Compositions and methods for treating advanced solid tumors

Abstract

Methods for treating solid tumors with anti-PD-L1 and anti-CTLA-4 antibodies concurrently with chemoradiotherapy (cCRT) are disclosed.

Description

[Technical Field]

[0001] The present disclosure relates to methods for treating advanced solid tumors with an anti-PD-L1 antibody concomitant with chemoradiotherapy (cCRT) and optionally an anti-CTLA-4 antibody. [Background technology]

[0002] Cancer continues to be a major global health burden. In the United States, it is the second leading cause of death after heart disease, accounting for nearly one in four deaths. The five-year survival rate for all cancers diagnosed between 1999 and 2006 was 68%, which is 18% higher than the rate reported between 1975 and 1977, likely reflecting advances in earlier diagnosis of certain cancers and improvements in treatment.

[0003] It is estimated that approximately 12.7 million cancer cases and 7.6 million cancer deaths occurred worldwide in 2008. In most cases, these cancers are diagnosed at an advanced or metastatic stage, when life expectancy is very short. Despite recent advances in chemotherapy and understanding the molecular biology of cancer, progress in treatment options for advanced and metastatic disease has been limited. The poor prognosis reflects the limited effectiveness of available treatment options and highlights the need for the development of newer treatment options. Summary of the Invention

[0004] The present disclosure relates generally to methods for treating advanced solid tumors with anti-PD-L1 antibodies concomitant with chemoradiotherapy (cCRT) and optionally anti-CTLA-4 antibodies.

[0005] In one aspect, the disclosure provides a method of increasing overall response rate (ORR) in patients with small cell lung cancer (SCLC), comprising concurrently treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiation therapy.

[0006] In another aspect, the disclosure provides a method of increasing the disease control rate (DCR) in a patient with SCLC, the method comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiotherapy.

[0007] In a further aspect, the disclosure provides a method of treating a patient with SCLC, comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiation therapy.

[0008] In a further aspect, the disclosure provides a method of increasing the overall response rate (ORR) in patients with head and neck squamous cell carcinoma (HNSCC), comprising concurrently treating the patient with a human anti-PD-L1 antibody and chemoradiation therapy.

[0009] In a further aspect, the disclosure provides a method of increasing the disease control rate (DCR) in patients with HNSCC, comprising concurrently treating the patient with a human anti-PD-L1 antibody and chemoradiation therapy.

[0010] In a further aspect, the disclosure provides a method of treating a patient with HNSCC, comprising concurrently treating the patient with a human anti-PD-L1 antibody and chemoradiation therapy.

[0011] In a further aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy for use in a method of increasing the overall response rate (ORR) in patients with SCLC.

[0012] In a further aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy for use in a method of increasing the disease control rate (DCR) in patients with SCLC.

[0013] In a further aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody and concurrent chemoradiotherapy for use in the treatment of SCLC.

[0014] In a further aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy for use in a method of increasing the overall response rate (ORR) in patients with HNSCC.

[0015] In a further aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy for use in a method of increasing the disease control rate (DCR) in patients with HNSCC.

[0016] In a further aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy for use in the treatment of HNSCC.

[0017] In a further aspect, the disclosure herein provides for the use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy in the manufacture of a medicament for use in a method of increasing overall response rate (ORR) in patients with SCLC.

[0018] In a further aspect, the disclosure herein provides for the use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy in the manufacture of a medicament for use in a method of increasing the disease control rate (DCR) in patients with SCLC.

[0019] In a further aspect, the disclosure provides for the use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody and concurrent chemoradiation therapy in the manufacture of a medicament for use in the treatment of SCLC.

[0020] In a further aspect, the disclosure herein provides the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy in the manufacture of a medicament for use in a method of increasing the overall response rate (ORR) in patients with HNSCC.

[0021] In a further aspect, the disclosure herein provides the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy in the manufacture of a medicament for use in a method of increasing the disease control rate (DCR) in patients with HNSCC.

[0022] In a further aspect, the disclosure herein provides for the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy in the manufacture of a medicament for use in the treatment of HNSCC. [Brief explanation of the drawings]

[0023] [Figure 1] 1 shows a general study design for the methods disclosed herein. [Figure 2] 1 shows a detailed study flow chart for the head and neck squamous cell carcinoma (HNSCC) cohort described in Example 1. [Figure 3] 1 shows a detailed study flow chart for the non-small cell lung cancer (NSCLC) cohort described in Example 1. [Figure 4] 1 shows a detailed study flow chart for the small cell lung cancer (SCLC) cohort described in Example 1. [Figure 5] Disease-free survival in HNSCC is shown. [Figure 6] Overall survival in HNSCC is shown. [Figure 7] 1 shows progression-free survival (PFS) and overall survival (OS) in SCLC in arms 1 and 2 of the study. [Figure 8] 1 shows progression-free survival (PFS) and overall survival (OS) in SCLC in arms 1 and 2 of the study by treatment arm. [Figure 9]1 shows progression-free survival (PFS) and overall survival (OS) in SCLC in arms 3 and 4 of the study. [Figure 10] 1 shows progression-free survival (PFS) and overall survival (OS) in SCLC in arms 3 and 4 of the study by treatment arm. DETAILED DESCRIPTION OF THE INVENTION

[0024] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide those skilled in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings set forth below, unless otherwise specified.

[0025] 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, and "consisting essentially of" or "consists essentially of" have the meaning ascribed to them in U.S. patent law and are open-ended, allowing for the presence of more than what is recited, but excluding prior art aspects, so long as the basic or novel characteristics of what is recited are not changed by the presence of more than what is recited.

[0026] Unless specifically stated or clear from context, the term "or" as used herein is understood to be inclusive. Unless specifically stated or clear from context, the terms "a," "an," and "the" as used herein are understood to be singular or plural.

[0027] Unless specifically stated 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 to mean 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.

[0028] Any composition or method provided herein can be combined with one or more of any of the other compositions and methods provided herein.

[0029] Ranges provided herein are understood to be shorthand for all values ​​within that range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, 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.

[0030] As used herein, 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 antibodies, monoclonal antibodies, monospecific antibodies, multispecific antibodies, nonspecific antibodies, humanized antibodies, single-chain antibodies, chimeric antibodies, synthetic antibodies, recombinant antibodies, hybrid antibodies, mutated antibodies, and grafted antibodies. As in "intact antibody," unless specifically modified by the term "intact," for purposes of this disclosure, the term "antibody" also includes 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.

[0031] As used herein, the terms "antigen-binding domain," "antigen-binding fragment," and "binding fragment" refer to a portion of an antibody molecule comprising amino acids involved in specific binding between the antibody and the antigen. In some instances, if the antigen is large, the antigen-binding domain may bind only to a portion of the antigen. The portion of the antigen molecule involved in the specific interaction with the antigen-binding domain is called an "epitope" or "antigenic determinant." The antigen-binding domain is typically comprised of an 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 HIt consists of only the domain but still retains some of the antigen-binding function of an intact antibody.

[0032] Disclosed herein, in some embodiments, are methods of increasing overall response rate (ORR) in patients with small cell lung cancer (SCLC), the methods comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiation therapy.

[0033] Disclosed herein, in some embodiments, are methods of increasing disease control rates (DCR) in patients with SCLC, the methods comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiotherapy.

[0034] Disclosed herein, in some embodiments, are methods of treating a patient with SCLC, the methods comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiation therapy.

[0035] Disclosed herein, in some embodiments, are methods of increasing overall response rate (ORR) in patients with head and neck squamous cell carcinoma (HNSCC), comprising concurrently treating the patient with a human anti-PD-L1 antibody and chemoradiation therapy.

[0036] Disclosed herein, in some embodiments, are methods of increasing the disease control rate (DCR) in patients with HNSCC, comprising concurrently treating the patient with a human anti-PD-L1 antibody and chemoradiation therapy.

[0037] Disclosed herein, in some embodiments, are methods of treating a patient with HNSCC, comprising concurrently treating the patient with a human anti-PD-L1 antibody and chemoradiation therapy.

[0038] In some embodiments, the anti-PD-L1 antibody is durvalumab, avelumab, atezolizumab, or sugemalimab. In some embodiments, the anti-PD-L1 antibody is durvalumab. Durvalumab (MEDI4736, Imfinzi®) is a human monoclonal antibody against human PD-L1 that is capable of blocking the binding of PD-L1 to both the PD1 and CD80 receptors. Disclosures regarding durvalumab can be found in U.S. Patent Nos. 8,779,108 and 9,493,565, which are incorporated herein by reference.

[0039] Durvalumab for use in the methods, compositions, and combinations provided herein comprises a heavy chain and a light chain, or a heavy chain variable region and a light chain variable region. In some embodiments, durvalumab for use in the methods, compositions, and combinations 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 some embodiments, durvalumab for use in the methods, compositions, and combinations provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8. Those of skill in the art can readily identify CDR definitions based on the Chothia definition, Abm definition, or other definitions known to those of skill in the art. In some embodiments, durvalumab for use in the methods, compositions, and combinations 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, which are incorporated herein by reference in their entireties.

[0040] Durvalumab light chain (LC) variable region: EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK (SEQ ID NO: 1)

[0041] Durvalumab heavy chain (HC) variable region: EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS (SEQ ID NO: 2)

[0042] Durvalumab heavy chain CDRs: HC-CDR1: GFTFSRYWMS (SEQ ID NO: 3) HC-CDR2: NIKQDGSEKYYVDSVKG (SEQ ID NO: 4) HC-CDR3: EGGWFGELAFDY SEQ ID NO: 5)

[0043] Durvalumab, light chain CDR: LC-CDR1: RASQRVSSSYLA (SEQ ID NO: 6) LC-CDR2: DASSRAT (SEQ ID NO: 7) LC-CDR3: QQYGSLPWT (SEQ ID NO: 8)

[0044] In some embodiments, the anti-CTLA-4 antibody is tremelimumab. Tremelimumab for use in the methods, compositions, and combinations provided herein comprises a heavy chain and a light chain, or a heavy chain variable region and a light chain variable region. In some embodiments, tremelimumab for use in the methods, compositions, and combinations provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, tremelimumab for use in the methods, compositions, and combinations provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 11-13, and the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 14-16. Those of skill in the art can readily identify CDR definitions based on the Chothia definition, Abm definition, or other definitions known to those of skill in the art. In some embodiments, tremelimumab for use in the methods, compositions, and combinations provided herein comprises the variable heavy and variable light chain CDR sequences of the 11.2.1 antibody disclosed in U.S. Patent No. 6,682,736, which is incorporated herein by reference in its entirety.

[0045] Tremelimumab light chain (LC) variable region: PSSLSASVGDRVTITCRASQSINSYLDWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV (SEQ ID NO: 9)

[0046] Tremelimumab heavy chain (HC) variable region: GVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPRGATLYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH (SEQ ID NO: 10)

[0047] Tremelimumab heavy chain CDR HC-CDR1: GFTFSSYGMH (SEQ ID NO: 11) HC-CDR2: VIWYDGSNKYYADSV (SEQ ID NO: 12) HC-CDR3:DPRGATLYYYYYGMDV (SEQ ID NO: 13)

[0048] Tremelimumab light chain CDR1 LC-CDR1: RASQSINSYLD (SEQ ID NO: 14) LC-CDR2: AASSLQS (SEQ ID NO: 15) LC-CDR3: QQYYSTPFT (SEQ ID NO: 16)

[0049] Antibody binding fragments can be 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 be antibodies in which each of their binding sites is 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 antigens. As used herein, the term "Fv" refers to the minimum fragment of an antibody that retains both the antigen-recognition and antigen-binding sites. As used herein, the term "Fab" refers to an antibody fragment containing the constant domain of the light chain and the CHI domain of the heavy chain.

[0050] In some embodiments, the methods, compositions, and combinations disclosed herein relate to treating a subject for a tumor and / or cancer disorder. In some embodiments, the tumor is an advanced solid tumor. In some embodiments, the cancer is selected from small cell lung cancer, squamous cell carcinoma of the head and neck, and / or non-small cell lung cancer.

[0051] In certain embodiments, the small cell lung cancer is in a limited stage.

[0052] As used herein, the term "solid tumor" refers to an abnormal mass of tissue that does not usually contain cysts or liquid areas.

[0053] As used herein, the term "treatment" or "treating" refers to both therapeutic treatment and prophylactic or preventative measures. Subjects in need of treatment include subjects with cancer as well as subjects prone to have cancer or subjects in which cancer is to be prevented. In some embodiments, the methods, compositions, and combinations disclosed herein can be used for the treatment of cancer. In other embodiments, subjects in need of treatment include subjects with a tumor as well as subjects prone to have a tumor or subjects in which a tumor is to be prevented. In certain embodiments, the methods, compositions, and combinations disclosed herein can be used for the treatment of tumors. In other embodiments, treating tumors includes inhibiting tumor growth, promoting tumor regression, or both inhibiting tumor growth and promoting tumor regression.

[0054] As used herein, the term "administration" or "administering" refers to providing, contacting, and / or delivering one or more compounds by any suitable route to achieve a desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ocular, inhalation, and implant.

[0055] Provided herein are methods of treating a tumor in a subject in need thereof, comprising administering to the subject an anti-PD-L1 antibody at a dose of 5 mg / kg to 20 mg / kg. In some embodiments, provided herein are methods of treating a tumor in a subject in need thereof, comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at a fixed dose of 1000 mg to 2000 mg. In some embodiments, provided are methods of treating a tumor in a subject in need thereof, comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at a fixed dose of 1500 mg.

[0056] In certain embodiments, the subject is administered one or more fixed doses. In some embodiments, a method of treating a tumor in a subject in need thereof is provided comprising administering to the subject an anti-PD-L1 antibody, wherein the dose is 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg. In some embodiments, the subject is administered one or more fixed doses of the anti-PD-L1 antibody, wherein the dose is 1500 mg.

[0057] In certain embodiments, the anti-PD-L1 antibody is administered over a 2-week treatment period, 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 a treatment period of one year or more. In certain embodiments, the anti-PD-L1 antibody is administered over a 3-week treatment period, a 6-week treatment period, a 9-week treatment period, a 12-week treatment period, a 24-week treatment period, or a treatment period of one year or more. In certain embodiments, the anti-PD-L1 antibody is administered over a 2-month treatment period, a 4-month treatment period, or a treatment period of six months or more.

[0058] As used herein, the terms "co-administered," "in combination," or "combination therapy" refer to the simultaneous or sequential administration of multiple compounds or agents. A first compound or agent can be administered prior to, simultaneously with, or after the administration of a second compound or agent. A first compound or agent and a second compound or agent can be administered simultaneously or sequentially on the same day, or sequentially within 1, 2, 3, 4, 5, 6 days, 1 week, 2 weeks, 3 weeks, or 1 month of each other. In some embodiments, the compounds or agents are co-administered for the period during which each compound or agent exerts and / or remains effective at least some physiological effect.

[0059] In some embodiments, the anti-PD-L1 antibody is administered concurrently with chemoradiotherapy. As used herein, the term "concurrently" refers to the administration of the anti-PD-L1 antibody and the chemoradiotherapy within about 3 days of each other. In some embodiments, the anti-PD-L1 antibody is administered within about 2 days of chemoradiotherapy. In some embodiments, the anti-PD-L1 antibody is administered within about 1 day of chemoradiotherapy. In some embodiments, the anti-PD-L1 antibody is administered on day 1 of cycle 1 of chemoradiotherapy.

[0060] In some embodiments, the anti-PD-L1 antibody is administered simultaneously with the anti-CTLA-4 antibody and chemoradiotherapy. In specific embodiments, the anti-PD-L1 antibody and anti-CTLA-4 antibody are administered simultaneously, separately, or sequentially. In some embodiments, the anti-PD-L1 antibody and anti-CTLA-4 antibody are administered within about 3 days of the administration of chemoradiotherapy. In some embodiments, the anti-PD-L1 antibody and anti-CTLA-4 antibody are administered within about 2 days of the administration of chemoradiotherapy. In some embodiments, the anti-PD-L1 antibody and anti-CTLA-4 antibody are administered within about 1 day of the administration of chemoradiotherapy. In some embodiments, the anti-PD-L1 antibody and anti-CTLA-4 antibody are administered on day 1 of cycle 1 of chemoradiotherapy.

[0061] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg. In specific embodiments, the subject receives one or more fixed doses of the anti-CTLA-4 antibody, the dose being 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.

[0062] In certain embodiments, the anti-CTLA-4 antibody is administered every week, every two weeks, every four weeks, every six weeks, every eight weeks, every ten weeks, or every twelve weeks.

[0063] In certain embodiments, the anti-CTLA-4 antibody is administered over a 2-week treatment period, 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 a treatment period of one year or more. In certain embodiments, the anti-CTLA-4 antibody is administered over a 3-week treatment period, a 6-week treatment period, a 9-week treatment period, a 12-week treatment period, a 24-week treatment period, or a treatment period of one year or more. In certain embodiments, the anti-CTLA-4 antibody is administered over a 2-month treatment period, a 4-month treatment period, or a treatment period of six months or more.

[0064] In some embodiments, the chemoradiotherapy comprises a platinum-based therapeutic agent.

[0065] In some embodiments, the concurrent chemoradiotherapy comprises any accepted standard first-line treatment for patients with small cell lung cancer, squamous cell carcinoma of the head and neck, and / or non-small cell lung cancer. In some embodiments, the standard first-line treatment may comprise chemotherapy, radiation therapy, or both (chemoradiotherapy). In some embodiments, the treatment may comprise one or more platinum-based chemotherapeutic agents. In some embodiments, the one or more platinum-based chemotherapeutic agents may be selected from carboplatin, cisplatin, oxaliplatin, or a combination thereof. As described herein, the platinum-based therapy may comprise a single-agent or double-agent regimen, such as administering cisplatin or carboplatin together with another anticancer agent, such as paclitaxel, docetaxel, etoposide, gemcitabine, or vinorelbine.

[0066] In some embodiments, provided herein is a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy for use in a method of increasing the overall response rate (ORR) in patients with SCLC.

[0067] In some embodiments, provided herein is a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy for use in a method of increasing the disease control rate (DCR) in patients with SCLC.

[0068] In some embodiments, provided herein is a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiotherapy for use in the treatment of SCLC.

[0069] In some embodiments, provided herein is a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy for use in a method of increasing the overall response rate (ORR) in patients with HNSCC.

[0070] In some embodiments, provided herein is a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy for use in a method of increasing the disease control rate (DCR) in patients with HNSCC.

[0071] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy in the manufacture of a medicament for use in a method of increasing overall response rate (ORR) in patients with SCLC.

[0072] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy in the manufacture of a medicament for use in a method of increasing the disease control rate (DCR) in patients with SCLC.

[0073] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiation therapy in the manufacture of a medicament for use in the treatment of SCLC.

[0074] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy in the manufacture of a medicament for use in a method of increasing the overall response rate (ORR) in patients with HNSCC.

[0075] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy in the manufacture of a medicament for use in a method of increasing the disease control rate (DCR) in patients with HNSCC.

[0076] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiation therapy in the manufacture of a medicament for use in the treatment of HNSCC.

[0077] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a compound or composition that can induce a desired therapeutic effect when properly administered to a subject. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one antibody of the present disclosure.

[0078] As used herein, the term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" refers to one or more antibodies suitable for achieving or enhancing the delivery of one or more binding proteins of the present disclosure.

[0079] When used for in vivo administration, the formulations of the present disclosure should be sterile. The formulations of the present disclosure can be sterilized by various sterilization methods, such as sterile filtration or irradiation. In one embodiment, the formulation is sterile filtered through a pre-sterilized 0.22 micron filter. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice, such as described in "Remington: The Science & Practice of Pharmacy," 21st ed., Lippincott Williams & Wilkins, (2005).

[0080] In some embodiments, antibodies can be formulated for a particular route of administration, e.g., oral, nasal, pulmonary, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral. As used herein, the terms "parenteral administration" and "parenterally administered" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. Formulations of the present disclosure suitable for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The antibodies and other active agents may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required (see, e.g., U.S. Pat. Nos. 7,378,110, 7,258,873, and 7,135,180; U.S. Patent Application Publication Nos. 2004 / 0042972 and 2004 / 0042971).

[0081] The formulations can be provided in unit dosage form and can be prepared by any method known in the art of pharmacy. The actual dosage level of the active ingredient in the formulations of the present disclosure can be varied to obtain an amount of the active ingredient that is not toxic to the subject and is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration (e.g., a "therapeutically effective amount"). The dosage can also be administered via continuous infusion (e.g., by pump). The administered dose can also depend on the route of administration. For example, subcutaneous administration may require a higher dose than intravenous administration.

[0082] The disclosed treatment methods can provide substantial improvements in patient overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the proportion of patients alive 12 months from randomization (OS12).

[0083] In some embodiments, the method results in an increase in PFS compared to placebo. In some embodiments, the method results in an increase in ORR compared to placebo. In some embodiments, the method results in an increase in DCR compared to placebo. In some embodiments, the method results in an increase in OS compared to placebo.

[0084] The practice of the methods disclosed herein employs, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are well within the skill of those in the art. Such techniques are explained fully in such references as "Molecular Cloning: A Laboratory Manual," second edition (Sambrook, 1989); "Oligonucleotide Synthesis" (Gait, 1984); "Animal Cell Culture" (Freshney, 1987); "Methods in Enzymology"; "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). [Example]

[0085] Example 1: Efficacy of durvalumab and tremelimumab in combination with chemoradiotherapy in patients with solid tumors An open-label, multicenter, phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary efficacy of durvalumab ± tremelimumab in combination with chemoradiotherapy in patients with advanced solid tumors. The initial cohort included patients with locally advanced HNSCC, locally advanced unresectable (stage III) NSCLC, and limited-stage SCLC. The study consisted of a dose-limiting toxicity (DLT) evaluation phase (Part A) and an expansion phase (Part B). A study schematic is shown in Figure 1.

[0086] Study design HNSCC cohort Part A: DLT evaluation phase The study included one group. Details of the initial group are as follows: Group 1: Cisplatin and radiation plus durvalumab in patients with locally advanced HNSCC Group 1 used the standard durvalumab dose / administration regimen (durvalumab 1500 mg every 4 weeks [q4w]) along with chemoradiotherapy.

[0087] Over a period of approximately 7 weeks, the primary tumor and involved lymph nodes ideally receive 70 Gy in 35 daily fractions (i.e., 2 Gy / fraction, 5 fractions per week), and asymptomatic disease sites ideally receive 56 Gy in 35 daily fractions (i.e., 1.6 Gy / fraction, 5 fractions per week). If areas considered at high risk of microscopic disease are identified, these may be treated to a total dose of 61.25 Gy in 35 fractions (i.e., 1.75 Gy / fraction, 5 fractions per week).

[0088] In Part A, a total of up to 12 patients were assigned to Arm 1 for evaluation of DLTs in patients treated with durvalumab along with chemoradiotherapy.

[0089] Part B: Expansion Phase In Part B, up to 30 additional patients were assigned to arms.

[0090] The detailed study flow chart of the HNSCC cohort is shown in Figure 2.

[0091] NSCLC cohort Part A: DLT evaluation phase The trial initially included three groups. Details of the initial groups are as follows: Group 1: Cisplatin and etoposide with radiation plus durvalumab in patients with locally advanced unresectable (stage III) NSCLC.

[0092] Group 2: Carboplatin and paclitaxel with radiation plus durvalumab in patients with locally advanced unresectable (stage III) NSCLC.

[0093] Arm 3 (non-squamous indications only): Investigator's choice of carboplatin and pemetrexed or cisplatin and pemetrexed with radiation plus durvalumab in patients with locally advanced unresectable (stage III) NSCLC.

[0094] Groups 1, 2, and 3 received the standard durvalumab dose / administration regimen (durvalumab 1500 mg q4w) along with chemoradiotherapy.

[0095] A total dose of 60 Gy was delivered in 30 daily fractions (i.e., 2 Gy / fraction, 5 weekly fractions) over a period of approximately 6 weeks. In Part A, a total of 18 patients were enrolled in groups 1, 2, and 3 (6 per group) for evaluation of DLTs in patients treated with durvalumab with chemoradiation therapy.

[0096] Part B: Expansion Phase Up to 30 additional patients were assigned to each arm in Part B. However, Arm 3 will enroll patients with only non-squamous NSCLC.

[0097] The detailed study flow chart for the NSCLC cohort is shown in Figure 3.

[0098] SCLC cohort Part A: DLT evaluation phase The trial included four groups. Details of the initial groups are as follows: Group 1: Cisplatin and etoposide with standard radiation plus durvalumab in patients with limited-stage SCLC. Patients started on cisplatin but had the option to switch to carboplatin (AUC 5) if cisplatin was not tolerated.

[0099] Group 2: Cisplatin and etoposide with hyperfractionated radiation plus durvalumab in patients with limited-stage SCLC. Patients started on cisplatin but had the option to switch to carboplatin (AUC 5) if cisplatin was not tolerated.

[0100] Group 3: Cisplatin and etoposide with standard radiation plus durvalumab and tremelimumab in patients with limited-stage SCLC. Patients started on cisplatin but had the option to switch to carboplatin (AUC 5) if cisplatin was not tolerated.

[0101] Group 4: Cisplatin and etoposide with hyperfractionated radiation plus durvalumab and tremelimumab in patients with limited-stage SCLC. Patients started on cisplatin but had the option to switch to carboplatin (AUC 5) if cisplatin was not tolerated.

[0102] Groups 1, 2, 3, and 4 used the standard durvalumab ± tremelimumab dose / administration regimen (durvalumab 1500 mg q4w ± tremelimumab 75 mg q4w) with chemoradiation administered according to National Comprehensive Cancer Network guidelines for radiation therapy and local prescribing information for chemotherapy.

[0103] A total dose of 60-70 Gy was delivered in 30-35 fractions (i.e., 2 Gy / fraction, 5 fractions per week) for groups 1 and 3 over a period of 6-7 weeks (starting within the first or second cycle of chemotherapy). A total dose of 45 Gy was delivered in 30 fractions (i.e., 1.5 Gy / fraction, 2 fractions per day [at least 6 hours apart], 10 fractions per week) for groups 2 and 4 over a period of 3 weeks (starting within the first or second cycle of chemotherapy).

[0104] If the initial dosing schedule of tremelimumab (75 mg q4w) in Groups 3 and 4 (Schedule 0) was not tolerated, it was adjusted (Schedule 1). Tremelimumab was administered once on Day 1 (Week 0) and three additional doses were administered after chemoradiotherapy. If this schedule was still not tolerated, the tremelimumab schedule was adjusted again (Schedule 2), in which all four doses were administered after chemoradiotherapy (Table 1). For Schedules 1 and 2, postchemoradiotherapy tremelimumab administration began at least 48 hours after completion of the initial chemoradiotherapy and any recommended prophylactic cranial irradiation (PCI) and was administered together with the next scheduled dose of durvalumab.

[0105] [Table 1] a PCI is permitted at the investigator's discretion for patients who respond to initial therapy (CR or PR). PCI should be administered according to guidelines. If indicated, PCI will be given after resolution of acute toxicity from initial chemoradiation therapy and no later than 2 weeks after the final dose of tremelimumab. b The maintenance dose of tremelimumab should be administered q4w concurrently with the next scheduled dose of durvalumab in eligible patients and at least 48 hours after completion of PCI. cSubsequent initiation of thoracic radiation in patients may be limited to within the second cycle of chemotherapy, at the discretion of the safety review committee, if a DLT occurs in the first cycle of chemoradiation therapy on Schedule 0). CR complete response PCI prophylactic cranial irradiation, PR partial response, q4w every 4 weeks.

[0106] PCI was permitted at the investigator's discretion for patients in the SCLC cohort who responded to initial therapy (complete response [CR] or partial response [PR]). If indicated, PCI was administered after resolution of acute toxicity from initial chemoradiotherapy and at least 2 weeks after the final dose of tremelimumab. PCI was recommended for eligible patients 4 to 11 weeks after completion of chemoradiotherapy. Patients in Groups 1 and 2 underwent PCI after resolution of acute toxicity from initial chemoradiotherapy. For patients in Groups 3 and 4, those in Schedule 0 underwent PCI after resolution of acute toxicity from initial chemoradiotherapy and at least 2 weeks after the final dose of tremelimumab, whereas patients in Schedules 1 and 2 underwent PCI after resolution of acute toxicity from initial chemoradiotherapy and before starting postchemoradiotherapy administration of tremelimumab. In Part A, a total of 12 patients were enrolled in Groups 1 and 2 for evaluation of DLTs in patients treated with durvalumab together with chemoradiotherapy. If additional safety data were required, an additional 6 patients were enrolled in each group.

[0107] Part B: Expansion Phase In the expansion phase, investigators could choose to combine either cisplatin or carboplatin with etoposide to further evaluate the safety and tolerability of concurrent chemoradiation therapy with durvalumab and / or tremelimumab. A minimum of five patients were assigned to the carboplatin regimen in each progressing arm. A maximum of 30 additional patients were enrolled in each progressing arm.

[0108] The detailed study flow chart for the SCLC cohort is shown in Figure 4.

[0109] the purpose Main purpose

[0110] [Table 2] AE = adverse event; BP = blood pressure; DLT = dose-limiting toxicity; ECG = electrocardiogram.

[0111] secondary purpose

[0112] [Table 3] BoR Best objective response rate; DCR Disease control rate; DFS Disease-free survival; DFS12 Disease-free survival at 12 months; DFS18 Disease-free survival at 18 months; DFS24 Disease-free survival at 24 months; DoR Duration of response; HNSCC Squamous cell carcinoma of the head and neck; NSCLC Non-small cell lung cancer; ORR Objective response rate; OS Overall survival; PFS12 Progression-free survival at 12 months; PFS18 Progression-free survival at 18 months; PFS24 Progression-free survival at 24 months; RECIST 1.1 Response Evaluation Criteria in Solid Tumors Version 1.1; SCLC Small cell lung cancer.

[0113] Target Patient Population To be included in the study, patients met the following criteria: age ≥ 18 years at screening and no prior exposure to immune-mediated therapies, including but not limited to other anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, or therapeutic anti-cancer vaccines.

[0114] For the HNSCC cohort, patients had histologically or cytologically confirmed locally advanced HNSCC, were eligible for definitive chemoradiotherapy treatment, and were not considered for primary surgery based on investigator decision or patient refusal. Patients with the following subtypes of HNSCC were eligible for this study: Unresectable oral stage IVa and IVb Pharynx: Stage IVa and IVb Hypopharynx: T3-4N0, T2-4N1-3 (stages III, IVa, and IVb) HPV-negative oropharynx: T3-4N0 or T2-4N1-3 (stages III, IVa, and IVb) HPV-positive oropharynx: N2b / N2c or T4 or N3 (stages III, IVa, and IVb) regardless of smoking status and history of ≥ 10 pack-years

[0115] For the HNSCC and NSCLC cohorts, patients had histologically or cytologically proven NSCLC presenting with locally advanced unresectable (stage III) disease.

[0116] For the SCLC cohort, patients had histologically or cytologically proven limited stage SCLC (I-III SCLC [T any, N any, M0]), i.e., patients whose disease could be encompassed within the definitive radiation portal.

[0117] Efficacy evaluation Efficacy assessments of ORR, best objective response rate (BoR), DoR, DCR, and PFS were derived using investigator RECIST 1.1 assessments. Baseline investigator RECIST 1.1 tumor assessments utilized images from CT (preferred) or MRI (each preferably with IV contrast) of applicable regions for that cohort's tumor type. FDG-PET / CT with IV contrast and brain MRI (preferred or CT with IV contrast) scans were obtained during the screening period for staging purposes (to identify metastatic tumor sites) and for any in-study subjects to evaluate new lesions; they were not used for baseline RECIST 1.1 selection of target lesions (TL) and non-target lesions (NTL). Any other areas of disease involvement were additionally imaged based on individual patient signs and symptoms. Baseline assessments were performed within 28 days prior to the start of study drug, ideally as close as possible to and before the start of study drug. RECIST 1.1 assessment of baseline images identified a maximum of five total TLs, no more than two TLs (defined as measurable) and NTLs per organ, and each lesion (and any new lesions) was evaluated on subsequent follow-up images, allowing for determination of follow-up TL response, NTL response, new lesions, and overall time-point tumor response (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], or not evaluable [NE]).

[0118] Dosage and Mode of Administration Where applicable, for all cohorts, if a patient's weight dropped below 30 kg (≤30 kg), they received weight-based dosing equivalent to 20 mg / kg durvalumab q4w and 1 mg / kg tremelimumab q4w until their weight improved to >30 kg, at which point they began receiving a fixed dose of durvalumab 1500 mg + tremelimumab 75 mg q4w.

[0119] On days when multiple intraperitoneal (IP) doses were administered, IV tremelimumab was administered first, followed by durvalumab and then cisplatin, if needed.

[0120] Tremelimumab was administered first. The durvalumab infusion was initiated immediately after the end of the tremelimumab infusion. The standard infusion time for both tremelimumab and durvalumab was 1 hour (± 15 minutes). However, if there was an interruption during the infusion, the total allowed time exceeded 8 hours at room temperature. If there were clinical concerns related to the tolerability of immediate sequential administration, subsequent cycles of durvalumab were given up to 1 hour after the end of the tremelimumab infusion, at the investigator's discretion.

[0121] When durvalumab and chemotherapy were administered on the same day, durvalumab was administered first, followed by chemotherapy (number of infusions according to institutional standards).

[0122] Radiation was administered according to the National Comprehensive Cancer Network recommended treatment guidance.

[0123] HNSCC cohort Durvalumab (MEDI4736) monotherapy with chemoradiotherapy (Group 1) Patients in Group 1 received: Durvalumab: Patients received 1500 mg of durvalumab (MEDI4736) by IV infusion q4w for 2 years unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0124] Radiation: External beam radiation (1.6–2 Gy / fraction) was administered daily from weeks 1 to 7 (5 fractions per week for approximately 7 weeks of treatment) unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0125] Cisplatin: Patients will receive cisplatin 100 mg / m unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met (whichever occurs first). 2 was administered via IV infusion q3w starting at week 1 with the final dose received at week 7 (3 doses). Table 2 shows the dosing scheme for the HNSCC cohort.

[0126] [Table 4] a Please note that the final dose of durvalumab will be administered at week 100. NOTE: All drugs administered have a dosing window of ±3 days (except for Day 1, which has a dosing window of +3 days). Note: Durvalumab dose is 1500 mg. Cisplatin dose is 100 mg / m 2 Radiation is administered at a dose of 1.6-2 Gy / fraction, 5 times weekly. CisCisplatin; DurvaDurvalumab; HNSCCSquamous cell carcinoma of the head and neck.

[0127] NSCLC cohort Durvalumab (MEDI4736) monotherapy with chemoradiotherapy (Group 1) Patients in Group 1 received: Durvalumab: Patients received 1500 mg durvalumab (MEDI4736) by IV infusion q4w until PD unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0128] Radiation: External beam radiation (2 Gy / fraction) was administered daily from week 0 to week 5 (5 weekly fractions for approximately 6 weeks of treatment, totaling 60 Gy) unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0129] Cisplatin: Patients will receive cisplatin 50 mg / m unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met (whichever occurs first). 2 via IV infusion on days 1, 8, 29, and 36 (weeks 0, 1, 4, and 5, respectively).

[0130] Etoposide: Patients received etoposide 50 mg / m unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first). 2 were received via IV infusion on days 1-5 (week 0) and days 29-33 (week 4).

[0131] Durvalumab (MEDI4736) monotherapy with chemoradiotherapy (Group 2) Patients in Group 2 received: Durvalumab: Patients received 1500 mg durvalumab (MEDI4736) by IV infusion q4w until PD unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0132] Radiation: External beam radiation (2 Gy / fraction) was administered daily from week 0 to week 5 (5 weekly fractions for approximately 6 weeks of treatment, totaling 60 Gy) unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0133] Carboplatin: Patients received carboplatin AUC 2 IV infusion q1w starting at week 0 with the final dose at week 5 (6 doses), followed by consolidation with carboplatin AUC 6 IV infusion on days 43 (week 6) and 64 (week 9) (day 1 of two 21-day cycles [q3w]) unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first). Carboplatin consolidation cycles were optional and depended on local practice.

[0134] Paclitaxel: Patients received paclitaxel 45–50 mg / m2 IV infusion q1w starting at week 0 with a final dose at week 5 (6 doses), followed by consolidation with paclitaxel 200 mg / m2 IV infusion on days 43 (week 6) and 64 (week 9) (day 1 of two 21-day cycles [q3w]) unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first). Paclitaxel consolidation cycles were optional and dependent on local practice.

[0135] Durvalumab (MEDI4736) monotherapy with chemoradiotherapy (Group 3) Patients in Group 3 received: Durvalumab: Patients received 1500 mg durvalumab (MEDI4736) by IV infusion q4w until PD unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0136] Radiation: External beam radiation (2 Gy / fraction) was administered daily from week 0 to week 5 (5 weekly fractions for approximately 6 weeks of treatment, totaling 60 Gy) unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0137] Carboplatin / cisplatin: At the investigator's discretion, patients may receive carboplatin AUC 5 or cisplatin 75 mg / m via IV infusion on days 1 (week 0), 22 (week 3), and 43 (week 6) (day 1 of three 21-day cycles [q3w]) unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met (whichever occurs first). 2 received.

[0138] Pemetrexed: Patients will receive pemetrexed 500 mg / m via IV infusion on days 1 (week 0), 22 (week 3), and 43 (week 6) (day 1 of three 21-day cycles [q3w]) unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met (whichever occurs first). 2 received.

[0139] Table 3 shows the dosing scheme for the NSCLC cohort.

[0140] [Table 5] a Cisplatin 50 mg / m 2 will be administered to patients in Group 1 on days 1, 8, 29 and 36. b Etoposide 50 mg / m 2 will be administered to patients in Group 1 on days 1-5 and days 29-33. c Carboplatin AUC 2 and paclitaxel (45-50 mg / m 2 ) will be administered to patients in Group 2 q1w during weeks 0-5. d Carboplatin AUC 6 and paclitaxel (200 mg / m 2 ) will be administered to patients in Arm 2 on days 43 and 64 (day 1 of 21-day cycles [q3w] for two cycles). Carboplatin / paclitaxel intensification cycles are optional and depend on local practice. e For patients in Group 3, the investigators performed the following analyses on Days 1, 22, and 43 (3 cycles): ル On day 1 of a 21-day cycle (q3w), carboplatin AUC 5 or cisplatin ン (75 mg / m 2 ) may be administered. f Pemetrexed (500 mg / m 2 ) will be administered to patients in Group 3 on days 1, 22, and 43 (day 1 of three 21-day cycles [q3w]). NOTE: All drugs administered have a dosing window of ±3 days (except for Day 1, which has a dosing window of +3 days). Note: Durvalumab dose is 1500 mg (q4w) and radiation is 2 Gy / fraction, 5 fractions per week (60 Gy total). AUC area under the plasma drug concentration-time curve; Carbo carboplatin; Cis cisplatin; Durva durvalumab; Etop etoposide; NSCLC non-small cell lung cancer; Pac paclitaxel; Pem pemetrexed; PD advanced disease; q1w once weekly; q3w every 3 weeks; q4w every 4 weeks.

[0141] SCLC cohort Durvalumab (MEDI4736) monotherapy with chemoradiotherapy (Group 1) Patients in Group 1 received: Durvalumab: Patients received 1500 mg durvalumab (MEDI4736) by IV infusion q4w until PD unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0142] Radiation: External beam radiation (2 Gy / fraction) was administered daily, starting within the first or second cycle of chemotherapy, for a total of 60–70 Gy in five weekly fractions over 6–7 weeks unless unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met (whichever occurred first).

[0143] Cisplatin and etoposide: Patients will receive cisplatin 60–80 mg / m on days 1 (week 0), 22 (week 3), 43 (week 6), 64 (week 9), 85 (week 12), and 106 (week 15) (day 1 of 4–6 21-day cycles [q3w], according to local guidelines), and days 1–3 (week 0), starting at week 0, unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met (whichever occurs first). 2, etoposide 100–120 mg / m on days 22–24 (week 3), 43–45 (week 6), 64–66 (week 9), 85–87 (week 12), and 106–108 (week 15) (days 1–3 of four to six 21-day cycles, according to local guidelines) 2 Patients received cisplatin via IV infusion. Patients were initiated on cisplatin but had the option to switch to carboplatin (AUC 5) if cisplatin was not tolerated. The total cisplatin dose per cycle could be split across days 1, 2, and 3 of each chemotherapy cycle in Part B only, if there were tolerability concerns and only after consultation with the global medical team.

[0144] Durvalumab (MEDI4736) monotherapy with chemoradiotherapy (Group 2) Patients in Group 2 received: Durvalumab: Patients received 1500 mg durvalumab (MEDI4736) by IV infusion q4w until PD unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0145] Radiation: External beam radiation (1.5 Gy / fraction) was administered daily, starting within the first or second cycle of chemotherapy, for a total of 45 Gy in 10 weekly fractions [2 fractions per day, at least 6 hours apart] over 3 weeks, unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0146] Cisplatin and etoposide: Patients will receive cisplatin 60–80 mg / m on days 1 (week 0), 22 (week 3), 43 (week 6), 64 (week 9), 85 (week 12), and 106 (week 15) (day 1 of 4–6 21-day cycles [q3w], according to local guidelines), and days 1–3 (week 0), starting at week 0, unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met (whichever occurs first). 2, etoposide 100–120 mg / m on days 22–24 (week 3), 43–45 (week 6), 64–66 (week 9), 85–87 (week 12), and 106–108 (week 15) (days 1–3 of four to six 21-day cycles, according to local guidelines) 2 Patients received cisplatin via IV infusion. Patients were initiated on cisplatin but had the option to switch to carboplatin (AUC 5) if cisplatin was not tolerated. The total cisplatin dose per cycle could be split across days 1, 2, and 3 of each chemotherapy cycle in Part B only, if there were tolerability concerns and only after consultation with the global medical team.

[0147] Durvalumab (MEDI4736) + tremelimumab combination therapy with chemoradiotherapy (Group 3) Patients in Group 3 received: Durvalumab and tremelimumab: Patients received durvalumab (MEDI4736) (1500 mg q4w) in combination with tremelimumab (75 mg IV q4w; 4 doses total) followed by durvalumab (MEDI4736) 1500 mg q4w until PD unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0148] If the initial dosing schedule of tremelimumab (75 mg q4w) in Group 3 (Schedule 0) was not tolerated, it was adjusted (Schedule 1). Tremelimumab was administered once on Day 1 (Week 0) and three additional doses q4w after chemoradiotherapy. If this schedule was still not tolerated, the tremelimumab schedule was adjusted again (Schedule 2), in which the full dose was administered after chemoradiotherapy (Table 1). For Schedules 1 and 2, tremelimumab maintenance dosing was initiated upon completion of the initial chemoradiotherapy and at least 48 hours after any recommended PCI and was administered together with the next scheduled dose of durvalumab.

[0149] Radiation: External beam radiation (2 Gy / fraction) was administered daily, starting within the first or second cycle of chemotherapy, for a total of 60–70 Gy in five weekly fractions over 6–7 weeks unless unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met (whichever occurred first).

[0150] Cisplatin and etoposide: Patients will receive cisplatin 60–80 mg / m on days 1 (week 0), 22 (week 3), 43 (week 6), 64 (week 9), 85 (week 12), and 106 (week 15) (day 1 of 4–6 21-day cycles [q3w], according to local guidelines), and days 1–3 (week 0), starting at week 0, unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met (whichever occurs first). 2 , etoposide 100–120 mg / m on days 22–24 (week 3), 43–45 (week 6), 64–66 (week 9), 85–87 (week 12), and 106–108 (week 15) (days 1–3 of four to six 21-day cycles, according to local guidelines) 2 Patients received cisplatin via IV infusion. Patients were initiated on cisplatin but had the option to switch to carboplatin (AUC 5) if cisplatin was not tolerated. The total cisplatin dose per cycle could be split across days 1, 2, and 3 of each chemotherapy cycle in Part B only, if there were tolerability concerns and only after consultation with the global medical team.

[0151] Durvalumab (MEDI4736) + tremelimumab combination therapy with chemoradiotherapy (Group 4) Patients in Group 4 will receive: Durvalumab and tremelimumab: Patients received durvalumab (MEDI4736) (1500 mg q4w) in combination with tremelimumab (75 mg IV q4w; 4 doses total) followed by durvalumab (MEDI4736) 1500 mg q4w until PD unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0152] If the initial dosing schedule of tremelimumab (75 mg q4w) in Group 4 (Schedule 0) was not tolerated, it was adjusted (Schedule 1). Tremelimumab was administered once on Day 1 (Week 0) and three additional doses q4w after chemoradiotherapy. If this schedule was still not tolerated, the tremelimumab schedule was adjusted again (Schedule 2), in which the full dose was administered after chemoradiotherapy (Table 1). For Schedules 1 and 2, tremelimumab maintenance dosing was initiated upon completion of the initial chemoradiotherapy and at least 48 hours after any recommended PCI and was administered together with the next scheduled dose of durvalumab.

[0153] Radiation: External beam radiation (1.5 Gy / fraction) was administered daily for a total of 45 Gy over 3 weeks in 10 fractions per week, 2 fractions per day, at least 6 hours apart, starting within the first or second cycle of chemotherapy, unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion was met (whichever occurred first).

[0154] Cisplatin and etoposide: Patients will receive cisplatin 60–80 mg / m on days 1 (week 0), 22 (week 3), 43 (week 6), 64 (week 9), 85 (week 12), and 106 (week 15) (day 1 of 4–6 21-day cycles [q3w], according to local guidelines), and days 1–3 (week 0), starting at week 0, unless unacceptable toxicity, consent withdrawal, or another discontinuation criterion is met (whichever occurs first). 2 , etoposide 100–120 mg / m on days 22–24 (week 3), 43–45 (week 6), 64–66 (week 9), 85–87 (week 12), and 106–108 (week 15) (days 1–3 of four to six 21-day cycles, according to local guidelines) 2Patients received cisplatin via IV infusion. Patients were initiated on cisplatin but had the option to switch to carboplatin (AUC 5) if cisplatin was not tolerated. The total cisplatin dose per cycle could be split across days 1, 2, and 3 of each chemotherapy cycle in Part B only, if there were tolerability concerns and only after consultation with the global medical team.

[0155] Table 4 shows the dosing scheme for the SCLC cohort.

[0156] [Table 6] a Cisplatin 60-80mg / m 2 will be administered to patients in groups 1, 2, 3, and 4 on days 1, 22, 43, 64, 85, and 106 (day 1 of 4 to 6 21-day cycles [q3w]) according to local guidelines. b Etoposide 100-120 mg / m 2 will be administered to patients in groups 1, 2, 3, and 4 on days 1–3, 22–24, 43–45, 64–66, 85–87, and 106–108 (days 1–3 of four to six 21-day cycles) according to local guidelines. c Patients should be initiated on cisplatin but have the option to switch to carboplatin (AUC 5) if cisplatin is not tolerated. The total cisplatin dose per cycle may be split across days 1, 2, and 3 of each chemotherapy cycle in Part B only, if there are tolerability concerns and only after consultation with the global medical team. dIf the initial dosing schedule of tremelimumab (75 mg q4w) in Groups 3 and 4 (Schedule 0) is not tolerated, it will be adjusted (Schedule 1). Tremelimumab will be administered once on Day 1 (Week 0) and three more doses q4w after chemoradiotherapy. If this schedule is still not tolerated, the tremelimumab schedule will be adjusted again (Schedule 2), in which the full dose is administered after chemoradiotherapy (Table 1). For Schedules 1 and 2, tremelimumab maintenance dosing may begin upon completion of the initial chemoradiotherapy and at least 48 hours after any recommended PCI and should be administered together with the next scheduled dose of durvalumab. PCI should be administered according to National Comprehensive Cancer Network guidelines. e Arm 3 will be open only if the regimen in Arm 1 is safe and tolerable, and Arm 4 will be open only if the regimen in Arm 2 is safe and tolerable. f For patients receiving 5 or 6 cycles of chemotherapy. NOTE: All drugs administered have a dosing window of ±3 days (except for Day 1, which has a dosing window of +3 days). Note: Durvalumab dose is 1500 mg (q4w). Tremelimumab dose is 75 mg. Cisplatin dose is 60-80 mg / m 2 The dose of etoposide is 100-120 mg / m 2 The radiation dose was 2 Gy / fraction, 5 fractions per week (total 60-70 Gy) in groups 1 and 3, and 1.5 Gy / fraction, 10 fractions per week (2 fractions per day, at least 6 hours apart, total 45 Gy) in groups 2 and 4.

[0157] result HNSCC A total of eight patients were enrolled in the HNSCC cohort. Overall, the safety and tolerability profile of durvalumab plus cisplatin plus RT was manageable and consistent with the known safety profiles of durvalumab alone and cisplatin plus RT. No unexpected safety findings were observed with this combination regimen. Specifically, patients in the HNSCC cohort demonstrated the following: · No DLT. CTCAE grade 3 or 4 adverse events were reported in seven patients, most frequently lymphopenia, stomatitis, increased amylase, and leukopenia. Serious adverse events (SAEs) were experienced by two patients (subdural hematoma, acute kidney injury). Three patients with AEs led to discontinuation of any study treatment. Of these, one led to discontinuation of durvalumab (acute kidney injury—also the only fatal AE). Five patients had immune-mediated adverse events (imAEs). The most common grouping term categories were hypothyroidism and pancreatitis. No imAEs led to discontinuation or death.

[0158] Efficacy in the HNSCC cohort demonstrated an overall response rate (ORR) of 71%, disease control rates (DCR) of 86% at 18 weeks and 83% at 48 weeks, disease-free survival rates of 85.7% at 12 months, 51.4% at 18 months and 24 months, and overall survival of 20.1 months.

[0159] NSCLC A total of 64 patients were enrolled in the HNSCC cohort. Overall, safety findings were consistent with the known safety profile of durvalumab and cCRT, and there was no evidence that the addition of durvalumab to standard-of-care chemoradiotherapy affected the tolerability of standard-of-care chemoradiotherapy. Specifically, patients in the NSCLC cohort demonstrated the following: One DLT in Arm 1 (grade 3 increased AST / grade 4 increased ALT) leading to discontinuation of study treatment. CTC grade 3 / 4 AEs and SAEs were experienced by 77% and 60% of patients; the majority of these events were expected based on the established toxicity profiles of chemotherapy, radiation therapy, and immunotherapy, or due to the patient's primary tumor location and / or medical history. Fatal cardiac events occurred in four patients. All patients had a significant smoking history, and three-quarters had significant cardiac-related MH. Four additional patients experienced fatal AEs (acute respiratory failure, pneumonia, PCP pneumonia, sepsis). Fourteen patients had AEs leading to discontinuation of any study treatment (n=13, durvalumab), including eight patients with fatal AEs and one patient with a DLT. Esophagitis (42%), radiation pneumonitis (15%), and pneumonitis (25%) events were primarily grade 1 / 2 in severity. Events were manageable and rarely led to treatment discontinuation. No events had a fatal outcome. Twenty patients had imAEs across the three treatment groups. Two patients experienced imAEs leading to discontinuation (no hepatic events, pneumonia, or events with fatal outcomes).

[0160] Efficacy results for the NSCLC cohort showed ORRs of 66.7%, 54.5%, and 61.9% for Groups 1, 2, and 3, respectively. The NSCLC cohort demonstrated DCRs of 100% at 18 weeks and 84.2% at 48 weeks, 88.9% at 18 weeks and 72.2% at 48 weeks, and 95.2% at 18 weeks and 75% at 48 weeks for Groups 1, 2, and 3, respectively. The median progression-free survival (mPFS) was 13.4 months overall, and the 12-month progression-free survival was 53.6%. The mPFS for Groups 1, 2, and 3 was 14.4 months, 12.8 months, and 10.8 months, respectively. The 12-month progression-free survival for Groups 1, 2, and 3 was 67.3%, 54.5%, and 40.8%, respectively. Median OS was not reached, with 1-year OS rates above 80% (estimated) for all three groups.

[0161] Limited Stage SCLC (LS-SCLC) A total of 33 patients were enrolled in the LS-SCLC cohort. Overall, safety findings were consistent with the known safety profile of durvalumab ± tremelimumab and cCRT. There was no evidence that the addition of durvalumab ± tremelimumab to standard-of-care chemoradiotherapy affected the tolerability of standard-of-care chemoradiotherapy. Specifically, patients in arms 1 and 2 of the LS-SCLC cohort demonstrated the following: · No DLT. CTCAE grade 3 or 4 and SAE adverse events were reported in 79% and 21% of patients, respectively. The most frequent grade 3 / 4 AE was hematologic toxicity. No fatal AEs. Two patients had AEs leading to discontinuation of any study treatment, including durvalumab (pneumonia, IgA nephropathy). Esophagitis, pneumonitis, and radiation pneumonitis events were primarily grade 1 / 2 in severity. Events were manageable, with one event leading to treatment discontinuation; no events had fatal outcomes. Four patients across the t2 treatment arms had imAEs (pneumonitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, dermatitis / rash). Only the pneumonitis imAE led to discontinuation. No fatal imAEs.

[0162] In SCLC groups 3 and 4, patients showed the following: Group 3 completed enrollment in Part A. There were no DLTs, but Group 4 did not complete enrollment due to study termination. Of the three patients enrolled in Group 4, no DLTs were observed. CTCAE grade 3 or 4 adverse events were reported in 76% of patients, most frequently neutropenia and anemia. Four patients experienced SAEs, two of which were radiation pneumonitis. No fatal AEs. Two patients had AEs leading to discontinuation of any durvalumab-containing study treatment (pneumonitis, radiation pneumonitis). Esophagitis, pneumonitis, and radiation pneumonitis events were primarily grade 1 / 2 in severity. Events were manageable with two treatment discontinuations. No events had fatal outcomes. Three patients had imAEs across the two treatment arms, all in arm 3. The most common grouping term category was pneumonia, and only one of these led to discontinuation. No fatal imAEs.

[0163] In Groups 1 and 2, efficacy for the SCLC cohort showed an ORR of 67%, a median DOR of 13.4 months, DCR of 96% at 18 weeks and 78% at 48 weeks, mPFS of 9.3 months, and a PFS12 rate of 41%. Median OS was not reached, and the OS12 rate was estimated to be 90%.

[0164] In groups 3 and 4, efficacy in the SCLC cohort demonstrated an ORR of 89%, with a DCR of 100% at 18 weeks and 100% at 48 weeks. Overall mPFS and median OS were not reached. The OS rate was estimated to be 100%.

Claims

1. A method of increasing overall response rate (ORR) in patients with small cell lung cancer (SCLC), comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiotherapy.

2. A method for increasing disease control rate (DCR) in a patient with SCLC, comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiotherapy.

3. A method of treating a patient with SCLC, comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiotherapy.

4. The method of any one of claims 1 to 3, wherein the SCLC is in limited stage.

5. The method of any one of claims 1 to 4, wherein the chemoradiotherapy comprises 60 to 70 Gy in 30 to 35 fractions.

6. 6. The method of claim 5, wherein the chemoradiotherapy comprises 2 Gy / fraction, 5 fractions per week, for 6-7 weeks.

7. The method of any one of claims 1 to 4, wherein the chemoradiotherapy comprises hyperfractionated radiation.

8. 8. The method of claim 7, wherein the hyperfractionated radiation comprises 45 Gy in 30 fractions.

9. 9. The method of claim 8, wherein the multi-fractionated radiation comprises 1.5 Gy / fraction, 2 fractions per day at least 6 hours apart, 10 fractions per week for 3 weeks.

10. The method according to any one of claims 1 to 9, wherein the chemoradiotherapy comprises cisplatin and / or carboplatin and etoposide.

11. The method of any one of claims 1 to 10, wherein the anti-CTLA-4 antibody is tremelimumab.

12. The method of any one of claims 1 to 11, wherein the anti-PD-L1 antibody is durvalumab, avelumab, atezolizumab, or sugemalimab.

13. 13. The method of any one of claims 1 to 12, wherein the treatment with the human anti-PD-L1 antibody comprises intravenously administering 1500 mg of the anti-PD-L1 antibody to the patient every four weeks (Q4W).

14. 14. The method of any one of claims 1 to 13, wherein the anti-CTLA-4 antibody treatment comprises intravenously administering 75 mg of the anti-CTLA-4 antibody to the patient every four weeks (Q4W).

15. The method of any one of claims 1 to 14, wherein the anti-PD-L1 antibody and the anti-CTLA-4 antibody are administered on the first day of chemoradiotherapy.

16. A method of increasing overall response rate (ORR) in patients with head and neck squamous cell carcinoma (HNSCC), comprising concurrently treating the patient with a human anti-PD-L1 antibody and chemoradiotherapy.

17. A method of increasing disease control rate (DCR) in a patient with HNSCC, comprising concurrently treating said patient with a human anti-PD-L1 antibody and chemoradiotherapy.

18. A method of treating a patient with HNSCC, comprising concurrently treating the patient with a human anti-PD-L1 antibody and chemoradiotherapy.

19. The method of any one of claims 16 to 18, wherein the chemoradiotherapy comprises 70 Gy over 35 fractions.

20. 20. The method of claim 19, wherein the chemoradiotherapy comprises 2 Gy / fraction, 5 fractions per week, for 7 weeks.

21. 19. The method of any one of claims 16 to 18, wherein the chemoradiotherapy comprises 56 Gy over 35 fractions.

22. 19. The method of any one of claims 16 to 18, wherein the chemoradiotherapy comprises 61.25 Gy over 35 fractions.

23. 23. The method of claim 21 or claim 22, wherein the chemoradiotherapy comprises 1.6 Gy / fraction, 5 fractions per week, for 7 weeks.

24. The method of any one of claims 16 to 18, wherein the chemoradiotherapy comprises hyperfractionated radiation.

25. The method of any one of claims 16 to 24, wherein the anti-PD-L1 antibody is durvalumab, avelumab, atezolizumab, or sugemalimab.

26. 26. The method of any one of claims 16 to 25, wherein the treatment with the human anti-PD-L1 antibody comprises intravenously administering 1500 mg of the anti-PD-L1 antibody to the patient every four weeks (Q4W).

27. The method of any one of claims 16 to 26, wherein the anti-PD-L1 antibody is administered on the first day of chemoradiotherapy.

28. A combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody and concurrent chemoradiotherapy for use in a method of increasing overall response rate (ORR) in patients with SCLC.

29. A combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody and concurrent chemoradiotherapy for use in a method for increasing the disease control rate (DCR) in patients with SCLC.

30. A combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody and concurrent chemoradiotherapy for use in the treatment of SCLC.

31. The combination for use according to any one of claims 28 to 30, wherein the SCLC is in limited stage.

32. The combination for use according to any one of claims 28 to 31, wherein said chemoradiotherapy comprises 60 to 70 Gy in 30 to 35 fractions.

33. 33. The combination for use according to claim 32, wherein said chemoradiotherapy comprises 2 Gy / fraction, 5 fractions per week, for 6-7 weeks.

34. The combination for use according to any one of claims 28 to 31, wherein said chemoradiotherapy comprises hyperfractionated radiation.

35. 35. The combination for use according to claim 34, wherein said hyperfractionated radiation comprises 45 Gy in 30 fractions.

36. 36. The combination for use of claim 35, wherein said hyperfractionated radiation comprises 1.5 Gy / fraction, 2 fractions per day at least 6 hours apart, 10 fractions per week for 3 weeks.

37. A combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for use in a method of increasing overall response rate (ORR) in patients with HNSCC.

38. A combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for use in a method of increasing the disease control rate (DCR) in patients with HNSCC.

39. A combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for use in the treatment of HNSCC.

40. 40. The method of any one of claims 37 to 39, wherein the chemoradiotherapy comprises 70 Gy over 35 fractions.

41. 41. The method of claim 40, wherein the chemoradiotherapy comprises 2 Gy / fraction, 5 fractions per week, for 7 weeks.

42. 40. The method of any one of claims 37 to 39, wherein the chemoradiotherapy comprises 56 Gy over 35 fractions.

43. 40. The method of any one of claims 37 to 39, wherein the chemoradiotherapy comprises 61.25 Gy over 35 fractions.

44. 44. The method of claim 42 or claim 43, wherein the chemoradiotherapy comprises 1.6 Gy / fraction, 5 fractions per week, for 7 weeks.

45. The combination for use according to any one of claims 28 to 44, wherein said chemoradiotherapy comprises cisplatin and / or carboplatin and etoposide.

46. The combination for use according to any one of claims 28 to 45, wherein the anti-CTLA-4 antibody is tremelimumab.

47. The combination for use according to any one of claims 28 to 46, wherein the anti-PD-L1 antibody is durvalumab, avelumab, atezolizumab, or sugemalimab.

48. 48. The combination for use of any one of claims 28 to 47, wherein treatment with the human anti-PD-L1 antibody comprises intravenously administering 1500 mg of the anti-PD-L1 antibody to the patient every four weeks (Q4W).

49. 49. The combination for use of any one of claims 28 to 48, wherein said treatment with anti-CTLA-4 antibody comprises intravenously administering 75 mg of said anti-CTLA-4 antibody to said patient every four weeks (Q4W).

50. The combination for use according to any one of claims 28 to 49, wherein the anti-PD-L1 antibody and the anti-CTLA-4 antibody are administered on the first day of chemoradiotherapy.

51. Use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiotherapy in the manufacture of a medicament for use in a method of increasing overall response rate (ORR) in patients with SCLC.

52. Use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiotherapy in the manufacture of a medicament for use in a method for increasing disease control rate (DCR) in patients with SCLC.

53. Use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody and concurrent chemoradiotherapy in the manufacture of a medicament for use in the treatment of SCLC.

54. Use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy in the manufacture of a medicament for use in a method of increasing overall response rate (ORR) in patients with HNSCC.

55. Use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy in the manufacture of a medicament for use in a method for increasing disease control rate (DCR) in patients with HNSCC.

56. 1. Use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy in the manufacture of a medicament for use in the treatment of HNSCC.

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