JP2023103254A - Compositions and methods for treating late-stage lung cancer - Google Patents

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

Applied for application of Article 30, Paragraph 2 of the Patent Act Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer

Approximately one-third of patients with non-small cell lung cancer (NSCLC) have stage III locally advanced disease at diagnosis. Standard treatment for patients with good performance status (PS) and unresectable stage III NSCLC is platinum-based doublet chemotherapy concurrent with radiation therapy. However, the median time to progression (PFS) with concurrent chemoradiation therapy (cCRT) in this population is approximately 8 months, with only 15% of patients alive at 5 years. Additionally, there have been no major advances in this setting for many years. Therefore, there remains a great unmet need for new therapeutic approaches that increase patient survival over cCRT.

Programmed cell 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 PD-L1 binding to PD-1 and CD80, allowing T cells to recognize and kill tumor cells. Durvalumab has shown enhanced anti-tumor activity in early clinical trials across multiple advanced solid tumors and is approved for post-platinum locally advanced or metastatic urothelial carcinoma.

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

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.

In one aspect, the disclosure provides a method of prolonging time to progression (PFS) in a patient 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.

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

In one aspect, the disclosure provides a method of increasing the 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.

In some aspects, the method provides a 12% increase in ORR compared to placebo.

In another aspect, the present 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.

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-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy. In some aspects, a lower incidence of metastases can be in lymph nodes, brain, lung, liver, adrenal glands, bone, abdomen, biliary system, breast, chest, kidney, ovary, pancreas, pericardium, ascites, peritoneum, retroperitoneum, skin, spleen, and/or intrauterine. In some aspects, a lower incidence of metastasis may be within lymph nodes, brain, lung, liver, adrenal glands, and/or bone.

In a related aspect, the disclosure provides a method of reducing the incidence of brain metastases 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.

In some aspects, 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. In some aspects, the methods provide a reduction in the incidence of metastases or brain metastases for at least 5 months relative to placebo.

In another aspect, the present 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.

In certain aspects of any of the above aspects, the chemoradiation therapy 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.

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 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 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; It has the amino acid sequence numbered 8.

In any of the above aspects, the treatment comprises administering the human anti-PD-L1 antibody intravenously once every two weeks at a dose of 10 mg/kg.

In any of the above aspects, the patient may express genes (ie, have a phenotype) associated with a therapeutic response to therapy comprising a human anti-PD-L1 antibody. In some aspects, the patient is PD-L1(+). In another aspect, the patient is PD-L1(-). In some aspects, the patient is EGFR mutated (+). In another aspect, the patient is EGFR mutated (-) or wild type. In some aspects, the patient may develop any combination of PD-L1 and EGFR mutation phenotypes.

In another aspect, the present disclosure provides a method of prolonging time to progression (PFS) 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.

In an aspect of this aspect, the chemoradiation therapy 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.

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

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

In aspects of this embodiment, the patient may express genes (ie, have a phenotype) associated with a therapeutic response to therapy comprising a human anti-PD-1 antibody. In some aspects, the patient is PD-L1(+). In another aspect, the patient is PD-L1(-). In some aspects, the patient is EGFR mutated (+). In another aspect, the patient is EGFR mutated (-) or wild type. In some aspects, the patient may develop any combination of PD-L1 and EGFR mutation phenotypes.

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-1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy. In some aspects, a lower incidence of metastases can be in lymph nodes, brain, lung, liver, adrenal glands, bone, abdomen, biliary system, breast, chest, kidney, ovary, pancreas, pericardium, ascites, peritoneum, retroperitoneum, skin, spleen, and/or intrauterine. In some aspects, a lower incidence of metastasis may be within lymph nodes, brain, lung, liver, adrenal glands, and/or bone.

In a related aspect, the disclosure provides a method of reducing the incidence of brain metastases 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 chemoradiation therapy.

In some aspects, 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. In some aspects, the methods provide a reduction in the incidence of metastases or a reduction in the incidence of brain metastases for at least 5 months relative to placebo.

In aspects of these related aspects, the patient may express genes (ie, have a phenotype) associated with a therapeutic response to therapy comprising a human anti-PD-L1 antibody. In some aspects, the patient is PD-L1(+). In another aspect, the patient is PD-L1(-). In some aspects, the patient is EGFR mutated (+). In another aspect, the patient is EGFR mutated (-) or wild type. In some aspects, the patient may develop any combination of PD-L1 and EGFR mutation phenotypes.

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

Other features, aspects, aspects, and advantages provided by the present disclosure will become apparent from the detailed description below.

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. The following reference provides one skill with many general 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); f 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 unless otherwise specified.

In this disclosure, the terms "comprises," "comprising," "containing," and "having," etc., may have the meanings ascribed to them in United States patent law and may mean "includes," "including," etc.; Able to have the meaning ascribed to them in patent law, these terms are open-ended, permitting the existence of other than what is recited, but excluding prior art aspects, so long as the basic or novel characteristics of what is recited are not altered by the existence of what is recited.

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

Unless otherwise specified or clear from context, the term "about" as used herein is understood as within the normal tolerance in the art, e.g., within 2 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 otherwise clear from the context, all numerical values provided herein are modified by abbreviations.

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. A recitation of an aspect with respect to a variable or aspect herein includes the aspect as any single aspect or in combination with any other aspect or portion thereof.

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

Ranges provided herein are understood to be shorthand for all numbers within the range. For example, the range from 1 to 50 is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,4 It is understood to be any number, combination of numbers, or subranges from the group consisting of 1, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

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, eg, in US Pat. Nos. 8,779,108 and 9,493,565, incorporated herein by reference. In some aspects, durvalumab, avelumab, or atezolizumab durvalumab are exemplary PD-L1 antibodies. In a further aspect, durvalumab is an exemplary PD-L1 antibody.

By "anti-PD-1 antibody" is meant an antibody or antigen-binding fragment thereof that selectively binds to a PD-1 polypeptide. In some aspects, nivolumab or pembrolizumab are exemplary PD-1 antibodies.

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 over 4 weeks from the date of first documentation. New non-measurable lesions preclude CR.

A “partial response” (PR) refers to a reduction in tumor burden of ≧50% over baseline. This confirmation can be obtained using consecutive repeat assessments for at least 4 weeks from the date of first documentation.

“Progressive disease” (PD) refers to an increase in tumor burden of ≧25% relative to minimal record (nadir). This 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.

"Stable disease" (SD) refers to not meeting criteria for CR, PR or PD. SD indicates that a reduction in tumor burden of 50% over baseline cannot be established and an increase of 25% over nadir cannot be established.

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

As referred to herein, "PD-L1" can refer to a polypeptide or polynucleotide sequence, or fragment thereof, having at least about 85%, 95% or 100% sequence identity to a PD-L1 sequence. PD-L1 is also referred to in the art as B7-H1. In some aspects, the PD-L1 polypeptide, or fragment thereof, has at least about 85%, 95%, or 100% sequence identity to NCBI Accession No. NP_001254635 and has PD-1 and CD80 binding activity.
PD-L1 Polypeptide Sequence NCBI Accession No. NP_001254635

In some aspects, a "PD-L1 nucleic acid molecule" comprises a polynucleotide that encodes a PD-L1 polypeptide. Exemplary PD-L1 nucleic acid molecule sequences are provided in NCBI Accession No. NM_001267706.
PD-L1 Nucleic Acid Sequence NCBI Accession No. NM_001267706 mRNA

Programmed death-1 (“PD-1”) is an approximately 31 kD type I membrane protein member of the expanded CD28/CTLA4 family of T cell regulators (Ishida, Y. et al. (1992) Induced Expression Of PD-1, A Novel Member Of The Immunoglobulin Gene Sup Erfamily, Upon Programmed Cell Death, "EMBO J. 11:3887-3895).

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. 8(5):765-772; Yamazaki, T. et al. (2002) "Expression Of Programmed Death 1 Ligands By Murine T Cells And APC," J. Immunol. (NK) expressed at low levels in T cells (Nishimura, H. et al. (2000) "Facilitation of Beta Selection and Modification of Positive Selection in the Thymus of PD-l-Deficient Mice," J. Exp. Med., 191:891-898; Martin-Orozco, N. et al. PD-1 is a receptor involved in the 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):288-2 98) 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. 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) 10 5(30):10483-10488). This process is exploited in many tumors through overexpression of PD-L1, resulting in suppression of the immune response.

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. Competitive 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 to treat infections and tumors and to upregulate adaptive immune responses has been proposed.

As used in this disclosure, the term "antibody" refers to an immunoglobulin or fragment or derivative thereof and includes any polypeptide that contains an antigen binding site, whether it is generated in vitro or in vivo. The term includes, but is not limited to, polyclonal, monoclonal, monospecific, multispecific, non-specific, humanized, single chain, chimeric, synthetic, recombinant, hybrid, variant, 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 the antigen-binding function, i.e., the ability to specifically bind to PD-L1. Typically such fragments will comprise the antigen binding domain.

The terms "antigen-binding domain,""antigen-bindingfragment," and "binding fragment" refer to the portion of the antibody molecule containing the amino acids involved in the specific binding of the antibody and antigen. If the antigen is large, the antigen binding domain may bind only part of the antigen. The portion of an antigen molecule that participates in specific interaction with the antigen-binding domain is called the "epitope" or "antigenic determinant." An antigen-binding domain typically includes an antibody light chain variable region (V _L ) and an antibody heavy chain variable region (V _H ), but need not necessarily include both. For example, so-called Fd antibody fragments consist only of the _VH domain but still retain some of the antigen-binding functions of the intact antibody.

Binding fragments of antibodies are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab')2, Fv, and single chain antibodies. An antibody other than a "bispecific" or "bifunctional" antibody is understood to have each of its binding sites identical. Digestion of antibodies with the enzyme papain yields two identical antigen-binding fragments, also known as "Fab" fragments, and an "Fc" fragment, which has no antigen-binding activity but the ability to crystallize. Digestion of antibody with the enzyme pepsin yields an F(ab')2 fragment that leaves two arms of the antibody molecule linked and contains two antigen-binding sites. F(ab')2 fragments have the ability to cross-link antigen. "Fv" as used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites. "Fab" as used herein refers to a fragment of an antibody that contains the constant domains of the light chains and the CHI domains of the heavy chains.

The term "Ab" refers to a monoclonal antibody. Antibodies of the 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.

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

By "specifically binds" is meant a compound (e.g., an antibody) that recognizes and binds a molecule (e.g., a polypeptide) but does not substantially recognize and bind other molecules in a sample, such as a biological sample. For example, two molecules that specifically bind form a complex that is relatively stable under physiological conditions. Specific binding is usually characterized by high affinity and low to moderate capacity, as distinguished from nonspecific binding, which has low affinity and moderate to high capacity. Typically, binding is considered specific if the affinity constant K _A is greater than 10 ⁶ M ⁻¹ , more preferably greater than 10 ⁸ M ⁻¹ . If desired, non-specific binding can be reduced without substantially affecting specific binding by varying the binding conditions. Suitable binding conditions, such as concentration of antibody, ionic strength of the solution, temperature, time allowed for binding, concentration of blocking agents (e.g., serum albumin, bovine milk casein), etc., can be optimized using routine techniques by those skilled in the art.

As generally used herein, the terms “treat,” “treating,” “treatment,” etc. refer to alleviating, ameliorating, or delaying a disorder or disease and/or symptoms associated with the disorder or disease. It will be appreciated that treatment of a disorder, disease or condition does not require complete elimination of the disorder, disease or condition, or associated symptoms, although they are not excluded. In certain aspects and aspects related to NSCLC, "treat," "treating," "treatment" can refer to achieving any one or combination of primary or secondary clinical endpoints.

Statistical analysis showing time to progression (PFS) in the intention-to-treat population by Blinded Independent Central Review (BICR) is provided. Kaplan-Meier curve 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); median PFS was 16.8 months (13.0-18.1, 95% CI (durvalumab)) and 5.6 (4.6-7.8, 95% CI (placebo)); 12-month PFS rate was 55.9% (51.0 18-month PFS rates were 35.3% (29.0-41.7% 95% CI (durvalumab)) and 27.0% (19.9-34.5%, 95% CI (placebo)); is. Symbols indicate censored observations. The intention-to-treat population included all patients who underwent randomization. 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 <20 events. 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. FIG. 1 shows a CONSORT flow diagram of data obtained in clinical trials. ^† Four patients (3 in the durvalumab group and 1 in the placebo group) were randomized but did not receive treatment due to patient determination (n=2), neutropenia (n=1), and exacerbation of chronic obstructive pulmonary disease (n=1). ^‡ Patients who completed 12 months of treatment reported on the electronic case report form (eCRF) that they had reached the maximum cycle of immunotherapy. ^¶ Two patients randomized to placebo received one dose of durvalumab and were included in the safety analysis set. PFS (as defined by RECIST v.1.1) subgroup analyzes of additional factors in the intention-to-treat population are shown (assessed by BICR). Hazard ratios and 95% CIs are not calculated if the subgroup level has less than 20 events. It shows the incidence of new lesions by BICR (ITT) and may include more than one new lesion site. Others include: lesions in the abdominal wall, biliary system, breast, chest wall, kidney, ovary, pancreas, pericardium, ascites, peritoneum, retroperitoneum, skin, spleen, uterus and others (unspecified). Statistical analysis of time to death or distant metastasis (TDDM) in the intention-to-treat population is shown. The probability of death or distant metastases is associated with a median TDDM of 23.2 months (23.2-NR, 95% CI) for durvalumab and 14.6 months (10.6-18.6, 95% CI) for placebo. The calculated hazard ratio is 0.52 (95% CI, 0.39-0.69). Statistical analysis of duration of response in the intention-to-treat population plotted as the percentage of patients remaining in response near clinical evaluation as a function of time (months). The median duration of response (DoR) (months) for durvalumab was "not reported," whereas placebo showed a median DoR of 13.8 months (6.0-NR, 95% CI).

Sequence The durvalumab light chain variable region amino acid sequence is provided as SEQ ID NO:1.

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

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

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

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

Thus, in various aspects described below, the disclosed methods provide treatment for patients with locally advanced, unresectable NSCLC who have not progressed after definitive chemoradiation therapy, wherein the treatment prolongs time to progression (PFS); increases response rate (ORR); increases time to death or metastasis (TTDM); decreases incidence of metastases; and/or the proportion of patients alive and progression-free (APF) can be increased.

In one aspect, the disclosure provides a method of prolonging time to progression (PFS) in a patient 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.

In one aspect, the present disclosure provides a method of increasing the 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.

In another aspect, the present 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.

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-L1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

In a related aspect, the disclosure provides a method of reducing the incidence of brain metastases 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.

In another aspect, the present 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.

In another aspect, the present disclosure provides a method of prolonging time to progression (PFS) 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.

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-1 antibody, wherein the patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.

In one aspect, the disclosure provides a method of reducing the incidence of brain metastases 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 chemoradiation therapy.

In embodiments of these embodiments, the chemoradiotherapy comprises a platinum-based therapeutic agent.

In some aspects of the above aspects, the lower incidence of metastases can be lymph node, brain, lung, liver, adrenal gland, bone, abdomen, biliary system, breast, chest, kidney, ovary, pancreas, pericardium, ascites, peritoneum, retroperitoneum, skin, spleen, and/or intrauterine. In some aspects, a lower incidence of metastasis may be within lymph nodes, brain, lung, liver, adrenal glands, and/or bone.

In some aspects 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 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 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; It has the amino acid sequence numbered 8.

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

In embodiments of the above embodiments, the method provides an increase in PFS of at least 5 months compared to placebo. In a further aspect, the method provides an increase in PFS of at least 13 months compared to placebo.

In some aspects of the above aspects, the method provides a 12% increase in ORR compared to placebo.

In some of the above aspects, the method provides an increase in TDDM of at least 4 months over placebo.

In some of the above aspects, 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. In some aspects, the methods provide a reduction in the incidence of metastases or brain metastases for at least 5 months relative to placebo.

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

In certain embodiments, the patient is administered one or more doses of anti-PD-1 antibody, wherein the dose is a fixed dose of 200 mg.

In certain embodiments, the patient is administered one or more doses of anti-PD-1 antibody, wherein the dose is a fixed dose of 240 mg.

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

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

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

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

In aspects of the above aspects, the patient may express genes (ie, have a phenotype) associated with a therapeutic response to therapy comprising a human anti-PD-L1 antibody. In some aspects, the patient is PD-L1(+). In another aspect, 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. Cutoffs and scoring algorithms have been previously determined for durvalumab (Study CP1108; ClinicalTrials.gov number NCT01693562).

In some aspects, the patient is EGFR mutated (+). In another aspect, the patient is EGFR mutated (-) or wild type. In some aspects, the patient may develop any combination of PD-L1 and EGFR mutation phenotypes.

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

Overall survival (OS) refers to the time from the day of treatment to death from any cause. OS can refer to overall survival within, for example, 12 months, 18 months, 24 months, and the like. Such a period can be identified as "OS24", which refers to the number (%) of patients alive 24 months after initiation of treatment, for example, by the Kaplan-Meier estimate of overall survival at 24 months.

Time to progression (PFS) relates 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 aspects, the methods provide increased PFS. In some aspects, the method provides a PFS of at least 9 months to at least about 24 months (eg, 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).

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 first documented response of progression or death in the absence of progression. In embodiments, the method provides an increase in DoR from at least about 9 months to at least about 36 months.

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 from at least about 9 months to at least about 36 months.

Percentage 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, for example, periods of 12 months, 18 months, 24 months, and the like. Such a period can be determined, for example, by the Kaplan-Meier estimate of progression-free survival at 12 months with APF12 to determine the number of patients alive and progression-free at 12 months after initiation of treatment.

Time to death or distant metastasis (TTDM) refers to any new lesion outside the radiation field. In some aspects, the method provides increased TTDM. In some aspects, the methods provide TTDM from 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).

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

The disclosed methods include administration of therapeutic agents (eg, human anti-PD-L1 antibodies or human anti-(andi) PD-1 antibodies) after previous treatment regimens that have failed to achieve one or more clinical endpoints. In certain embodiments, the method is performed after definitive chemoradiation therapy involving platinum-based drugs as discussed above. In some aspects, the methods are followed by 1, 2 or more rounds of definitive chemoradiation therapy that does not inhibit progression of NSCLC, including a platinum-based drug. In some aspects of the treatment methods provided herein, administration of the human anti-PD-L1 antibody or human anti-(andi) PD-1 antibody can be initiated after determination that the NSCLC has not responded to previous therapeutic regimens. In some aspects, the patient can be treated within 1 to about 42 days (eg, 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, or 42 or more days) after the patient receives chemoradiation therapy.

As described herein and shown in the Examples, the methods provide treatment of locally advanced, unresectable NSCLC. In some aspects, "unresectable" cancer includes cancer that cannot be completely removed by surgery for at least one of several medical reasons. Reasons a cancer may be unresectable include, for example, tumor size (e.g., may be too large to safely remove and/or require extensive removal of portions of essential organs), tumor location (e.g., tumors physically entwined with critical structures such as blood vessels or nerves), tumor metastases where removal of the tumor may not be effective in controlling all cancers, or other medical conditions that increase the risk of surgery to unacceptable levels (e.g., heart disease, lung disease, diabetes). Furthermore, unresectable NSCLC may not be permanently unresectable after aggressive treatment, which may be effective in reducing the size of the tumor to the extent that viable surgical resection is possible. Additionally, unresectable NSCLC can also refer to NSCLC (or distant metastases) that may 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 a lung cancer and part of a metastatic lesion.

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

As noted above and presented herein, the methods treat patients with late-stage (e.g., stage III), locally advanced, unresectable NSCLC that has not progressed after definitive chemoradiation therapy. Cancer staging can be performed using any test commonly known and accepted in the art. In embodiments, cancer staging can include the American Joint Committee on Cancer's (AJCC's) TNM system. In general, 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 the lymph nodes and, if so, the location and number of affected 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 cancers (metastases, M). Each type of cancer can have its own specific system, but the TNM staging system generally uses a scaled scoring for each letter.

For tumors, "T" is associated with a number (eg, 0-4) that describes the general tumor size, location, and whether it has invaded nearby tissue. Larger or invasive tumors may be given a higher number and, depending on the cancer, a lower case letter such as 'a', 'b' or 'm' (in plural cases) may be added to provide further detail.

Similarly for nodes, "N" is associated with a number (eg, 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 in the cancer.

For metastasis, "M" indicates whether the cancer has spread to other parts of the body, labeled M0 if not spread or M1 if spread.

The T, N, and M results are combined to determine the stage of the cancer, typically one of four stages: stages I(1)-IV(4). Some cancers also have stage 0 (zero). Stage 0 describes carcinoma in situ that remains local to the tissue of origin without any spread to neighboring tissues. Cancers at this stage are often highly curable, usually by surgical removal of the entire tumor. Stage I or early cancer is typically used to describe a small cancer or tumor that has not grown deeply into nearby tissues and has not spread to lymph nodes or other parts of the body. Stages II and III describe larger cancers or tumors that have grown deep 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.

Staging may optionally include analysis of prognostic factors to provide opportunities for recovery and recommended treatment. Prognostic factors may include classification of cancer based on appearance of cancer cells; analysis of tumor marker expression; and analysis of tumor genetics.

Cancers can be restaged using the same initial system to determine the efficacy of treatment or to obtain more information on recurrent cancers.

Stage Classification of NSCLC NSCLC has 5 stages: stage 0 (zero) and stages I-IV (1-4). Stage 0 NSCLC indicates that the cancer has not grown into nearby tissues or spread outside the lung.

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

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

Stage III includes substages IIIA or IIIB. In many stage IIIA cancers and nearly all stage IIIB cancers, the spread of the cancer to the lymph nodes or growth to nearby structures within the lung makes surgery difficult or impossible. Surgery in either situation typically requires partial removal of the cancer.

Stage IV NSCLC is associated with spread to more than one area in the other lung, fluid around 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 not be possible if it spreads to lymph nodes above the collarbone or to critical structures within the chest (e.g., the heart, great vessels, or major pulmonary structures). In certain aspects, the patients disclosed herein are stage IV NSCLC patients.

Recurrent NSCLC is detected after a course of treatment.

Anti-PD-L1 Antibodies Antibodies that specifically bind and inhibit PD-L1 activity (eg, bind PD-1 and/or CD80) are useful in the methods disclosed herein.

Durvalumab is an exemplary anti-PD-L1 antibody that is selective for PD-L1 and blocks PD-L1 binding to PD-1 and CD80 receptors. Durvalumab can alleviate PD-L1-mediated suppression of human T-cell activation in vitro and inhibit 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.

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

Information regarding durvalumab (or fragments thereof) used in the methods provided herein can be found in US Pat. Nos. 8,779,108 and 9,493,565, the entire disclosures of which are incorporated herein by reference. The fragment crystallizable (Fc) domain of durvalumab contains triple mutations within the constant domain of the IgG1 heavy chain that reduce binding to the complement components C1q and Fcγ receptors that play a role in mediating antibody-dependent T cell-mediated cytotoxicity (ADCC).

Durvalumab and antigen-binding fragments thereof used in the methods provided herein include heavy and light chains or heavy and light chain variable regions. In certain aspects, the durvalumab or antigen-binding fragment thereof used in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2. In certain aspects, the durvalumab or antigen-binding fragment thereof used in the methods provided herein comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the Kabat defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOS:3-5, and the light chain variable region comprising the Kabat defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOS:6-8. One skilled in the art will readily be able to identify Chothia definitions, Abm definitions or other CDR definitions known to those skilled in the art. In certain aspects, the durvalumab or 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 disclosed in U.S. Pat.

Patients with late-stage (III or IV), locally advanced, unresectable NSCLC that has not progressed after definitive chemoradiation therapy 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 providing benefit to the patient. In a further aspect, the patient is administered additional subsequent doses. Subsequent doses may be administered at varying time intervals, depending on the patient's age, weight, clinical evaluation, tumor burden, and/or other factors, including the judgment of the attending physician.

In embodiments, multiple doses of durvalumab or an antigen-binding fragment thereof are administered to the patient. In some aspects, 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 or more (i.e., throughout the year of treatment) may be administered to the patient. In some aspects, durvalumab or an antigen-binding fragment thereof is administered every 2 weeks, for 2 weeks, for a 4-week treatment period, for a 6-week treatment period, for an 8-week treatment period, for a 12-week treatment period, for a 24-week treatment period, or for a treatment period of 1 year or more.

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 a further aspect, the interval between doses can be every two months (eg, during the maintenance phase).

In certain embodiments, the dosing interval can also be about every 14 days or about every 21 days. In some aspects, "about" every 14 days or "about" every 21 days refers to 14 days +/- 2 days or 21 days +/- 2 days. In some aspects, administration of durvalumab is about every 14-21 days.

In certain embodiments, the patient is administered one or more doses of anti-PD-L1 antibody, wherein the dose is a fixed dose of 1200 mg.

The amount of durvalumab or 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.

In certain embodiments, the patient is administered one or more doses of durvalumab, where the dose is about 1 mg/kg. In certain embodiments, the patient is administered one or more doses of durvalumab, where the dose is about 3 mg/kg. In certain embodiments, the patient is administered one or more doses of durvalumab, where 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.

In certain aspects, the patient is administered one or more doses of durvalumab, where the dose is a fixed dose of 1500 mg.

In certain embodiments, the patient is administered at least two doses of durvalumab or an antigen-binding fragment thereof once every two weeks, and the dose is about 10 mg/kg. In a further aspect, the patient is administered a 10 mg/kg dose of durvalumab every two weeks for up to one year or longer.

In certain aspects, the patient is administered 1500 mg durvalumab every 4 weeks.

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 embodiments, administration is by intravenous infusion.

In certain aspects, durvalumab or an antigen-binding fragment thereof is administered in combination or in conjunction with additional cancer therapy according to the methods provided herein. Such treatments include, but are 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.

The methods provided herein can provide additional clinical benefits beyond those specifically identified and indicated by the data, including, for example, reducing tumor size, slowing tumor growth, or maintaining steady state. In certain embodiments, reduction in tumor size can be significant based on appropriate statistical analysis. Reduction in tumor size can be measured by comparison to the size of the patient's tumor at baseline, comparison to expected tumor size, comparison to expected tumor size based on a large patient population, or comparison to control population tumor size. In certain embodiments provided herein, administration of durvalumab can reduce tumor size by at least 25%, at least 50%, or at least 75%.

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

According to the methods provided herein, administration of v 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 AUC to the end of the dosing period, while "AUC(inf)" refers to AUC to infinite time. Dosing can result in an AUC (tau) of about 100 to about 2,500 dμg/mL. Dosing 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 may be from about 5 to about 25 days. Additionally, clearance of durvalumab or an antigen-binding fragment thereof may be about 1-10 ml/day/kg.

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 (eg, by durvalumab). In some aspects, PD-L1 levels are reduced by at least 80%. In some aspects, PD-L1 levels are reduced by at least 90%. In some aspects, PD-L1 levels are reduced by at least 95%. In some aspects, PD-L1 levels are reduced by at least 99%. In some aspects, PD-L1 levels are eliminated following administration of durvalumab or an antigen-binding fragment thereof. In some aspects, administration of durvalumab or an antigen-binding fragment thereof reduces the rate of increase in PD-L1 levels, eg, compared to the rate of increase in PD-L1 levels prior to administration of durvalumab or an antigen-binding fragment thereof.

Practice of the methods disclosed herein employs, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, well within the scope of those skilled in the art. Such techniques are described in the literature such as Molecular Cloning: A Laboratory Manual", second edition (Sambrook, 1989); "Oligonucleotide Synthesis" (Gait, 1984); ); "Methods in Enzymology", "Handbook of Experimental Immunology" (Weir, 1996); "Gene Transfer Vectors for Mammalian Cells" (Miller and Calos, 1987); "PCR: The Polymerase Chain Reaction", (Mullis, 1994); "Current Protocols in Immunology" (Coligan, 1991).

The following examples provide illustrations of some of the aspects and aspects described above and are not intended to limit the scope of the claimed invention.

Example 1: Clinical Evaluation of Durvalumab in the Treatment of Locally Advanced Stage III Unresectable NSCLC This example is a randomized, double-blind, international phase 3 PACIFIC trial (ClinicalTrials.gov number) comparing durvalumab to placebo as consolidation therapy for patients with stage III locally advanced unresectable NSCLC whose disease had not progressed after platinum-based cCRT. provides the results of an interim analysis of NCT02125461). This is the first randomized phase 3 trial to evaluate immune checkpoint blockade in this setting.

Patients Eligible patients have stage III, locally advanced, unresectable NSCLC histologically or cytologically documented by the International Association for the Study of Lung Cancer Staging Manual of Thoracic Oncology (v7) and have received definitive radiation therapy (54 Gy to 66 Gy). Concomitantly received ≧2 cycles (as defined by local practice) of platinum-based chemotherapy (including etoposide, vinblastine, vinorelbine, taxanes [paclitaxel or docetaxel], or pemetrexed), meaning that the lung dose was <20 Gy and/or the V20 was <35% and should not have progressed after this procedure. Patients were ≧18 years of age, had a World Health Organization (WHO) PS of 0 or 1, had an estimated life expectancy of ≧12 weeks, and had completed a final dose of radiation 1-14 days prior to randomization (changed 1-42 days after protocol amendment).

Receipt of immunotherapy or investigational drug in the 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 comorbidity; evidence of ongoing or active infection; including ≧Grade 2 interstitial pneumonitis from previous CRT.

Design and Treatment Patients were randomized in a 2:1 ratio within 1-42 days after cCRT to receive durvalumab 10 mg/kg intravenously or matching placebo every 2 weeks (q2w) as consolidation therapy for up to 12 months. Patients were stratified by age (<65 or >65 years), gender and smoking history (current/former smokers vs. never smokers). Once patients were confirmed to be eligible, study drug administration began on Day 1 after randomization. Study drug was discontinued if there was documented 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 symptom 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.

Endpoints and Assessments The co-primary endpoints were PFS (assessed by the Blinded Independent Central Review [BICR] by Response Evaluation Criteria In Solid Tumors [RECIST] v1.1), and overall survival (OS). PFS was defined as the time from randomization to 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 investigators as a predefined sensitivity analysis.

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

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

Statistical Analysis A trial was considered positive (successful) if the analysis of either of the two co-primary 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 study 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, with a two-sided significance level of 2.5% for each co-primary endpoint based on the log-rank test. An interim analysis of PFS was planned when approximately 367 events occurred. In this interim analysis, PFS effects were estimated using the Kaplan-Meier method. Between-arm comparisons of PFS were performed using the log-rank test, stratified by age, sex and smoking history. Sensitivity analyzes of PFS included assessment of assessment bias, assessment time bias and attrition bias in determining progression, and adjustment for various covariates in estimating 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.

An external independent data monitoring committee (IDMC) is evaluating ongoing safety and assessing interim efficacy analyses.

Patients and Treatments Between May 2014 and April 2016, 709 of the 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).

All patients had a median age of 64 years, were predominantly male (70%) and were current/former smokers (91%); 46% of patients had squamous histology. Prior chemotherapy was also well balanced; 55.9% and 54.4% of patients in the durvalumab and placebo groups, respectively, had previously received a cisplatin-based definitive regimen and 41.8% and 43.0% had received a carboplatin-based regimen (Table 2). In addition, 25.8% and 28.7% had received induction chemotherapy prior to definitive cCRT.

Based on archival tumor samples before cCRT, which were not re-evaluated after cCRT, ≧25% PD-L1 expression (TC≧25%) on tumor cells occurred in 22% of patients (24% in durvalumab group and 19% in placebo group) and TC<25% occurred in 41% (39% in durvalumab group and 44% in placebo group); She had an 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 tumors in 67.3% of patients were EGFR-negative or wild-type (66.2% in the durvalumab group and 69.6% in the placebo group); EGFR mutation status was unknown in 27.7% and 24.5%, respectively (Table 3). There were no statistically significant differences (P<0.05) between groups in either PD-L1 expression or EGFR mutation status.

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 in the durvalumab group (range 1-27) and 14 in the placebo group (range 1-26); 6.3% and 5.1% were still receiving treatment at data cutoff (Table 4).

Efficacy Median PFS from randomization as assessed by BICR was 16.8 months (95% confidence interval [CI], 13.0-18.1) with durvalumab versus 5.6 months (95% CI, 4.6-7.8) with placebo (stratified hazard ratio [HR] for disease progression or death, 0.52; 95% CI, 0.39-0.70; P<0.0001; FIG. 1). The 12-month PFS rate was 55.9% (95% CI, 51.0-60.4) with durvalumab and 35.3% (95% CI, 29.0-41.7) with placebo, and the 18-month PFS rate was 44.2% (95% CI, 37.7-50.5) and 27.0% (95% CI, 19.7%), respectively. 9-34.5). PFS results, including investigator-assessed PFS, were robust and consistent across all prespecified sensitivity analyzes (stratified HR, 0.61; 95% CI, 0.50-0.76; two-sided P<0.0001).

PFS benefit with durvalumab was consistently observed across all pre-specified subgroups defined by patient demographics, baseline clinicopathologic characteristics, and response to previous treatment (Figure 2; additional non-prognostic factors are presented in Figure 4). Of note, a PFS benefit with durvalumab was observed regardless of pre-cCRT PD-L1 expression (when TC<25%, HR, 0.59; 95% CI, 0.43-0.82; and when TC≧25%, HR, 0.41, 95% CI: 0.26-0.65). PFS benefit was also evident in nonsmokers and patients with EGFR mutations.

Median TTDM was 23.2 months (95% CI, 23.2-NR) with durvalumab compared to 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 a lower incidence of new brain metastases with durvalumab (5.5% vs. 11.0%, respectively) (Table 5).

Treatment with durvalumab resulted in 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). A median DoR was not achieved with durvalumab versus 13.8 months with placebo (Table 6; Figure 6). Of patients who responded to durvalumab, 72.8% had sustained responses at both 12 and 18 months (Table 6).

Safety All-causal 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 from AE occurred in 4.4% and 5.6%, respectively (Table 7). Treatment-related AEs are summarized in Table 8.

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

Any grade AEs of particular interest (AESIs) were reported in 66.1% and 48.7% of patients in the durvalumab and placebo groups, respectively, regardless of causality. The majority were grade 1/2, and grade ≧3 incidence was rare (<10%) in both treatment groups. The most frequent any grade AESIs for durvalumab vs. placebo were diarrhea (18.3% vs. 18.8%), interstitial pneumonia (12.6% vs. 7.7%), rash (12.2% vs. 7.3%) and pruritus (12.2% vs. 4.7%). AESI requiring concomitant treatment was reported in 42.1% and 17.1% of patients, respectively; treatments for AESI 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).

Any grade immune-mediated AEs, regardless of causality, were reported in 24.2% and 8.1% of patients who received durvalumab and placebo, respectively; grade 3/4 immune-mediated AEs were reported in 3.4% and 2.6% of patients, respectively (Table 9). Treatments 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).

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

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

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

Durvalumab had a favorable safety profile in this population, consistent with other immunotherapies as monotherapy and their known safety profile in patients with more severe disease (stage IIIB/IV NSCLC). The incidence of several all-causal AEs, including interstitial/radiation pneumonitis, was higher with both durvalumab and placebo in this study, which was not unexpected in this definitive dose post-cCRT setting. In addition, interstitial/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 reported in other trials in the same setting. The favorable safety profile of durvalumab after cCRT shown here may have implications for other disease settings.

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

The data demonstrate a statistically significant and clinically meaningful improvement in PFS with durvalumab after cCRT in stage III unresectable NSCLC and a manageable safety profile. These positive findings in an unselected patient population suggest a potential novel role for durvalumab in this setting, regardless of baseline pre-cCRT tumor PD-L1 expression, and, more generally, suggest that additional clinical benefits may be achieved through the use of immunotherapy in multimodal therapy.

ALTERNATIVE ASPECTS From the foregoing description, it will be apparent that changes and modifications may be made to the invention described herein to adapt it to various uses and situations. Such aspects are also included in the following claims.

Reference to a list of elements in any definition of a variable herein includes definitions of the variable as any single element or combination (or subcombination) of the listed elements. Reference to an aspect herein includes that aspect as any single aspect or in combination with any other aspect or portion thereof.

All patents and publications mentioned herein 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.

The disclosure includes the following sequence information.
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All patents and publications mentioned herein 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. The present disclosure includes the following embodiments.
[1] A method of prolonging the time to progression (PFS) of a patient with unresectable non-small cell lung cancer (NSCLC), said method comprising treating said patient with a human anti-PD-L1 antibody, said patient being a Stage III patient who has not progressed after definitive chemoradiation therapy.
[2] The method of embodiment 1, wherein said chemoradiation therapy is platinum-based.
[3] The method of embodiment 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:
a VH CDR1 having the amino acid sequence of SEQ ID NO:3; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and
a VH CDR3 having the amino acid sequence of SEQ ID NO:5; and
a VL CDR1 having the amino acid sequence of SEQ ID NO:6; and
a VL CDR2 having the amino acid sequence of SEQ ID NO:7; and
VL CDR3 having the amino acid sequence of SEQ ID NO:8
2. The method of embodiment 1, comprising:
[5] The method of embodiment 1, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.
[6] The method of embodiment 1, wherein the treatment with said human anti-PD-L1 antibody is 10 mg/kg intravenous Q2W.
[7] The method of embodiment 1, wherein PFS is increased over placebo by at least 5 months.
[8] The method of embodiment 1, wherein the PFS is at least 13 months.
[9] The method of embodiment 1, wherein said patient is PD-L1(+).
[10] The method of embodiment 1, wherein the patient is PD-L1(-).
[11] The method of embodiment 1, wherein said patient is EGFR mutated (+).
[12] The method of embodiment 1, wherein the patient is EGFR mutant (-) or wild type.
[13] A method of increasing the response rate (ORR) of a patient with unresectable NSCLC, said method comprising treating said patient with a human anti-PD-L1 antibody, wherein said patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.
[14] The method of embodiment 13, wherein said chemoradiation therapy is platinum-based.
[15] The method of embodiment 13, wherein said 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.
[16] wherein the human anti-PD-L1 antibody:
a VH CDR1 having the amino acid sequence of SEQ ID NO:3; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and
a VH CDR3 having the amino acid sequence of SEQ ID NO:5; and
a VL CDR1 having the amino acid sequence of SEQ ID NO:6; and
a VL CDR2 having the amino acid sequence of SEQ ID NO:7; and
VL CDR3 having the amino acid sequence of SEQ ID NO:8
14. The method of embodiment 13, comprising:
[17] The method of embodiment 13, wherein said human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.
[18] The method of embodiment 13, wherein the treatment with said human anti-PD-L1 antibody is 10 mg/kg intravenous Q2W.
[19] The method of embodiment 13, wherein said ORR is increased by at least 12% relative to placebo.
[20] The method of embodiment 13, wherein said patient is PD-L1(+).
[21] The method of embodiment 13, wherein said patient is PD-L1(-).
[22] The method of embodiment 13, wherein said patient is EGFR mutated (+).
[23] The method of embodiment 13, wherein said patient is EGFR mutated (-) or wild type.
[24] A method of increasing time to death or metastasis (TTDM) in a patient with unresectable NSCLC, said method comprising treating said patient with a human anti-PD-L1 antibody, wherein said patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.
[25] The method of embodiment 24, wherein said chemoradiation therapy is platinum-based.
[26] The method of embodiment 24, wherein said 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.
[27] wherein the human anti-PD-L1 antibody:
a VH CDR1 having the amino acid sequence of SEQ ID NO:3; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and
a VH CDR3 having the amino acid sequence of SEQ ID NO:5; and
a VL CDR1 having the amino acid sequence of SEQ ID NO:6; and
a VL CDR2 having the amino acid sequence of SEQ ID NO:7; and
VL CDR3 having the amino acid sequence of SEQ ID NO:8
25. The method of embodiment 24, comprising:
[28] The method of embodiment 24, wherein said human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.
[29] The method of embodiment 24, wherein the treatment with the human anti-PD-L1 antibody is 10 mg/kg intravenous Q2W.
[30] The method of embodiment 24, wherein said TDDM is increased relative to placebo by at least 4 months.
[31] A method of reducing the incidence of brain metastases in a patient with unresectable NSCLC, said method comprising treating said patient with a human anti-PD-L1 antibody, wherein said patient is a Stage III patient who has not progressed after definitive chemoradiation therapy.
[32] The method of embodiment 31, wherein said chemoradiation therapy is platinum-based.
[33] The method of embodiment 31, wherein said 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.
[34] wherein the human anti-PD-L1 antibody:
a VH CDR1 having the amino acid sequence of SEQ ID NO:3; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and
a VH CDR3 having the amino acid sequence of SEQ ID NO:5; and
a VL CDR1 having the amino acid sequence of SEQ ID NO:6; and
a VL CDR2 having the amino acid sequence of SEQ ID NO:7; and
VL CDR3 having the amino acid sequence of SEQ ID NO:8
32. The method of embodiment 31, comprising:
[35] The method of embodiment 31, wherein said human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.
[36] The method of embodiment 31, wherein the treatment with said human anti-PD-L1 antibody is 10 mg/kg intravenous Q2W.
[37] The method of embodiment 31, wherein the incidence of brain metastases is reduced relative to placebo by at least 5 months.
[38] A method of treating a patient with stage III unresectable NSCLC, said method comprising treating said patient with a human anti-PD-L1 antibody, wherein said patient has not progressed after definitive chemoradiation therapy.
[39] The method of embodiment 38, wherein said 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] wherein the human anti-PD-L1 antibody:
a VH CDR1 having the amino acid sequence of SEQ ID NO:3; and
a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; and
a VH CDR3 having the amino acid sequence of SEQ ID NO:5; and
a VL CDR1 having the amino acid sequence of SEQ ID NO:6; and
a VL CDR2 having the amino acid sequence of SEQ ID NO:7; and
VL CDR3 having the amino acid sequence of SEQ ID NO:8
39. The method of embodiment 38, comprising:
[41] The method of embodiment 38, wherein said anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab.
[42] The method of embodiment 38, wherein the treatment with said human anti-PD-L1 antibody is 10 mg/kg intravenous Q2W.

Claims (42)

A method of prolonging time to progression (PFS) in a patient with unresectable non-small cell lung cancer (NSCLC), said method comprising treating said patient with a human anti-PD-L1 antibody, said patient being a Stage III patient who has not progressed after definitive chemoradiation therapy. 2. The method of claim 1, wherein said chemoradiation therapy is platinum-based. 2. The method of claim 1, wherein said 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. wherein said 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;
2. The method of claim 1, comprising: 2. The method of claim 1, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. 2. The method of claim 1, wherein the treatment with the human anti-PD-L1 antibody is 10 mg/kg, intravenous Q2W. 2. The method of claim 1, wherein PFS is increased over placebo by at least 5 months. 2. The method of claim 1, wherein the PFS is at least 13 months. 2. The method of claim 1, wherein said patient is PD-L1(+). 2. The method of claim 1, wherein the patient is PD-L1(-). 2. The method of claim 1, wherein said patient is EGFR mutated (+). 2. The method of claim 1, wherein said patient is EGFR mutated (-) or wild type. A method of increasing the response rate (ORR) of a patient with unresectable NSCLC, said method comprising treating said patient with a human anti-PD-L1 antibody, wherein said patient is a Stage III patient who has not progressed after definitive chemoradiation therapy. 14. The method of claim 13, wherein said chemoradiation therapy is platinum-based. 14. The method of claim 13, wherein said 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. wherein said 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;
14. The method of claim 13, comprising: 14. The method of claim 13, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. 14. The method of claim 13, wherein the treatment with the human anti-PD-L1 antibody is 10 mg/kg, intravenous Q2W. 14. The method of claim 13, wherein the ORR is increased by at least 12% over placebo. 14. The method of claim 13, wherein said patient is PD-L1(+). 14. The method of claim 13, wherein the patient is PD-L1(-). 14. The method of claim 13, wherein said patient is EGFR mutated (+). 14. The method of claim 13, wherein the patient is EGFR mutant (-) or wild type. A method of increasing time to death or metastasis (TTDM) in a patient with unresectable NSCLC, said method comprising treating said patient with a human anti-PD-L1 antibody, wherein said patient is a Stage III patient who has not progressed after definitive chemoradiation therapy. 25. The method of claim 24, wherein said chemoradiation therapy is platinum-based. 25. The method of claim 24, wherein said 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. wherein said 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;
25. The method of claim 24, comprising: 25. The method of claim 24, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. 25. The method of claim 24, wherein the treatment with the human anti-PD-L1 antibody is 10 mg/kg intravenous Q2W. 25. The method of claim 24, wherein the TDDM increases relative to placebo by at least 4 months. A method of reducing the incidence of brain metastases in a patient with unresectable NSCLC, said method comprising treating said patient with a human anti-PD-L1 antibody, wherein said patient is a Stage III patient who has not progressed after definitive chemoradiation therapy. 32. The method of claim 31, wherein said chemoradiation therapy is platinum-based. 32. The method of claim 31, wherein said 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. wherein said 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;
32. The method of claim 31, comprising: 32. The method of claim 31, wherein the human anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. 32. The method of claim 31, wherein the treatment with the human anti-PD-L1 antibody is 10 mg/kg intravenous Q2W. 32. The method of claim 31, wherein the incidence of brain metastases is reduced relative to placebo by at least 5 months. A method of treating a patient with stage III unresectable NSCLC, said method comprising treating said patient with a human anti-PD-L1 antibody, wherein said patient has not progressed after definitive chemoradiation therapy. 39. The method of claim 38, wherein said 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. wherein said 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;
39. The method of claim 38, comprising: 39. The method of claim 38, wherein the anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. 39. The method of claim 38, wherein the treatment with the human anti-PD-L1 antibody is 10 mg/kg intravenous Q2W.