoradiotherapy comprises a platinum-based therapeutic agent. In some aspects, the platinum-based therapeutic agent may be selected from cisplatin or carboplatin, or a combination of cisplatin and carboplatin.

[0015] In some aspects of any of the above aspects, the human anti-PD-L1 antibody comprises durvalumab (IMFINZI®), avelumab (BAVENCIO®), or atezolizumab (TECENTRIQ®). In a further aspect, the human anti-PD-L1 antibody comprises durvalumab. In aspects, 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 a further aspect, the human anti-PD-L1 antibody comprises heavy and light chain variable region CDR sequences, wherein VH CDR1 has the amino acid sequence of SEQ ID NO: 3; VH CDR2 has the amino acid sequence of SEQ ID NO: 4; VH CDR3 has the amino acid sequence of SEQ ID NO: 5; VL CDR1 has the amino acid sequence of SEQ ID NO: 6; VL CDR2 has the amino acid sequence of SEQ ID NO: 7; and VL CDR3 has the amino acid sequence of SEQ ID NO: 8.

[0016] In any of the above embodiments, the treatment comprises administering the human anti-PD-L1 antibody intravenously once every two weeks at a dosage of 10 mg / kg.

[0017] In 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.

[0018] In another aspect, the disclosure provides a method of extending progression-free survival (PFS) in patients with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy.

[0019] In some aspects of this embodiment, the chemoradiotherapy comprises a platinum-based therapeutic agent. In some aspects, the platinum-based therapeutic agent may be selected from cisplatin or carboplatin, or a combination of cisplatin and carboplatin.

[0020] In some aspects of this embodiment, the human anti-PD1 antibody comprises nivolumab (OPDIVO®) or pembrolizumab (KEYTRUDA®).

[0021] In some embodiments, the method provides an increase in PFS of at least 5 months compared to placebo. In some embodiments, the method provides an increase in PFS of at least 13 months compared to placebo.

[0022] In embodiments of this embodiment, the patient may express a gene (i.e., have a phenotype) associated with a therapeutic response to a therapy comprising a human anti-PD-1 antibody. In some embodiments, the patient is PD-L1(+). In other embodiments, the patient is PD-L1(-). In some embodiments, the patient is EGFR mutant(+). In other embodiments, the patient is EGFR mutant(-) or wild-type. In some embodiments, the patient may express any combination of PD-L1 and EGFR mutant phenotypes.

[0023] In a further aspect, the present disclosure provides methods of reducing the incidence of metastases in patients with unresectable NSCLC, the methods comprising treating the patient with a human anti-PD-1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy. In some aspects, the lower incidence of metastases can be in the lymph nodes, brain, lungs, liver, adrenal glands, bone, abdomen, biliary tree, breast, chest, kidneys, ovaries, pancreas, pericardium, ascites, peritoneum, retroperitoneum, skin, spleen, and / or uterus. In some aspects, the lower incidence of metastases can be in the lymph nodes, brain, lungs, liver, adrenal glands, and / or bone.

[0024] In a related aspect, the disclosure provides a method of reducing the incidence of brain metastases in patients with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy.

[0025] In some embodiments, the methods provide a reduction in the incidence of metastases or a reduction in the incidence of metastases of at least about 20% to about 50% compared to placebo, hi some embodiments, the methods provide a reduction in the incidence of metastases or a reduction in the incidence of brain metastases of at least 5 months relative to placebo.

[0026] In embodiments of these related embodiments, 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 embodiments, the patient is PD-L1(+). In other embodiments, the patient is PD-L1(-). In some embodiments, the patient is EGFR mutant(+). In other embodiments, the patient is EGFR mutant(-) or wild-type. In some embodiments, the patient may express any combination of PD-L1 and EGFR mutant phenotypes.

[0027] In various embodiments of the above aspects, treatment can include administration of at least about 10 mg / kg of durvalumab, or an antigen-binding fragment thereof. In some embodiments, administration is repeated about every 14 days for up to 52 weeks.

[0028] Other features, aspects, aspects, and advantages provided by the present disclosure will become apparent from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0029] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs. The following references provide one of the skills with many common definitions 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 HarperCollins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0030] In this disclosure, "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them in U.S. patent law and can mean "includes," "including," and the like; "consisting essentially of" or "consisting essentially of," and the like can similarly have the meaning ascribed to them in U.S. patent law, and these terms are open-ended, allowing for the presence of things other than those recited, but excluding prior art aspects, so long as the basic or novel characteristics of the recited things are not changed by the presence of the recited things.

[0031] Unless otherwise stated or clear from context, as used herein, the term "or" is understood as inclusive. Unless otherwise stated or clear from context, as used herein, the terms "a," "an," and "the" are understood as singular or plural.

[0032] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within normal tolerances in the art, e.g., within two standard deviations of the mean. 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. Unless clear from the context, all numerical values ​​provided herein are modified by the term about.

[0033] The recitation of a list of chemical groups in any definition of a variable herein includes definitions 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.

[0034] Any composition or method provided herein may be combined with one or more of any of the other compositions and methods provided herein.

[0035] Ranges provided herein are understood to be shorthand for all numbers within that range. For example, a range of 1 to 50 is understood to be any number, combination of numbers, or subrange 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.

[0036] By "anti-PD-L1 antibody" is meant 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 embodiments, durvalumab, avelumab, or atezolizumab-durvalumab is an exemplary PD-L1 antibody. In a further embodiment, durvalumab is an exemplary PD-L1 antibody.

[0037] "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.

[0038] A "complete response" (CR) refers to the disappearance of all lesions, whether measurable or not, and the absence of new lesions. This confirmation can be obtained using repeated serial assessments for 4 weeks or more from the date of first documentation. The absence of new non-measurable lesions precludes a CR.

[0039] A "partial response" (PR) refers to a reduction in tumor burden of ≥ 50% relative to baseline, confirmed using serial repeat assessments for at least 4 weeks from the date of first documentation.

[0040] "Progressive disease" (PD) refers to an increase in tumor burden of ≥ 25% relative to the lowest recorded value (nadir). Confirmation can be obtained by serial repeat assessments for at least 4 weeks from the date of first documentation. New non-measurable lesions do not define PD.

[0041] "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.

[0042] Non-small cell lung cancer (NSCLC) can refer to any of three main subtypes of NSCLC: squamous cell carcinoma, adenocarcinoma, and large cell (undifferentiated) carcinoma. Other subtypes include adenosquamous carcinoma and sarcomatoid carcinoma.

[0043] 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. PD-L1 polypeptide sequence NCBI accession number NP_001254635 [ka]

[0044] 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. PD-L1 nucleic acid sequence NCBI Accession Number NM_001267706 mRNA [ka] [ka]

[0045] 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).

[0046] PD-1 is expressed on activated T cells, B cells, and monocytes (Agata, Y. 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, T. et al. (2002) "Expression of programmed death 1 ligands by murine T cells and APCs," J. Immunol. 169:5538-5545), and is expressed at low levels on 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, N. et al. al. (2007) “Inhibitory Costimulation And Anti-Tumor Immunity,” Semin. Cancer Biol. 17(4):288-298).PD-1 is a receptor involved in downregulation of the immune system after activation by binding of PDL-1 or PDL-2 (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.

[0047] 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 / PDL-1 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.

[0048] As used in this disclosure, the term "antibody" refers to an immunoglobulin or a fragment or derivative thereof, and encompasses any polypeptide containing an antigen-binding site, whether produced in vitro or in vivo. This term includes, but is not limited to, polyclonal, monoclonal, monospecific, polyspecific, nonspecific, humanized, single-chain, chimeric, synthetic, recombinant, hybrid, mutant, and grafted antibodies. For the purposes of this disclosure, unless otherwise modified by the term "intact," as in "intact antibody," the term "antibody" also includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen-binding function, i.e., the ability to specifically bind to PD-L1. Typically, such fragments will include the antigen-binding domain.

[0049] The terms "antigen-binding domain," "antigen-binding fragment," and "binding fragment" refer to the portion of an antibody molecule that contains the amino acids that are responsible for the specific binding of the antibody to the antigen. If the antigen is large, the antigen-binding domain may bind only a portion of the antigen. The portion of the antigen molecule that is responsible for the specific interaction with the antigen-binding domain is called the "epitope" or "antigenic determinant." The antigen-binding domain is typically comprised of the antibody light chain variable region (V L ) and antibody heavy chain variable region (V H ), but not necessarily both. For example, so-called Fd antibody fragments contain V H domains but still retain some of the antigen-binding function of an intact antibody.

[0050] Antibody binding fragments are produced by recombinant DNA technology or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single-chain antibodies. Antibodies other than "bispecific" or "bifunctional" antibodies are understood to have each of their binding sites identical. Digestion of antibodies with the enzyme papain produces two identical antigen-binding fragments, also known as "Fab" fragments, and an "Fc" fragment, which has no antigen-binding activity but is capable of crystallization. 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.

[0051] The term "bi-Ab" 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 unconventional antibodies.

[0052] The terms "isolated," "purified," or "biologically pure" refer to material that is free, or contains to varying degrees, components that normally accompany it when found in its native state. "Isolate" indicates some degree of separation from the original source or its surroundings. "Purify" indicates a degree of separation that goes beyond isolation. A "purified" or "biologically pure" protein is sufficiently free of other materials such that the impurities do not substantially affect the biological properties of the protein or produce other adverse consequences.

[0053] "Specifically binds" refers to a compound (e.g., an antibody) that recognizes and binds a molecule (e.g., a polypeptide) but does not substantially recognize or bind other molecules in a sample, e.g., a biological sample. For example, two molecules that specifically bind form a complex that is relatively stable under physiological conditions. Specific binding is typically characterized by high affinity and low-to-moderate capacity, as distinguished from nonspecific binding, which typically has low affinity and moderate-to-high capacity. Typically, binding is determined by an affinity constant, K A is 10 6 M -1 More than 10 8 M -1 A specific binding is considered to be specific if it exceeds 100%. If necessary, non-specific binding can be reduced by varying the binding conditions without substantially affecting specific binding. Suitable binding conditions, such as antibody concentration, ionic strength of the solution, temperature, time allowed for binding, and concentration of blocking agent (e.g., serum albumin, bovine milk casein), can be optimized by those skilled in the art using routine techniques.

[0054] As generally used herein, the terms "treat," "treating," "treatment," and the like refer to alleviating, reversing, or delaying a disorder or disease and / or symptoms associated with the disorder or disease. It will be recognized, although not excluded, that treatment of a disorder, disease, or condition does not require 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. [Brief explanation of the drawings]

[0055] [Figure 1]Statistical analysis showing time to progression (PFS) in the intention-to-treat population by Blinded Independent Central Review (BICR) is provided. Kaplan-Meier curves of PFS (defined by Response Evaluation Criteria In Solid Tumors (RECIST v1.1); assessed by BICR) in patients receiving durvalumab or placebo. The total number of events / total number of patients was 214 / 476 (durvalumab) and 157 / 237 (placebo); the median PFS was 16.8 months (13.0-18.1, 95% CI (durvalumab)) and 5.6 (4.6-7.8, 95% CI (placebo)); the 12-month PFS rates were 55.9% (51.0-60.4%, 95% CI (durvalumab)) and 44.2% (37.7-50.5%, 95% CI (placebo)); and the 18-month PFS rates were 35.3% (29.0-41.7%, 95% CI (durvalumab)) and 27.0% (19.9-34.5%, 95% CI (placebo)). Symbols indicate censored observations. The intention-to-treat population included all patients who underwent randomization. [Figure 2] PFS (defined by RECIST v.1.1) subgroup analysis of prognostic factors in the intention-to-treat population (assessed by BICR) is shown. Hazard ratios and 95% CIs are not calculated if the subgroup level had less than 20 events. CR is complete response; EGFR is epidermal growth factor receptor; PD-L1 is programmed cell death ligand 1; PR is partial response; SD is stable disease; WHO is World Health Organization. [Figure 3]A CONSORT flow diagram of data obtained from the clinical trial is shown. †Four patients (three in the durvalumab group and one in the placebo group) were randomized but did not receive treatment due to patient decision (n=2), neutropenia (n=1), and worsening chronic obstructive pulmonary disease (n=1). ‡Patients who completed 12 months of treatment reported reaching a maximum number of cycles of immunotherapy on their electronic case report form (eCRF). ¶Two patients randomized to placebo received one dose of durvalumab and were included in the safety analysis set. [Figure 4] PFS (as defined by RECIST v.1.1) subgroup analysis of additional factors in the intention-to-treat population (assessed by BICR) is shown. Hazard ratios and 95% CIs are not calculated if the subgroup level has less than 20 events. [Figure 5] Incidence of new lesions by BICR (ITT) is shown and may include more than one new lesion site. Other includes lesions in: abdominal wall, biliary tree, breast, chest wall, kidney, ovary, pancreas, pericardium, ascites, peritoneum, retroperitoneum, skin, spleen, uterus, and other (unspecified). [Figure 6] Statistical analysis of time to death or distant metastasis (TDDM) in the intention-to-treat population is shown. The probability of death or distant metastasis is associated with a median TDDM of 23.2 months (23.2-NR, 95% CI) with durvalumab and 14.6 months (10.6-18.6, 95% CI) with placebo. The calculated hazard ratio is 0.52 (95% CI, 0.39-0.69). [Figure 7] Figure 1 shows a statistical analysis of duration of response in the intention-to-treat population plotted as the proportion of patients who remained in response at around clinical evaluation as a function of time (months). The median duration of response (DoR) (months) for durvalumab was "not reported," while placebo showed a median DoR of 13.8 months (6.0-NR, 95% CI).

[0056] array The durvalumab light chain variable region amino acid sequence is provided as SEQ ID NO:1.

[0057] The durvalumab heavy chain variable region amino acid sequence is provided as SEQ ID NO:2.

[0058] 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).

[0059] 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).

[0060] The present disclosure relates to methods of treating patients with unresectable, late-stage non-small cell lung cancer (NSCLC) that have not progressed after definitive chemoradiotherapy, the methods comprising administering a human anti-PD-L1 antibody to the patient. In particular, data from clinical results disclosed herein provide improved treatment methods and substantially redefine the existing standard of care for treating unresectable, late-stage (e.g., Stage III) non-small cell lung cancer (NSCLC) in patients that have not progressed after definitive chemoradiotherapy. The disclosed treatment methods can provide substantial improvements in patients' progression-free survival (PFS), objective response rate (ORR), time to death or metastasis (TTDM), duration of response (DoR), and / or a lower incidence of metastatic spread of the patient's NSCLC. The data support a new standard of care for treating locally advanced, unresectable, late-stage non-small cell lung cancer (NSCLC) that has not progressed after definitive chemoradiotherapy.

[0061] Thus, in various embodiments described below, the disclosed methods provide treatment for patients with locally advanced, unresectable NSCLC who have not progressed after definitive chemoradiotherapy, and the treatment can extend progression-free survival (PFS); increase objective response rate (ORR); increase time to death or metastasis (TTDM); reduce the incidence of metastases; reduce the incidence of brain metastases; increase overall survival (OS); increase duration of response (DoR); and / or increase the proportion of patients alive and progression-free (APF).

[0062] In one aspect, the disclosure provides a method of extending progression-free survival (PFS) in patients with unresectable non-small cell lung cancer (NSCLC), the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

[0063] In one aspect, the disclosure provides a method of increasing overall response rate (ORR) in a patient with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

[0064] In another aspect, the disclosure provides a method of increasing time to death or metastasis (TTDM) in a patient with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

[0065] In a further aspect, the disclosure provides a method of reducing the incidence of metastasis in a patient with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

[0066] In a related aspect, the disclosure provides a method of reducing the incidence of brain metastases in patients with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy.

[0067] In another aspect, the disclosure provides a method of treating a patient with Stage III locally advanced unresectable NSCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, wherein the patient has not progressed after definitive chemoradiation therapy.

[0068] In another aspect, the disclosure provides a method of extending progression-free survival (PFS) in patients with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy.

[0069] In a further aspect, the present disclosure provides a method of reducing the incidence of metastasis in a patient with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy.

[0070] In one aspect, the disclosure provides a method of reducing the incidence of brain metastases in patients with unresectable NSCLC, the method comprising treating the patient with a human anti-PD-1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiotherapy.

[0071] In an aspect of these embodiments, the chemoradiotherapy comprises a platinum-based therapeutic agent.

[0072] In some of the above aspects, the lower incidence of metastasis can be in lymph nodes, brain, lungs, liver, adrenal glands, bone, abdomen, biliary tree, breast, chest, kidney, ovary, pancreas, pericardium, ascites, peritoneum, retroperitoneum, skin, spleen, and / or uterus. In some aspects, the lower incidence of metastasis can be in lymph nodes, brain, lungs, liver, adrenal glands, and / or bone.

[0073] In some of the above embodiments, the human anti-PD-L1 antibody comprises durvalumab (IMFINZI®), avelumab (BAVENCIO®), or atezolizumab (TECENTRIQ®). In further embodiments, the human anti-PD-L1 antibody comprises durvalumab. In embodiments, 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 further embodiments, the human anti-PD-L1 antibody comprises heavy and light chain variable region CDR sequences, wherein VH CDR1 has the amino acid sequence of SEQ ID NO: 3; VH CDR2 has the amino acid sequence of SEQ ID NO: 4; VH CDR3 has the amino acid sequence of SEQ ID NO: 5; VL CDR1 has the amino acid sequence of SEQ ID NO: 6; VL CDR2 has the amino acid sequence of SEQ ID NO: 7; and VL CDR3 has the amino acid sequence of SEQ ID NO: 8.

[0074] In an embodiment of the above embodiment, the treatment comprises administering the human anti-PD-L1 antibody intravenously once every two weeks at a dosage of 10 mg / kg.

[0075] In an embodiment of the above embodiment, the method provides an increase in PFS of at least 5 months compared to placebo. In a further embodiment, the method provides an increase in PFS of at least 13 months compared to placebo.

[0076] In some of the above embodiments, the method provides an increase in ORR of 12% compared to placebo.

[0077] In some of the above embodiments, the method provides an increase in TDDM over placebo of at least 4 months.

[0078] In some of the above embodiments, the method provides a reduction in the incidence of metastases or a reduction in the incidence of metastases of at least about 20% to about 50% compared to placebo, hi some embodiments, the method provides a reduction in the incidence of metastases or brain metastases of at least 5 months relative to placebo.

[0079] In some of the above embodiments, the human anti-PD1 antibody comprises nivolumab (OPDIVO®) or pembrolizumab (KEYTRUDA®).

[0080] In certain embodiments, the patient receives one or more doses of the anti-PD-1 antibody, and the dose is a fixed dose of 200 mg.

[0081] In certain embodiments, the patient receives one or more doses of the anti-PD-1 antibody, and the dose is a fixed dose of 240 mg.

[0082] In certain embodiments, the patient receives one or more doses of the anti-PD-1 antibody, and the dose is a fixed dose of 480 mg.

[0083] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered every two weeks.

[0084] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered every three weeks.

[0085] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered every four weeks.

[0086] In some embodiments of the above, the patient may express (i.e., have a phenotype of) a gene 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 the sample contained 25% or more tumor cells with PDL1 membrane staining. The cutoff and scoring algorithm have been previously determined for durvalumab (Study CP1108; ClinicalTrials.gov number NCT01693562).

[0087] 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.

[0088] In various embodiments of the above aspects, treatment can include administration of at least about 10 mg / kg of durvalumab, or an antigen-binding fragment thereof. In some embodiments, administration is repeated about every 14 days for up to 52 weeks.

[0089] Overall survival (OS) refers to the period from the date of treatment to death from any cause.OS can refer to the overall survival period, for example, within 12 months, 18 months, 24 months, etc. Such period can be specified as "OS24", which refers to the number (%) of patients who are alive 24 months after the start of treatment, for example, by Kaplan-Meier estimation of overall survival period at 24 months.

[0090] Progression-free survival (PFS) refers to the period 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, and up to about 5 years).

[0091] 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.

[0092] 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.

[0093] The proportion of patients alive and progression-free (APF) refers to the number (%) of patients alive and progression-free according to RECIST 1.1. APF can refer to a period, for example, 12 months, 18 months, 24 months, etc. Such a period can be determined, for example, by Kaplan-Meier estimation of progression-free survival at 12 months with APF12 to determine the number of patients alive and progression-free 12 months after initiation of treatment.

[0094] Time to death or distant metastasis (TTDM) refers to any new lesions outside the radiation field. In some embodiments, the methods provide an increase in TTDM. In some embodiments, the methods provide TTDM of at least 9 months to at least about 24 months (e.g., at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or more, and up to about 5 years).

[0095] In embodiments, the method is administered to patients who have not progressed after definitive concurrent chemoradiotherapy. In some embodiments, the concurrent chemoradiotherapy comprises any accepted standard first-line treatment for patients with advanced NSCLC. In certain embodiments, the standard first-line treatment can include chemotherapy, radiation therapy, or both (chemoradiotherapy). In some embodiments, the treatment can include one or more platinum-based chemotherapeutic agents. In some embodiments, the one or more platinum-based chemotherapeutic agents can be selected from carboplatin, cisplatin, oxaliplatin, or combinations thereof. As further described herein, the platinum-based treatment can include singlet or doublet treatment regimens, for example, administering cisplatin or carboplatin together with other anticancer agents, such as paclitaxel, docetaxel, etoposide, gemcitabine, vinorelbine, etc.

[0096] The disclosed methods involve administration of a therapeutic agent (e.g., a human anti-PD-L1 antibody or a human anti-(andi)PD-1 antibody) after a previous treatment regimen that failed to achieve one or more clinical endpoints. In certain embodiments, the methods are administered after definitive chemoradiotherapy including a platinum-based drug as discussed above. In some embodiments, the methods are administered after one, two, or more rounds of definitive chemoradiotherapy including a platinum-based drug that does not inhibit the progression of NSCLC. In some embodiments of the treatment methods provided herein, administration of a human anti-PD-L1 antibody or a human anti-(andi)PD-1 antibody can be initiated after a determination that the NSCLC has not responded to a previous treatment regimen. In some embodiments, the patient can be treated within 1 to about 42 days (e.g., 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, or 42 or more days) after the patient has received chemoradiotherapy.

[0097] As described herein and shown in the Examples, methods provide treatment for locally advanced, unresectable NSCLC. In some embodiments, "unresectable" cancer includes cancer that cannot be completely removed by surgery due to at least one of several medical reasons. Reasons why a cancer may be unresectable include, for example, tumor size (e.g., too large to safely remove and / or may require extensive removal of portions of vital organs), tumor location (e.g., tumors that are physically intertwined with vital structures such as blood vessels or nerves), tumor metastasis, where tumor removal may not be effective in controlling all cancer, or other medical conditions (e.g., heart disease, lung disease, diabetes) that increase the risk of surgery to an unacceptable level. Furthermore, unresectable NSCLC may not remain permanently unresectable after aggressive treatment, which may be effective in reducing the size of the tumor to the point where surgical resection is feasible. Furthermore, unresectable NSCLC can also refer to NSCLC (or distant metastasis) that will not be completely removed by surgery but may be partially removed by one or more surgical procedures. Examples include debulking surgery and surgery to remove part of the lung cancer and part of the metastatic lesion.

[0098] In certain embodiments, the methods disclosed herein can be used for "unresectable" cancers.

[0099] As described above and as shown herein, the method treats patients with late-stage (e.g., stage III) locally advanced, unresectable NSCLC who have not progressed after definitive chemoradiotherapy. Cancer staging can be performed using any commonly known and art-recognized test. In embodiments, cancer staging can include the American Joint Committee on Cancer's (AJCC's) TNM system. Generally, the TNM system provides results from 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.

[0100] 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 a higher number, and depending on the cancer, a lowercase letter such as "a," "b," or "m" (if plural) may be added to provide further detail.

[0101] Similarly, for nodes, "N" can be associated with a number (e.g., 0-3) to describe whether the cancer was found in a lymph node, and can also indicate the number of lymph nodes containing the cancer. Higher numbers are assigned if more lymph nodes are involved in the cancer.

[0102] 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.

[0103] The T, N, and M results 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 typically 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.

[0104] Staging may optionally include analysis of prognostic factors to provide chances of recovery and recommended treatments. Prognostic factors may include grading the cancer based on the appearance of the cancer cells; analysis of tumor marker expression; and analysis of tumor genetics.

[0105] The cancer may be staged again using the same initial system to determine the effectiveness of treatment or to obtain more information about recurrent cancer.

[0106] Staging of NSCLC NSCLC has five stages: stage 0 (zero) and stages I-IV (1-4). Stage 0 NSCLC indicates that the cancer has not grown into nearby tissue or spread outside the lungs.

[0107] Stage I NSCLC indicates a small tumor that has not spread to the lymph nodes. Stage I is divided into two substages based on tumor size: Stage IA tumors are less than 3 centimeters (cm) wide, and Stage IB tumors are more than 3 cm wide but less than 5 cm wide. Stage I NSCLC may be amenable to complete surgical removal of the cancer.

[0108] Stage II is divided into two substages (IIA and IIB). Stage IIA can be either a tumor more than 5 cm wide but less than 7 cm wide that has not spread to nearby lymph nodes, or a small tumor less than 5 cm wide that has spread to nearby lymph nodes. Stage IIB can describe either a tumor more than 5 cm wide but less than 7 cm wide that has spread to lymph nodes, or a tumor more than 7 cm wide that may or may not have grown into nearby structures in the lung but has not spread to lymph nodes. Stage II NSCLC may be treatable surgically, but other therapies are usually required to treat NSCLC at this stage.

[0109] Stage III includes substage IIIA or IIIB. In many stage IIIA cancers and nearly all stage IIIB cancers, surgery is difficult or impossible due to spread of the cancer to lymph nodes or growth into nearby structures in the lungs. Surgery in either situation typically requires partial removal of the cancer.

[0110] Stage IV NSCLC is associated with the spread of more than one area into the other lung, the fluid surrounding the lung or heart, or distant metastasis within the body. NSCLC is more likely to spread to the brain, bone, liver, and adrenal glands. Stage IV NSCLC includes substages IVA (intrathoracic spread) and IVB (extrathoracic spread). Surgery is rarely successful for most stage III or IV NSCLC, and removal may be impossible if the cancer has spread to lymph nodes above the collarbone or to critical structures within the chest (e.g., the heart, major blood vessels, or major pulmonary structures). In certain embodiments, the patient disclosed herein is a stage IV NSCLC patient.

[0111] After a course of treatment, recurrent NSCLC is detected.

[0112] Anti-PD-L1 antibody Antibodies that specifically bind to and inhibit PD-L1 activity (e.g., bind to PD-1 and / or CD80) are useful in the methods disclosed herein.

[0113] 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 relieve PD-L1-mediated suppression of human T cell activation in vitro and inhibit tumor growth in xenograft models via 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.

[0114] In certain embodiments, the antibody used in the methods disclosed herein is any agent that disrupts the PD-1 / PD-L1 axis.

[0115] 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 in the constant domain of the IgG1 heavy chain that reduces binding to complement components C1q and Fcγ receptors, which are responsible for mediating antibody-dependent T-cell-mediated cytotoxicity (ADCC).

[0116] 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 Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and the light chain variable region comprises Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8. One 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 embodiments, durvalumab or an antigen-binding fragment thereof used in the methods provided herein comprises the variable heavy and variable light chain CDR sequences of the 2.14H9OPT antibody, as disclosed in U.S. Pat. Nos. 8,779,108 and 9,493,565, the entire contents of which are incorporated herein by reference.

[0117] Patients with late-stage (III or IV) locally advanced, unresectable NSCLC that has not progressed after definitive chemoradiotherapy are administered an anti-PD-1 or anti-PD-L1 antibody, such as durvalumab or an antigen-binding fragment thereof. Durvalumab or an antigen-binding fragment thereof can be administered once every two weeks while still providing benefit to the patient. In a further embodiment, the patient is administered additional subsequent doses. Subsequent doses can 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 attending physician.

[0118] In embodiments, multiple doses of durvalumab or an antigen-binding fragment thereof are administered to the patient. In some embodiments, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses, at least 7 doses, at least 8 doses, at least 9 doses, at least 10 doses, at least 15 doses, or at least 26 doses (i.e., a full year of treatment) or more may be administered to the patient. In some embodiments, durvalumab or an antigen-binding fragment thereof is administered every 2 weeks for 2 weeks, for a 4-week treatment period, a 6-week treatment period, an 8-week treatment period, a 12-week treatment period, a 24-week treatment period, or for a treatment period of 1 year or more.

[0119] In certain embodiments, the interval between doses can be every 3 weeks. In certain embodiments, the interval between doses can be every 4 weeks. In further embodiments, the interval between doses can be every 2 months (e.g., during the maintenance phase).

[0120] In certain embodiments, the dosing interval can also be about every 14 days or about every 21 days. In some embodiments, "about" every 14 days or "about" every 21 days refers to 14 days + / - 2 days or 21 days + / - 2 days. In some embodiments, durvalumab is administered about every 14 to 21 days.

[0121] In certain embodiments, the patient receives one or more doses of the anti-PD-L1 antibody, and the dose is a fixed dose of 1200 mg.

[0122] The amount of durvalumab or an antigen-binding fragment thereof administered to a patient may be adjusted according to, and may 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.

[0123] 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.

[0124] In certain embodiments, the patient receives one or more doses of durvalumab, wherein the dose is a fixed dose of 1500 mg.

[0125] In certain embodiments, patients receive at least two doses of durvalumab or an antigen-binding fragment thereof every two weeks, where the dose is about 10 mg / kg. In further embodiments, patients receive a 10 mg / kg dose of durvalumab every two weeks for up to one year or more.

[0126] In certain embodiments, patients receive 1500 mg of durvalumab every four weeks.

[0127] In certain aspects, administration of durvalumab or an antigen-binding fragment thereof according to the methods provided herein is via parenteral administration. For example, durvalumab or an antigen-binding fragment thereof can be administered by intravenous infusion or subcutaneous injection. In some aspects, administration is by intravenous infusion.

[0128] In certain embodiments, 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, carboplatin, bevacizumab, erlotinib, or pemetrexed, or other chemotherapeutic agents, and radiation or any other anti-cancer treatment.

[0129] 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 size of the patient's tumor 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 can reduce tumor size by at least 25%, at least 50%, or at least 75%.

[0130] 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 based on a large patient population, or by comparison to tumor growth in a control population.

[0131] According to the methods provided herein, administration of durvalumab or an antigen-binding fragment thereof can result in desired 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 d·μg / mL. Administration can result in a maximum observed concentration (Cmax) of about 15 to about 350 μg / mL. The half-life of durvalumab or an antigen-binding fragment thereof can be about 5 to about 25 days. Additionally, the clearance of durvalumab or an antigen-binding fragment thereof can be about 1 to 10 ml / day / kg.

[0132] 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.

[0133] The practice of the methods disclosed herein will employ, 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 the literature, e.g., "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).

[0134] 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]

[0135] Example 1: Clinical evaluation of durvalumab in the treatment of locally advanced stage III unresectable NSCLC This example provides results from an interim analysis of the randomized, double-blind, international Phase 3 PACIFIC trial (ClinicalTrials.gov number NCT02125461), which compares durvalumab to placebo as consolidation therapy for patients with stage III locally advanced, unresectable NSCLC whose disease had not progressed after platinum-based cCRT. This is the first randomized Phase 3 trial evaluating immune checkpoint blockade in this setting.

[0136] patient Eligible patients had histologically or cytologically documented stage III locally advanced unresectable NSCLC according to the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology (v7), had received definitive radiation therapy (54 Gy–66 Gy) and ≥2 cycles (defined by local practice) of platinum-based chemotherapy (including etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed) concomitantly, meaning a lung dose <20 Gy and / or a V20 <35% and had not progressed after this treatment. Patients were ≥18 years old, had a World Health Organization (WHO) performance status of 0 or 1, an estimated life expectancy ≥12 weeks, and had completed their last dose of radiation 1–14 days (changed to 1–42 days after a protocol amendment) before randomization.

[0137] Key exclusion criteria included: previous exposure to anti-PD-1 or anti-PD-L1 antibodies; receipt of immunotherapy or investigational drugs within 4 weeks (6 weeks for monoclonal antibodies) prior to the first dose; history of active or previous autoimmune disease (in the past 2 years) or primary immunodeficiency; evidence of uncontrolled intercurrent illness; evidence of ongoing or active infection; unresolved toxicity from previous CRT >grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE]); and ≥grade 2 interstitial pneumonitis from previous CRT.

[0138] Design and treatment Patients were randomized 2:1 within 1 to 42 days after cCRT to receive durvalumab 10 mg / kg intravenously or matching placebo every 2 weeks (q2w) for up to 12 months as consolidation therapy. Patients were stratified by age (<65 or ≥65 years), sex, and smoking history (current / former smoker vs. non-smoker). Once patients were confirmed as eligible, study drug administration began on day 1 after randomization. Study drug was discontinued in the presence of confirmed disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, or withdrawal of consent. Patients were treated through progression (unless they had rapid tumor progression or symptomatic progression requiring urgent medical intervention) and could be re-treated if they achieved disease control at the end of 12 months but did not progress during follow-up.

[0139] Endpoints and Evaluation Coprimary endpoints were PFS (assessed by Blinded Independent Central Review [BICR] according to Response Evaluation Criteria In Solid Tumors [RECIST] v1.1) and overall survival (OS). PFS was defined as the time from randomization to the date of the first documented event of tumor progression or death in the absence of progression, and OS was defined as the time from randomization to death (any cause). PFS was assessed according to RECIST v1.1 by the investigator as a predefined sensitivity analysis.

[0140] Secondary endpoints included the proportion of patients alive and progression-free at 12 and 18 months, overall response rate (ORR), duration of response (DoR), and time to death or distant metastasis (TTDM), all by BICR, as well as OS at 24 months, safety and tolerability (graded using CTCAE v4.03), health-related quality of life, pharmacokinetics, and immunogenicity. Efficacy was assessed every 8 weeks for the first 12 months and every 12 weeks thereafter. All efficacy endpoints reported pertained to treatment with durvalumab or placebo alone, i.e., endpoints including prior cCRT therapy were not aggregated.

[0141] Patients provided archived tumor tissue samples for optional PD-L1 testing; however, enrollment was not restricted to any PD-L1 expression level threshold.

[0142] statistical analysis A trial was considered positive (successful) if the analysis of either of the two coprimary endpoints, PFS or OS, was statistically significant. Approximately 702 patients were required for 2:1 randomization to obtain 458 PFS events for the primary PFS analysis and 491 OS events for the primary OS analysis. The trial was estimated to have at least 95% statistical power to detect a PFS HR of 0.67 and at least 85% statistical power to detect an OS HR of 0.73 for each coprimary endpoint, based on the log-rank test, at a two-sided significance level of 2.5%. An interim analysis of PFS was planned when approximately 367 events had occurred. In this interim analysis, the PFS effect was estimated using the Kaplan-Meier method. Comparisons of PFS between arms were performed using the log-rank test, stratified by age, sex, and smoking history. Sensitivity analyses of PFS included assessment of assessment bias, assessment time bias, and attrition bias in determining progression, as well as adjustment for various covariates in estimating the PFS effect. Response rates were estimated using the Clopper-Pearson method and compared using Fisher's exact test. Efficacy was assessed in the intent-to-treat population; safety was assessed in the as-treated population.

[0143] An external independent data monitoring committee (IDMC) is assessing ongoing safety and reviewed interim efficacy analyses.

[0144] Patients and Procedures Between May 2014 and April 2016, 709 of 713 randomized patients (99%) received ≥1 dose of study drug as consolidation therapy (473 patients received durvalumab and 236 received placebo; Figure 3). Baseline characteristics were well balanced between the two treatment groups (Table 1).

[0145] [Table 1]

[0146] JPEG2023103254000006.jpg72125

[0147] The median age of all patients was 64 years, and the majority were men (70%) and current / former smokers (91%); 46% of patients had squamous cell histology. Prior chemotherapy was well balanced; 55.9% and 54.4% of patients in the durvalumab and placebo groups, respectively, had received a prior cisplatin-based definitive regimen, and 41.8% and 43.0% had received a carboplatin-based regimen (Table 2). In addition, 25.8% and 28.7% had received induction chemotherapy before definitive cCRT.

[0148] [Table 2]

[0149] Based on archival tumor samples taken before cCRT (which were not reassessed after cCRT), tumor cell PD-L1 expression of ≥25% (TC ≥25%) occurred in 22% of patients (24% in the durvalumab group and 19% in the placebo group), and TC <25% occurred in 41% (39% in the durvalumab group and 44% in the placebo group); 37% of patients had unknown PD-L1 status (Table 3). EGFR mutations were observed in 6.0% of patients (6.1% in the durvalumab group and 5.9% in the placebo group), whereas 67.3% of patients had EGFR-negative or wild-type tumors (66.2% in the durvalumab group and 69.6% in the placebo group); EGFR mutation status was unknown in 27.7% and 24.5%, respectively (Table 3). There were no statistically significant differences (P<0.05) between groups in either PD-L1 expression or EGFR mutation status.

[0150] [Table 3]

[0151] Within the data cutoff time for this analysis, the overall median follow-up was 14.5 months (range 0.2-29.9). The median number of infusions received was 20 (range 1-27) in the durvalumab group and 14 (range 1-26) in the placebo group; 6.3% and 5.1% were still receiving treatment at the time of data cutoff (Table 4).

[0152] [Table 4]

[0153] Effectiveness The median PFS from randomization, assessed by BICR, was 16.8 months (95% confidence interval [CI], 13.0-18.1) for durvalumab versus 5.6 months (95% CI, 4.6-7.8) for placebo (stratified hazard ratio [HR] for disease progression or death, 0.52; 95% CI, 0.39-0.70; two-sided P<0.0001; Figure 1). The 12-month PFS rates were 55.9% (95% CI, 51.0-60.4) for durvalumab and 35.3% (95% CI, 29.0-41.7) for placebo, and the 18-month PFS rates were 44.2% (95% CI, 37.7-50.5) and 27.0% (95% CI, 19.9-34.5), respectively. PFS results, including investigator-assessed PFS, were robust and consistent across all pre-specified sensitivity analyses (stratified HR, 0.61; 95% CI, 0.50-0.76; two-sided P<0.0001).

[0154] The PFS benefit with durvalumab was consistently observed across all prespecified subgroups defined by patient demographics, baseline clinicopathologic characteristics, and response to prior treatment (Figure 2; additional non-prognostic factors are presented in Figure 4). Notably, the PFS benefit with durvalumab was observed regardless of PD-L1 expression before cCRT (for TC<25%, HR, 0.59; 95% CI, 0.43-0.82, and for TC≥25%, HR, 0.41; 95% CI: 0.26-0.65). The PFS benefit was also evident in non-smokers and patients with EGFR mutations.

[0155] The median TTDM was 23.2 months (95% CI, 23.2-NR) with durvalumab compared with 14.6 months (95% CI, 10.6-18.6) with placebo (HR, 0.52; 95% CI, 0.39-0.69; two-sided P<0.0001; Figure 5). In addition, the frequency of new lesions assessed by BICR was 20.4% with durvalumab and 32.1% with placebo, with durvalumab accounting for a lower incidence of new brain metastases (5.5% vs. 11.0%, respectively) (Table 5).

[0156] [Table 5]

[0157] Treatment with durvalumab resulted in a clinically meaningful improvement in ORR based on BICR (28.4% vs. 16.0%, respectively; P<0.001) (Table 2); 16.5% and 27.7% of patients receiving durvalumab and placebo, respectively, experienced progressive disease (Table 6). The median DoR was 13.8 months with placebo versus not achieved with durvalumab (Table 6; Figure 6). Of patients who responded to durvalumab, 72.8% had ongoing responses at both 12 and 18 months (Table 6).

[0158] [Table 6]

[0159] safety All-cause AEs of any grade occurred in 96.8% and 94.9% of patients receiving durvalumab and placebo, respectively (Table 7). Grade 3 / 4 AEs occurred in 29.9% and 26.1%, respectively. The most common grade 3 / 4 AE was pneumonia (4.4% vs. 3.8%). Discontinuation due to AEs occurred in 15.4% and 9.8% of patients in the durvalumab and placebo groups, respectively. Death due to AEs occurred in 4.4% and 5.6%, respectively (Table 7). Treatment-related AEs are summarized in Table 8.

[0160] [Table 7]

[0161] [Table 8]

[0162] The most common AEs leading to discontinuation of durvalumab and placebo were interstitial pneumonitis / radiation pneumonitis (6.3% vs. 4.3%) and pneumonitis (1.1% vs. 1.3%). Any grade (grade 3 / 4) interstitial pneumonitis / radiation pneumonitis occurred in 33.9% vs. 24.8% (3.4% vs. 2.6%) of patients receiving durvalumab and placebo, respectively, and any grade (grade 3 / 4) pneumonitis occurred in 13.1% vs. 7.7% (4.4% vs. 3.8%).

[0163] AEs of special interest (AESIs) of any grade, regardless of causality, were reported in 66.1% and 48.7% of patients in the durvalumab and placebo groups, respectively. Most were grade 1 / 2, with grade ≥3 incidence rare (<10%) in both treatment groups. The most common AESIs of any grade for durvalumab vs. placebo were diarrhea (18.3% vs. 18.8%), interstitial pneumonitis (12.6% vs. 7.7%), rash (12.2% vs. 7.3%), and pruritus (12.2% vs. 4.7%). AESIs requiring concomitant treatment were reported in 42.1% and 17.1% of patients, respectively; treatments for AESIs included steroids (15.2% vs. 6.8%), high-dose steroids (8.8% vs. 5.1%), endocrine therapy (11.6% vs. 1.3%), and other immunosuppressants (0.4% in both groups).

[0164] Immune-mediated AEs of any grade, regardless of causality, were reported in 24.2% and 8.1% of patients receiving durvalumab and placebo, respectively; grade 3 / 4 immune-mediated AEs were reported in 3.4% and 2.6% of patients, respectively (Table 9). Treatment for immune-mediated AEs included systemic steroids (14.3% vs. 5.6%), high-dose steroids (8.2% vs. 4.3%), endocrine therapy (10.7% vs. 1.3%), and other immunosuppressants (0.4% in both groups).

[0165] [Table 9]

[0166] After an AE, patients may continue to receive treatment with durvalumab. Treatment methods are disclosed in Table 10 below.

[0167] [Table 10]

[0168] JPEG2023103254000016.jpg152125

[0169] As shown above, this method was able to meet the co-primary endpoint of PFS. Durvalumab demonstrated a statistically significant and robust improvement in PFS of more than 11 months compared with placebo in patients with locally advanced, unresectable NSCLC (HR 0.52; P<0.0001). This disclosure represents the largest absolute PFS benefit demonstrated to date by immunotherapy in any cancer or setting, and it is particularly noteworthy that this was achieved in a biomarker-unselected population. Patients with PD-L1 expression status of <25% comprised a higher proportion of participants in this study than patients with TC≥25%. In addition, the PFS improvement with durvalumab was demonstrated across all pre-specified subgroups, including patients who were not expected to respond based on trials in the advanced or metastatic setting.

[0170] Outcomes with durvalumab were clinically meaningful, as evidenced by improvements in all secondary endpoints, including a clinically meaningful improvement in ORR of 12% compared with placebo (P<0.001). In addition, responses with durvalumab were durable compared with placebo (median DoR not reached vs. 13.8 months, respectively). Durvalumab also had a favorable effect on the frequency of new metastases, including a lower incidence of new brain metastases.

[0171] Durvalumab had a favorable safety profile in this population, consistent with other immunotherapies as monotherapy and their known safety profiles in patients with more severe disease (stage IIIB / IV NSCLC). The incidence of several all-cause AEs, including interstitial pneumonitis / radiation pneumonitis, was higher with durvalumab than with placebo in this study, which was not unexpected in this setting after definitive cCRT. Additionally, interstitial pneumonitis / radiation pneumonitis with durvalumab was mostly low grade, and the incidence of clinically significant grade 3 / 4 events was well balanced between the two treatment groups (3.4% vs. 2.6%) and lower than that reported in other studies in the same setting. The favorable safety profile of durvalumab after cCRT demonstrated herein may have implications for other disease settings.

[0172] Preclinical evidence suggests that PD-L1 expression is upregulated in tumor cells after chemotherapy and / or radiation therapy, thereby attenuating immune activation. Therefore, tumors may be more sensitive to anti-PD-L1 treatment after cCRT. This disclosure suggests that efficacy with durvalumab was observed regardless of PD-L1 expression status or platinum doublet type before cCRT. Furthermore, Dovedi et al. suggested that concomitant, but not sequential, administration of anti-PD-L1 treatment and fractionated radiation therapy may improve survival. However, the data disclosed herein clearly demonstrate the clinical benefit of sequential administration of durvalumab within 42 days after cCRT.

[0173] These data demonstrate a statistically significant and clinically meaningful improvement in PFS with durvalumab after cCRT in stage III unresectable NSCLC, as well as a manageable safety profile. These positive findings in an unselected patient population, regardless of baseline pre-cCRT tumor PD-L1 expression, suggest a potential novel role for durvalumab in this setting and, more generally, that additional clinical benefit may be achieved by using immunotherapy in multimodality therapy.

[0174] Another aspect From the foregoing description it will be apparent that the invention described herein may be adapted for various uses and situations, and such embodiments are intended to fall within the scope of the following claims.

[0175] 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.

[0176] All patents and publications mentioned in this specification are incorporated by reference to the same extent as if each individual patent and publication was specifically and individually indicated to be incorporated by reference.

[0177] The present disclosure includes the following sequence information: SEQUENCE LISTING <110> ASTRAZENECA AB <120> COMPOSITIONS AND METHODS FOR TREATING LATE STAGE LUNG CANCER <130> PA23-193 <160> 10 <170> PatentIn version 3.5 <210> 1 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 1 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 2 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 2 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 3 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 3 Gly Phe Thr Phe Ser Arg Tyr Trp Met Ser 1 5 10 <210> 4 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 4 Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys 1 5 10 15 Gly <210> 5 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 5 Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr 1 5 10 <210> 6 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 6 Arg Ala Ser Gln Arg Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 7 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 7 Asp Ala Ser Ser Arg Ala Thr 1 5 <210> 8 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 8 Gln Gln Tyr Gly Ser Leu Pro Trp Thr 1 5 <210> 9 <211> 176 <212> PRT <213> Homo sapiens <400> 9 Met Arg Ile Phe Ala Val Phe Ile Phe Met Thr Tyr Trp His Leu Leu 1 5 10 15 Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro 20 25 30 Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys 35 40 45 Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys 50 55 60 Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr 65 70 75 80 Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr 85 90 95 Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile 100 105 110 Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His Leu Val 115 120 125 Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr Phe Ile 130 135 140 Phe Arg Leu Arg Lys Gly Arg Met Met Asp Val Lys Lys Cys Gly Ile 145 150 155 160 Gln Asp Thr Asn Ser Lys Lys Gln Ser Asp Thr His Leu Glu Glu Thr 165 170 175 <210> 10 <211> 3349 <212> DNA <213> Homo sapiens <400> 10 ggcgcaacgc tgagcagctg gcgcgtcccg cgcggcccca gttctgcgca gcttcccgag 60 gctccgcacc agccgcgctt ctgtccgcct gcagggcatt ccagaaagat gaggatattt 120 gctgtcttta tattcatgac ctactggcat ttgctgaacg ccccatacaa caaaatcaac 180 caaagaattt tggttgtgga tccagtcacc tctgaacatg aactgacatg tcaggctgag 240 ggctacccca aggccgaagt catctggaca agcagtgacc atcaagtcct gagtggtaag 300 accaccacca ccaattccaa gagagaggag aagcttttca atgtgaccag cacactgaga 360 atcaacacaa caactaatga gattttctac tgcactttta ggagattaga tcctgaggaa 420 aaccatacag ctgaattggt catcccagaa ctacctctgg cacatcctcc aaatgaaagg 480 actcacttgg taattctggg agccatctta ttatgccttg gtgtagcact gacattcatc 540 ttccgtttaa gaaaagggag aatgatggat gtgaaaaaat gtggcatcca agatacaaac 600 tcaaagaagc aaagtgatac acatttggag gagacgtaat ccagcattgg aacttctgat cttcaagcag ggattctcaa cctgtggttt aggggttcat cggggctgag cgtgacaaga ggcccgtggg atgcaggca tgtgggactt aaaaggccca agcactgaaa atggaacctg gcgaaagcag aggaggaa tgaagaaaga tggagtcaaa cagggagcct ggagggagac cttgatactt tcaaatgcct gaggggctca tcgacgcctg tgacagggag aaaggatact tctgaacaag gagcctccaa gcaaatcatc cattgctcat cctaggaaga cgggttgaga atccctaatt tgagggtcag ttcctgcaga agtgcccttt gcctccactc 1020 aatgcctcaa tttgttttct gcatgactga gagtctcagt gttggaacgg gacagtattt atgtatgagt ttttcctatt tattttgagt ctgtgaggtc ttcttgtcat gtgagtgtgg ttgtgaatga tttcttttga agatatattg tagtagtgt tacaattttg tcgccaaact aaacttgctg cttaatgatt tgctcacatc tgtaaaca tggagtattt gtaggtgct 1260 tggtctccctc tataactaca agtatacatt ggaagcataa agatcaacc gttggttgca 1320 taggatgtca cctttatta accattaat actctggttg acctaatctt attctcagac 1380 ctcaagtgtc tgtgcagtat ctgttccatt taaatatcag ctttacaatt atgtggtagc 1440 ctacacacat aatctcattt catcgctgta accaccctgt tgtgataacc actattattt 1500 tacccatcgt acagctgagg aagcaaacag attackactaac ttgcccaac cagtaatag 1560 cagacctcag actgccaccc actgtcttt tataatacaa tttacagcta tattttactt 1620 taagcaattc ttttattca aaaccatttta ttaagtgccc ttgcaatc aatcgctgtg 1680 ccaggcattg aatctacaga tgtgagcaag aaagtacc tgtcctcaag gagctcatag 1740 taatgagg agatacaa gaaatgtat tattacaatt tagtccagtg tcatagcata 1800 aggatgatgc gagggaaaa cccgagcagt gttgccaaga gaggaata ggccaatgtg 1860 gtctgggacg gttggatata cttaacacatc ttaataatca gagtatttt catttacaaa 1920 gagaggtcgg tacttaaat aaccctgaaa ataacactg gattcctttt tctagcatta 1980 tattattcc tgatttgcct ttgccatata atctaatgct tgtttatata gtgtctgta 2040 ttgtttaaca gttctgtctt ttctatttaa atgccactaa attttaaatt catacctttc 2100 catgattcaa attcaaag atcccatggg agatggttgg aaatctcca cttcatccctc 2160 caagccattc aagttttcctt tccagaagca actgctactg ccttcattc atatgttctt 2220 ctaaagatag tctacatttg gaatgtag ttaaaagcac gtatttttaa attttttc 2280 ctaaatagta acacattgta tgtctgctgt gtactttgct atttttatt attttagtgt 2340 ttcttatata gcagatggaa tgaatttgaa gttcccaggg ctgaggatcc atgccttctt 2400 tgtttctaag ttatctttcc catagctttt cattatcttt catatgatcc agtatatgtt 2460 aaatatgtcc tacatataca tttagacaac caccatttgt taagtatttg ctctaggaca 2520 gagtttggat ttgtttatgt ttgctcaaaa ggagacccat gggctctcca gggtgcactg 2580 agtcaatcta gtcctaaaaa gcaatcttat tattaactct gtatgacaga atcatgtctg 2640 gaacttttgt tttctgcttt ctgtcaagta taaacttcac tttgatgctg tacttgcaaa 2700 atcacatttt ctttctggaa attccggcag tgtaccttga ctgctagcta ccctgtgcca 2760 gaaaagcctc attcgttgtg cttgaaccct tgaatgccac cagctgtcat cactacacag 2820 ccctcctaag aggcttcctg gaggtttcga gattcagatg ccctgggaga tcccagagtt 2880 tcctttccct cttggccata ttctggtgtc aatgacaagg agtaccttgg ctttgccaca 2940 tgtcaaggct gaagaaacag tgtctccaac agagctcctt gtgttatctg tttgtacatg 3000 tgcatttgta cattaattgg tgtgacagtg ttctttgtgt gaattacagg caagaattgt 3060 ggctgagcaa ggcacatagt ctactcagtc tattcctaag tcctaactcc tccttgtggt 3120 gttggatttg taaggcactt tatccctttt gtctcatgtt tcatcgtaaa tggcataggc 3180 agagatgata cctaattctg catttgattg tcactttttg tacctgcatt aatttaataa 3240 aatattctta tttattttgt tacttggtac accagcatgt ccattttctt gtttttttg 3300 tgtttaataa aatgttcagt ttaacatccc agtggagaaa gttaaaaaa 3349

Claims

1. A pharmaceutical composition for use in a method to reduce the incidence of lung metastasis by 5% or more and extend progression-free survival (PFS) in patients with unresectable non-small cell lung cancer (NSCLC), wherein the composition comprises a human anti-PD-L1 antibody, and the method is a) Treat the patient with durvalumab, wherein the patient is a stage III patient who has not progressed after radical chemoradiotherapy, and b) Reduce the incidence of lung metastases in the aforementioned patients by 5% or more and extend the progression-free survival (PFS), The pharmaceutical composition comprising the above.

2. The composition according to claim 1, wherein the progression-free period (PFS) is extended by at least about five months compared to placebo.

3. The composition according to claim 1, wherein the progression-free period (PFS) is extended by at least about 12 months compared to placebo.

4. The composition according to claim 1, wherein the chemoradiotherapy is based on platinum.

5. The composition according to claim 1, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.

6. The aforementioned human anti-PD-L1 antibody: VH CDR1 having the amino acid sequence of SEQ ID NO: 3; and VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and VH CDR3 having the amino acid sequence of SEQ ID NO: 5; and VL CDR1 having the amino acid sequence of SEQ ID NO: 6; and VL CDR2 having the amino acid sequence of SEQ ID NO: 7; and VL CDR3 having the amino acid sequence of SEQ ID NO: 8 The composition according to claim 1, comprising:

7. The composition according to claim 1, wherein the human anti-PD-L1 antibody comprises a light chain variable domain containing the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable domain containing the amino acid sequence of SEQ ID NO:

2.

8. The composition according to claim 1, wherein the method comprises administering the antibody or its antigen-binding fragment to the patient at a dose of 10 mg / kg intravenously once every two weeks (Q2W).

9. A composition for use in a method of treating a patient with unresectable non-small cell lung cancer (NSCLC), wherein the composition comprises a human anti-PD-L1 antibody, and the method is: a) Treat the patient with a human anti-PD-L1 antibody, wherein the patient is a stage III patient whose condition has not progressed after curative chemoradiotherapy. b) Reduce the incidence of lung metastasis by 5% or more, and c) at least one of the following (i), (ii), and (iii), (i) Increase the overall survival (OS) of the patient compared to placebo, (ii) To extend the progression-free survival (PFS) in the aforementioned patients compared to placebo, (iii) Increase the time to death or distant metastasis (TTDM) in the patient compared to placebo. (iv) To increase the response rate (ORR) in the aforementioned patients compared to placebo, The composition comprising the above.

10. The composition according to claim 9, which extends the progression-free survival (PFS) by at least 5 months compared to placebo.

11. The composition according to claim 10, which extends the progression-free survival (PFS) by at least 12 months compared to placebo.

12. The composition according to claim 9, which extends the time to death or metastasis (TTDM) by at least four months compared to placebo.

13. The composition according to claim 12, which extends the time to death or metastasis (TTDM) by at least 12 months compared to placebo.

14. The composition according to claim 12, which increases the response rate (ORR) by at least 12% compared to placebo.

15. The composition according to claim 9, wherein the chemoradiotherapy is based on platinum.

16. The composition according to claim 9, wherein the patient is PD-L1(+).

17. The composition according to claim 9, wherein the patient is PD-L1(-).

18. The composition according to claim 9, wherein the patient is EGFR mutation (+).

19. The composition according to claim 9, wherein the patient is EGFR mutation- or wild-type.

20. The composition according to claim 9, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.

21. The aforementioned human anti-PD-L1 antibody, VH CDR1 having the amino acid sequence of SEQ ID NO: 3, and VH CDR2 having the amino acid sequence of SEQ ID NO: 4, and VH CDR3 having the amino acid sequence of SEQ ID NO: 5, and VL CDR1 having the amino acid sequence of SEQ ID NO: 6, and VL CDR2 having the amino acid sequence of SEQ ID NO: 7, and VL CDR3 having the amino acid sequence of SEQ ID NO: 8, The composition according to claim 9, comprising:

22. The composition according to claim 9, wherein the human anti-PD-L1 antibody comprises a light chain variable domain containing the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable domain containing the amino acid sequence of SEQ ID NO:

2.

23. The composition according to claim 9, wherein treating the patient with a human anti-PD-L1 antibody comprises administering the antibody to the patient intravenously at a dose of 10 mg / kg once every two weeks (Q2W).

24. A method for treating a patient with unresectable non-small cell lung cancer (NSCLC), wherein the method is: a) The patient shall be administered durvalumab intravenously at a dose of 10 mg / kg once every two weeks (Q2W), wherein the patient is a Stage III patient who has not progressed after curative chemoradiotherapy, and b) Reduce the incidence of lung metastasis by 5% or more. Methods that include...

Images