Compositions and methods for treating advanced solid tumors

Abstract

Methods of treating solid tumors with both an anti-PD-L1 antibody and an anti-CTLA-4 antibody in combination with chemoradiotherapy (cCRT) are disclosed.

Description

Technical Field

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

[0002] Cancer remains a major global health burden. In the United States, it is the second most common cause of death after heart disease, accounting for 1 in 4 deaths. The 5-year survival rate for all cancers diagnosed between 1999 and 2006 was 68%, 18% higher than the 5-year survival rate reported between 1975 and 1977, likely reflecting advances in earlier diagnosis of some cancers and improved treatment.

[0003] An estimated 12.7 million cancer cases and 7.6 million cancer deaths occurred worldwide in 2008. These cancers are often diagnosed at an advanced or metastatic stage, with very short life expectancy. Despite recent advances in chemotherapy and the molecular understanding of cancer biology, there has been limited progress in treatment options for advanced and metastatic disease. Poor prognosis reflects the limited efficacy of existing treatment options and highlights the need to develop newer therapeutic options. Summary of the invention

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

[0005] In one aspect, the disclosure herein provides a method of improving the overall response rate (ORR) in a patient 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.

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

[0007] In yet another aspect, the disclosure herein 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 chemoradiotherapy.

[0008] In yet another aspect, the disclosure herein provides a method of improving the overall response rate (ORR) in a patient with head and neck squamous cell carcinoma (HNSCC), comprising treating the patient concurrently with a human anti-PD-L1 antibody and chemoradiotherapy.

[0009] In yet another aspect, the disclosure herein provides a method of improving the disease control rate (DCR) of a patient with HNSCC, comprising treating the patient concurrently with a human anti-PD-L1 antibody and chemoradiotherapy.

[0010] In yet another aspect, the disclosure herein provides a method of treating a patient suffering from HNSCC, comprising treating the patient concurrently with a human anti-PD-L1 antibody and chemoradiotherapy.

[0011] In yet another 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 a method of improving the overall response rate (ORR) in patients with SCLC.

[0012] In yet another 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 a method of improving the disease control rate (DCR) in a patient with SCLC.

[0013] In yet another aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiotherapy for treating SCLC.

[0014] In yet another aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy, for use in a method of improving the overall response rate (ORR) in a patient with HNSCC.

[0015] In yet another aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy, for use in a method of improving the disease control rate (DCR) in a patient with HNSCC.

[0016] In yet another aspect, the disclosure herein provides a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for treating HNSCC.

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

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

[0019] In yet another aspect, the disclosure herein provides use of a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiotherapy in the preparation of a medicament for treating SCLC.

[0020] In yet another aspect, the disclosure herein provides use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for the preparation of a medicament in a method for improving the overall response rate (ORR) in a patient with HNSCC.

[0021] In yet another aspect, the disclosure herein provides use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for the preparation of a medicament in a method for improving the disease control rate (DCR) in a patient with HNSCC.

[0022] In yet another aspect, the disclosure herein provides use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy in the preparation of a medicament for treating HNSCC. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The general study design of the methods disclosed herein is shown.

[0024] Figure 2 A detailed study flow chart of the head and neck squamous cell carcinoma (HNSCC) cohort described in Example 1 is shown.

[0025] Figure 3 A detailed study flow chart of the non-small cell lung cancer (NSCLC) cohort described in Example 1 is shown.

[0026] Figure 4 A detailed study flow chart of the small cell lung cancer (SCLC) cohort described in Example 1 is shown.

[0027] Figure 5 Disease-free survival rates for HNSCC are shown.

[0028] Figure 6 Shown is the overall survival of HNSCC.

[0029] Figure 7 Shown are progression-free survival (PFS) and overall survival (OS) for SCLC in arms 1 and 2 of the study.

[0030] Figure 8 Shown are progression-free survival (PFS) and overall survival (OS) for SCLC in Cohorts 1 and 2 of the study by treatment group.

[0031] Fig. 9Shown are progression-free survival (PFS) and overall survival (OS) for SCLC in arms 3 and 4 of the study.

[0032] Fig.10 Shown are progression-free survival (PFS) and overall survival (OS) for SCLC in Cohorts 3 and 4 of the study by treatment group. DETAILED DESCRIPTION

[0033] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure belongs. The following references provide general definitions of many of the terms used in the present disclosure to the skilled person: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise indicated, the following terms have the meanings assigned to them below.

[0034] In the present disclosure, "comprising," "including," "containing," and "having," etc. may have the meanings ascribed to them in U.S. patent law, and may mean "including," "comprising," etc. "Consisting essentially of" has the meaning ascribed to them in U.S. patent law and is open ended, allowing for more than those listed, as long as the basic or novel characteristics of those listed are not altered by the presence of more than those listed, but excluding prior art aspects.

[0035] Unless otherwise specified or obvious from the context, the term "or" as used herein should be understood to be inclusive. Unless otherwise specified or obvious from the context, the terms "a", "an" and "the" as used herein should be understood to be singular or plural.

[0036] Unless otherwise specified or apparent from the context, the term "about" as used herein should be understood to mean within the normal tolerance range in the art, such as within 2 standard deviations of the mean. "About" may 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 the context clearly indicates otherwise, all numerical values ​​provided herein are modified by the term about.

[0037] Any composition or method provided herein can be combined with one or more of any other compositions and methods provided herein.

[0038] The ranges provided herein are to be understood as shorthand for all values ​​within the range. For example, a range of 1 to 50 is to be understood to include any number, combination of numbers, or subrange selected 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.

[0039] As used herein, the term "antibody" refers to an immunoglobulin or a fragment or derivative thereof, and encompasses any polypeptide comprising an antigen binding site, whether produced in vitro or in vivo. The term includes, but is not limited to, polyclonal antibodies, monoclonal antibodies, monospecific antibodies, multispecific antibodies, nonspecific antibodies, humanized antibodies, single-chain antibodies, chimeric antibodies, synthetic antibodies, recombinant antibodies, hybrid antibodies, mutant antibodies, and transplanted antibodies. Unless modified by the term "complete", as in "complete antibody", for the purposes of this disclosure, the term "antibody" also includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen binding function (ie, the ability to specifically bind to PD-L1). Typically, such fragments will contain an antigen binding domain.

[0040] As used herein, the terms "antigen binding domain", "antigen binding fragment" and "binding fragment" refer to a portion of an antibody molecule that contains amino acids responsible for the specific binding between the antibody and the antigen. In some cases, when the antigen is large, the antigen binding domain may bind only a portion of the antigen. The portion of the antigen molecule responsible for specific interaction with the antigen binding domain is called an "epitope" or "antigenic determinant". The antigen binding domain generally contains the variable region of the antibody light chain (V L ) and antibody heavy chain variable region (V H); however, it does not necessarily have to include both. For example, the so-called Fd antibody fragment consists only of V H domains, but still retains some of the antigen-binding function of the intact antibody.

[0041] In some embodiments, disclosed herein is a method of improving the overall response rate (ORR) in a patient with small cell lung cancer (SCLC), the method comprising simultaneously treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiotherapy.

[0042] In some embodiments, disclosed herein is a method of improving the disease control rate (DCR) of 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.

[0043] In some embodiments, disclosed herein is a method of treating a patient with SCLC, the method comprising treating the patient with a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and chemoradiotherapy simultaneously.

[0044] In some embodiments, disclosed herein is a method of improving the overall response rate (ORR) in a patient with head and neck squamous cell carcinoma (HNSCC), the method comprising treating the patient with a human anti-PD-L1 antibody and chemoradiotherapy simultaneously.

[0045] In some embodiments, disclosed herein is a method of improving the disease control rate (DCR) of a patient with HNSCC, the method comprising treating the patient with a human anti-PD-L1 antibody and chemoradiotherapy simultaneously.

[0046] In some embodiments, disclosed herein is a method of treating a patient having HNSCC, the method comprising treating the patient with a human anti-PD-L1 antibody and chemoradiotherapy simultaneously.

[0047] In some embodiments, the anti-PD-L1 antibody is durvalumab, avelumab, atezolizumab, or sugemalimab. In some embodiments, the anti-PD-L1 antibody is durvalumab. ) is a human monoclonal antibody against human PD-L1 that is capable of blocking the binding of PD-L1 to both PD1 and CD80 receptors. Disclosures regarding durvalumab can be found in U.S. Pat. Nos. 8,779,108 and 9,493,565, which are incorporated herein by reference.

[0048] Durvalumab for 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, the Durvalumab for the methods, compositions and combinations provided herein comprises a light chain variable region having an amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region having an amino acid sequence of SEQ ID NO: 2. In some embodiments, Durvalumab for 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 a CDR1, CDR2 and CDR3 sequence defined by Kabat of SEQ ID NO: 3-5, and wherein the light chain variable region comprises a CDR1, CDR2 and CDR3 sequence defined by Kabat of SEQ ID NO: 6-8. A person of ordinary skill in the art can easily identify other CDR definitions defined by Chothia, defined by Abm or known to a person of ordinary skill in the art. In some embodiments, durvalumab for use in the methods, compositions, and combinations provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H90PT antibody, as disclosed in U.S. Pat. Nos. 8,779,108 and 9,493,565, which are incorporated herein by reference in their entireties.

[0049] Durvalumab light chain (LC) variable region :

[0050] EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK(SEQ ID NO:1)

[0051] Durvalumab heavy chain (HC) variable region :

[0052] EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS(SEQ ID NO:2)

[0053] Durvalumab heavy chain CDR :

[0054] HC-CDR1: GTFFSRYWMS (SEQ ID NO: 3)

[0055] HC-CDR2:NIKQDGSEKYYVDSVKG(SEQ ID NO:4)

[0056] HC-CDR3:EGGWFGELAFDY(SEQ ID NO:5)

[0057] Durvalumab, light chain CDR :

[0058] LC-CDR1:RASQRVSSSYLA(SEQ ID NO:6)

[0059] LC-CDR2: DASSRAT(SEQ ID NO:7)

[0060] LC-CDR3: QQYGSLPWT(SEQ ID NO:8)

[0061] In some embodiments, the anti-CTLA-4 antibody is tremelimumab. The tremelimumab used 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, the tremelimumab used in the methods, compositions and combinations provided herein comprises a light chain variable region having an amino acid sequence of SEQ ID NO: 9 and a heavy chain variable region having an amino acid sequence of SEQ ID NO: 10. In some embodiments, the tremelimumab used 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 NO: 11-13, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2 and CDR3 sequences of SEQ ID NO: 14-16. A person of ordinary skill in the art can easily identify other CDR definitions defined by Chothia, Abm or known to a person of ordinary skill in the art. In some embodiments, tremelimumab for use in the methods, compositions, and combinations provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 11.2.1 antibody, as disclosed in U.S. Pat. No. 6,682,736, which is incorporated herein by reference in its entirety.

[0062] Tremelimumab light chain (LC) variable region :

[0063] PSSLSASVGDRVTITCRASQSINSYLDWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV(SEQID NO:9)

[0064] Tremelimumab heavy chain (HC) variable region :

[0065] GVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPRGATLYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH(SEQ ID NO:10)

[0066] Tremelimumab heavy chain CDR

[0067] HC-CDR1: GTFFSSYGMH (SEQ ID NO:11)

[0068] HC-CDR2:VIWYDGSNKYYADSV(SEQ ID NO:12)

[0069] HC-CDR3:DPRGATLYYYYYGMDV(SEQ ID NO:13)

[0070] Tremelimumab light chain CDR1

[0071] LC-CDR1:RASQSINSYLD(SEQ ID NO:14)

[0072] LC-CDR2:AASSLQS(SEQ ID NO:15)

[0073] LC-CDR3: QQYYSTPFT(SEQ ID NO:16)

[0074] The binding fragment of the antibody can be produced by recombinant DNA technology or by enzymatic or chemical cleavage of a complete antibody. Binding fragments include Fab, Fab', F(ab')2, Fv and single-chain antibodies. Antibodies that are different from "bispecific" or "bifunctional" antibodies are understood to be antibodies in which each binding site is identical. Digestion of antibodies with papain produces two identical antigen-binding fragments (also referred to as "Fab" fragments) and "Fc" fragments, which do not have antigen-binding activity but have the ability to crystallize. Digestion of antibodies with pepsin produces F(ab')2 fragments, in which the two arms of the antibody molecule remain connected and contain two antigen-binding sites. F(ab')2 fragments have the ability to cross-link antigens. As used herein, the term "Fv" refers to the smallest fragment of an antibody that retains an antigen recognition site and an antigen-binding site. As used herein, the term "Fab" refers to an antibody fragment comprising the constant domains of a light chain and the CHI domains of a heavy chain.

[0075] In some embodiments, the methods, compositions and combinations disclosed herein relate to treating a tumor condition and / or a cancer condition in a subject. In some embodiments, the tumor is an advanced solid tumor. In some embodiments, the cancer is selected from small cell lung cancer, head and neck squamous cell carcinoma, and / or non-small cell lung cancer.

[0076] In specific embodiments, the small cell lung cancer is limited stage.

[0077] As used herein, the term "solid tumor" refers to an abnormal mass of tissue that generally does not contain cysts or fluid areas.

[0078] As used herein, the term "treatment" refers to therapeutic treatment and prophylactic or preventive measures. Subjects in need of treatment include subjects with cancer and subjects who are prone to cancer or subjects for whom cancer will be prevented. In some embodiments, the methods, compositions and combinations disclosed herein can be used to treat cancer. In other embodiments, subjects in need of treatment include subjects with tumors and subjects who are prone to tumors or subjects for whom tumors will be prevented. In certain embodiments, the methods, compositions and combinations disclosed herein can be used to treat tumors. In other embodiments, the treatment of tumors includes inhibiting tumor growth, promoting tumor reduction, or both inhibiting tumor growth and promoting tumor reduction.

[0079] As used herein, the term "administering" refers to providing, contacting and / or delivering one or more compounds by any suitable route to obtain a desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection), transdermal, topical, oral, rectal, vaginal, nasal, ocular, via inhalation and implantation.

[0080] Provided herein are methods for treating tumors in subjects in need thereof, comprising administering an anti-PD-L1 antibody to the subject at a dose of 5 mg / kg to 20 mg / kg. In some embodiments, provided herein are methods for treating tumors in subjects in need thereof, comprising administering an anti-PD-L1 antibody or an antigen-binding fragment thereof to the subject at a flat dose of 1000 mg to 2000 mg. In some embodiments, provided herein are methods for treating tumors in subjects in need thereof, comprising administering an anti-PD-L1 antibody or an antigen-binding fragment thereof to the subject at a flat dose of 1500 mg.

[0081] In a specific embodiment, one or more flat doses are administered to the subject. In some embodiments, provided herein is a method of treating a tumor in a subject in need thereof, comprising administering an anti-PD-L1 antibody to the subject, 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, one or more flat doses of an anti-PD-L1 antibody are administered to the subject, wherein the dose is 1500 mg.

[0082] In specific embodiments, the anti-PD-L1 antibody is administered over a two-week treatment period, a four-week treatment period, a six-week treatment period, an eight-week treatment period, a twelve-week treatment period, a twenty-four-week treatment period, or a year or longer treatment period. In certain embodiments, the anti-PD-L1 antibody is administered over a three-week treatment period, a six-week treatment period, a nine-week treatment period, a twelve-week treatment period, a twenty-four-week treatment period, or a year or longer treatment period. In certain embodiments, the anti-PD-L1 antibody is administered over a two-month treatment period, a four-month treatment period, or a six-month or longer treatment period.

[0083] As used herein, the terms "co-administration," "combination," or "combination therapy" refer to the simultaneous or sequential administration of multiple compounds or agents. A first compound or agent may be administered before, simultaneously, or after the administration of a second compound or agent. The first compound or agent and the second compound or agent may be administered simultaneously or sequentially on the same day, or may be administered sequentially within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 1 month of each other. In some embodiments, the compounds or agents are co-administered during a period during which each of the compounds or agents exerts at least some physiological effect and / or has residual efficacy.

[0084] In some embodiments, the anti-PD-L1 antibody is administered simultaneously with the chemoradiotherapy. As used herein, the term "simultaneously" means that the administration of the anti-PD-L1 antibody and the administration of the chemoradiotherapy are performed within about three days of each other. In some embodiments, the anti-PD-L1 antibody is administered within about two days of the chemoradiotherapy. In some embodiments, the anti-PD-L1 antibody is administered within about one day of the chemoradiotherapy. In some embodiments, the anti-PD-L1 antibody is administered on Day 1 of Cycle 1 of the chemoradiotherapy.

[0085] In some embodiments, anti-PD-L1 antibodies are administered simultaneously with anti-CTLA-4 antibodies and chemoradiotherapy. In specific embodiments, anti-PD-L1 antibodies and anti-CTLA-4 antibodies are administered simultaneously, separately or sequentially. In some embodiments, anti-PD-L1 antibodies and anti-CTLA-4 antibodies are administered within about three days of the administration of chemoradiotherapy. In some embodiments, anti-PD-L1 antibodies and anti-CTLA-4 antibodies are administered within about two days of the administration of chemoradiotherapy. In some embodiments, anti-PD-L1 antibodies and anti-CTLA-4 antibodies are administered within about one day of the administration of chemoradiotherapy. In some embodiments, anti-PD-L1 antibodies and anti-CTLA-4 antibodies are administered on day 1 of cycle 1 of chemoradiotherapy.

[0086] In some embodiments, an anti-CTLA-4 antibody is administered, wherein the dose is 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg. In specific embodiments, one or more flat doses of an anti-CTLA-4 antibody are administered to a subject, wherein the dose is 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.

[0087] In specific 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.

[0088] In specific embodiments, the anti-CTLA-4 antibody is administered over a two-week treatment period, a four-week treatment period, a six-week treatment period, an eight-week treatment period, a twelve-week treatment period, a twenty-four-week treatment period, or a year or longer treatment period. In certain embodiments, the anti-CTLA-4 antibody is administered over a three-week treatment period, a six-week treatment period, a nine-week treatment period, a twelve-week treatment period, a twenty-four-week treatment period, or a year or longer treatment period. In certain embodiments, the anti-CTLA-4 antibody is administered over a two-month treatment period, a four-month treatment period, or a six-month or longer treatment period.

[0089] In some embodiments, the chemoradiotherapy comprises a platinum-based therapeutic agent.

[0090] In some embodiments, synchronous chemoradiotherapy includes any acceptable standard first-line treatment for patients with small cell lung cancer, head and neck squamous cell carcinoma and / or non-small cell lung cancer. In some embodiments, standard first-line treatment may include chemotherapy, radiotherapy or both (chemoradiotherapy). In some embodiments, the therapy may include one or more chemotherapeutic agents based on platinum. In some embodiments, the one or more chemotherapeutic agents based on platinum may be selected from carboplatin, cisplatin, oxaliplatin or a combination thereof. As described herein, platinum-based therapy may include a single drug or double drug regimen, for example, cisplatin or carboplatin is administered with another anticancer agent, such as paclitaxel, docetaxel, etoposide, gemcitabine, vinorelbine, etc.

[0091] 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 a method of improving the overall response rate (ORR) in patients with SCLC.

[0092] 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 a method of improving the disease control rate (DCR) in a patient with SCLC.

[0093] In some embodiments, provided herein is a combination comprising a human anti-PD-L1 antibody, an anti-CTLA-4 antibody, and concurrent chemoradiotherapy for treating SCLC.

[0094] In some embodiments, provided herein is a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy, for use in a method of improving the overall response rate (ORR) in a patient with HNSCC.

[0095] In some embodiments, provided herein is a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy, for use in a method of improving the disease control rate (DCR) in a patient with HNSCC.

[0096] 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 chemoradiotherapy for the preparation of a medicament in a method for improving the overall response rate (ORR) in patients with SCLC.

[0097] 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 chemoradiotherapy for the preparation of a medicament in a method for improving the disease control rate (DCR) in a patient with SCLC.

[0098] 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 chemoradiotherapy in the preparation of a medicament for the treatment of SCLC.

[0099] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for the preparation of a medicament in a method for improving the overall response rate (ORR) in a patient with HNSCC.

[0100] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for the preparation of a medicament in a method for improving the disease control rate (DCR) in a patient with HNSCC.

[0101] In some embodiments, provided herein is the use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy for the preparation of a medicament for the treatment of HNSCC.

[0102] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a compound or composition capable of inducing a desired therapeutic effect when appropriately administered to a subject. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one antibody of the present disclosure.

[0103] As used herein, the term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" refers to one or more formulation materials suitable for achieving or enhancing the delivery of one or more antibodies of the present disclosure.

[0104] When used for in vivo administration, the preparations of the present disclosure should be sterile. The preparations of the present disclosure can be sterilized by various sterilization methods, including, for example, aseptic filtration or radiation. In one embodiment, the preparation is sterilized by filtration using a pre-sterilized 0.22 micron filter. Sterile compositions for injection can be prepared according to conventional pharmaceutical practices described in "Remington: The Science & Practice of Pharmacy", 21st edition, Lippincott Williams & Wilkins, (2005).

[0105] In some embodiments, the antibody can be formulated for a specific route of administration, such as oral, nasal, pulmonary, topical (including oral and sublingual), rectal, vaginal and / or parenteral administration. As used herein, the term "parenteral administration" refers to modes of administration other than enteral and topical administration (usually by injection), and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, supradural 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 substances 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).

[0106] The preparation can exist in unit dosage form and can be prepared by any method known in the pharmaceutical field. The actual dosage level of the active ingredient in the preparation of the present disclosure can be varied to obtain the amount of the active ingredient (e.g., "therapeutically effective amount") that effectively obtains the desired treatment relief for a specific subject, composition, and mode of administration without toxicity to the subject. The dosage can also be administered via continuous infusion (such as by a pump). The dosage administered can also depend on the route of administration. For example, subcutaneous administration may require a higher dosage than intravenous administration.

[0107] The disclosed treatment methods can provide substantial improvements in patients' overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the proportion of patients alive 12 months after randomization (OS12).

[0108] In some embodiments, the method provides an increase in PFS relative to placebo. In some embodiments, the method provides an increase in ORR relative to placebo. In some embodiments, the method provides an increase in DCR relative to placebo. In some embodiments, the method provides an extension of OS relative to placebo.

[0109] Unless otherwise indicated, the practice of the methods disclosed herein employs conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the knowledge of those skilled in the art. Such techniques are fully explained in the literature, such 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).

[0110] Example

[0111] Example 1: Efficacy of durvalumab and tremelimumab in combination with chemoradiotherapy in patients with solid tumors

[0112] 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 and unresectable (stage III) NSCLC, and limited-stage SCLC. The study consisted of a dose-limiting toxicity (DLT) evaluation period (Part A) and an extension period (Part B). The study schematic is shown in Figure 1 middle.

[0113] Study Design

[0114] HNSCC Cohort

[0115] Section A: DLT Evaluation Period

[0116] This study includes 1 group. The details of the initial group are as follows:

[0117] Group 1: Cisplatin and radiation therapy plus durvalumab in patients with locally advanced HNSCC

[0118] Group 1 received standard durvalumab dosing / schedule (1500 mg durvalumab every 4 weeks [q4w]) combined with chemoradiotherapy.

[0119] The primary tumor and involved lymph nodes ideally received 70 Gy in 35 daily fractions (ie, 2 Gy / fraction, 5 times per week), and subclinical disease sites ideally received 56 Gy in 35 daily fractions (ie, 1.6 Gy / fraction, 5 times per week) over approximately 7 weeks. If areas considered to be at high risk for microscopic disease were identified, these areas may have been treated to a total dose of 61.25 Gy in 35 fractions (ie, 1.75 Gy / fraction, 5 times per week).

[0120] In Part A, a total of up to 12 patients will be assigned to Group 1 to evaluate DLT in patients treated with durvalumab and chemoradiotherapy.

[0121] Part B: Extension Period

[0122] In Part B, up to 30 additional patients will be assigned to this group.

[0123] The detailed study flow chart of the HNSCC cohort is shown in Figure 2 middle.

[0124] NSCLC Cohort

[0125] Section A: DLT Evaluation Period

[0126] The study initially included 3 groups. Details of the initial groups are as follows:

[0127] Group 1: Cisplatin and etoposide with radiation therapy plus durvalumab in patients with locally advanced and unresectable (stage III) NSCLC.

[0128] Group 2: Carboplatin and paclitaxel versus radiation therapy plus durvalumab in patients with locally advanced and unresectable (stage III) NSCLC.

[0129] Group 3 (nonsquamous indications only): Investigator's choice of carboplatin and pemetrexed or cisplatin and pemetrexed with radiation therapy plus durvalumab in patients with locally advanced and unresectable (stage III) NSCLC

[0130] Groups 1, 2, and 3 received standard durvalumab dose / administration regimen (durvalumab 1500 mgq4w) combined with chemoradiotherapy.

[0131] A total dose of 60 Gy was delivered in 30 daily fractions (i.e., 2 Gy / fraction, 5 times per week) over a period of approximately 6 weeks. In Part A, a total of 18 patients were enrolled in Groups 1, 2, and 3 (6 patients per group) to evaluate DLT in patients treated with durvalumab and chemoradiotherapy.

[0132] Part B: Extension Period

[0133] In Part B, up to 30 additional patients will be assigned to each group. However, Group 3 will only enroll patients with non-squamous NSCLC.

[0134] The detailed study flow chart of the NSCLC cohort is shown in Figure 3 middle.

[0135] SCLC Cohort

[0136] Section A: DLT Evaluation Period

[0137] The study consisted of 4 groups. Details of the initial group were as follows:

[0138] Group 1: Cisplatin and etoposide with standard radiation therapy + durvalumab in patients with limited-stage SCLC. Patients start with cisplatin, but if they cannot tolerate cisplatin, they have the option of switching to carboplatin (AUC 5).

[0139] Group 2: Cisplatin and etoposide with hyperfractionated radiotherapy + durvalumab in patients with limited-stage SCLC. Patients start with cisplatin, but if they cannot tolerate cisplatin, they have the option of switching to carboplatin (AUC 5).

[0140] Group 3: Cisplatin and etoposide versus standard radiation therapy plus durvalumab and tremelimumab in patients with limited-stage SCLC. Patients start with cisplatin, but if they cannot tolerate cisplatin, they have the option of switching to carboplatin (AUC5).

[0141] Group 4: Cisplatin and etoposide with hyperfractionated radiotherapy + durvalumab and tremelimumab in patients with limited-stage SCLC. Patients start with cisplatin, but if they cannot tolerate cisplatin, they have the option of switching to carboplatin (AUC 5).

[0142] Groups 1, 2, 3, and 4 received standard durvalumab ± tremelimumab dosing / administration regimen (durvalumab 1500 mg q4w ± tremelimumab 75 mg q4w) and chemoradiotherapy according to the National Comprehensive Cancer Network radiation therapy guidelines and local chemotherapy prescribing information.

[0143] A total dose of 60 Gy to 70 Gy was delivered in 30 to 35 fractions (i.e., 2 Gy / fraction, 5 times per week) over a period of 6 to 7 weeks (starting within the first or second cycle of chemotherapy) for Groups 1 and 3. A total dose of 45 Gy was delivered in 30 fractions (i.e., 1.5 Gy / fraction, 2 times per day [with at least 6 hours apart], 10 times per week) over a period of 3 weeks (starting within the first or second cycle of chemotherapy) for Groups 2 and 4.

[0144] If the initial dosing regimen of tremelimumab (75 mg q4w) in groups 3 and 4 (scheme 0) was not tolerated, it was adjusted (scheme-1); 1 dose of tremelimumab was given on day 1 (week 0) and 3 more doses were given after chemoradiotherapy. If this regimen was still not tolerated, the tremelimumab regimen was adjusted again (scheme-2), in which all 4 doses would be given after chemoradiotherapy (Table 1). For both schemes-1 and -2, post-chemoradiotherapy tremelimumab administration was initiated once the initial chemoradiotherapy was completed and at least 48 hours after any recommended prophylactic cranial irradiation (PCI) and was administered together with the next scheduled dose of durvalumab.

[0145] Table 1. Changes in the intensity of the tremelimumab regimen (for the tremelimumab-containing groups) in descending order

[0146]

[0147] a For patients who have a response (CR or PR) to initial treatment, PCI may be permitted at the investigator's discretion. PCI should be administered according to Error! Reference not found guidelines. In this case, PCI will be given after the acute toxicity of initial chemoradiotherapy has resolved and no earlier than 2 weeks after the last dose of tremelimumab.

[0148] b In eligible patients, maintenance doses of tremelimumab should be administered q4w with the next scheduled dose of durvalumab and at least 48 hours after completion of PCI.

[0149] c If a DLT occurred during the first chemoradiotherapy cycle in regimen 0, the safety review board had the discretion to restrict the start of thoracic RT to the second chemotherapy cycle in subsequent patients.

[0150] CR: complete remission; PCI: preventive cranial irradiation; PR: partial remission; q4w every 4 weeks.

[0151] For patients in the SCLC cohort who have a response to initial therapy (complete response [CR] or partial response [PR]), PCI may be permitted at the investigator's discretion. In this case, PCI will be given after the acute toxicity of the initial chemoradiotherapy resolves and no earlier than 2 weeks after the last dose of tremelimumab. PCI is recommended for eligible patients 4 to 11 weeks after the completion of chemoradiotherapy. Patients in groups 1 and 2 receive PCI after the acute toxicity of the initial chemoradiotherapy resolves. For patients in groups 3 and 4, those who follow regimen-0 receive PCI after the acute toxicity of the initial chemoradiotherapy resolves and at least 2 weeks after the last dose of tremelimumab, while those who follow regimen-1 and regimen-2 receive PCI after the acute toxicity of the initial chemoradiotherapy resolves and before the start of tremelimumab administration after chemoradiotherapy. In part A, a total of 12 patients will be enrolled in groups 1 and 2 for the evaluation of DLTs in patients treated with durvalumab and chemoradiotherapy. If additional safety data are needed, an additional 6 patients will be added to each group.

[0152] Part B: Extension Period

[0153] In the extension phase, the investigator may choose a combination of cisplatin or carboplatin with etoposide to further evaluate the safety and tolerability of concurrent chemoradiotherapy with durvalumab and / or tremelimumab. A minimum of 5 patients in each group at progression will be assigned to the carboplatin regimen. Up to 30 additional patients will be added to each group at progression.

[0154] The detailed study flow chart of the SCLC cohort is shown in Figure 4 middle.

[0155] Target

[0156] Main Objectives

[0157]

[0158] AE adverse events; BP blood pressure; DLT dose-limiting toxicity; ECG electrocardiogram.

[0159] Secondary Objectives

[0160]

[0161] BoR best objective response; DCR disease control rate; DFS disease-free survival rate; DFS12 12-month disease-free survival rate; DFS18 18-month disease-free survival rate; DFS24 24-month disease-free survival rate; DoR duration of response; HNSCC head and neck squamous cell carcinoma; NSCLC non-small cell lung cancer; ORR objective response rate; OS overall survival; PFS12 12-month progression-free survival rate; PFS18 18-month progression-free survival rate; PFS24 24-month progression-free survival rate; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, version 1.1; SCLC small cell lung cancer.

[0162] Target patient groups

[0163] To be included in the study, patients had to meet the following criteria: age ≥18 years at screening and had not previously received immune-mediated therapy, including but not limited to other anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies or therapeutic anticancer vaccines.

[0164] For the HNSCC cohort, patients had histologically or cytologically confirmed locally advanced HNSCC, were eligible for definitive chemoradiotherapy, and were not considered for primary surgery based on the investigator's decision or patient refusal. Patients with the following HNSCC subtypes were eligible for this study:

[0165] Unresectable oral stage IVa and IVb

[0166] Laryngeal: Stage IVa and IVb

[0167] Laryngopharynx: T3-4N0, T2-4N1-3 (stages III, IVa, and IVb)

[0168] HPV-negative oropharynx: T3-4N0 or T2-4N1-3 (stages III, IVa, and IVb)

[0169] HPV-positive oropharynx: ≥10 pack-year smoking history and either N2b / N2c or T4 or N3 (stages III, IVa, and IVb) regardless of smoking history

[0170] For the HNSCC cohort and NSCLC cohort, patients had histologically or cytologically confirmed NSCLC and presented with locally advanced, unresectable (stage III) disease.

[0171] For the SCLC cohort, patients were diagnosed with limited-stage SCLC (I-III SCLC [T any, Nany, M0]) confirmed by histology or cytology, that is, their disease was eligible for radical radiotherapy.

[0172] Efficacy evaluation

[0173] Efficacy assessments of ORR, best objective response (BoR), DoR, DCR, and PFS were derived using investigator RECIST 1.1 assessment. Investigator RECIST 1.1 baseline tumor assessment utilized images of CT (preferred) or MRI of the applicable area for the tumor type for the cohort, each with intravenous contrast. FDG-PET / CT with intravenous contrast and brain MRI (preferred; or CT with intravenous contrast) scans were obtained during screening for staging purposes (to determine metastatic tumor sites) and as a comparison to any same study scan to assess new lesions, and these scans must not be used for baseline RECIST 1.1 selection of target lesions (TL) and non-target lesions (NTL). Additional imaging of any other areas of disease involvement was performed based on the individual patient's signs and symptoms. Baseline assessments were performed no more than 28 days before the start of study drug, ideally as close to and before the start of study drug. RECIST 1.1 assessment of baseline images identified a total of up to 5 TLs, with no more than 2 TLs (defined as measurable) and NTLs per organ, and each lesion (and any new lesions) was evaluated on subsequent follow-up images. This allowed determination of subsequent TL responses, NTL responses, new lesions, and overall tumor response (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], or not evaluable [NE]) at a specific time point.

[0174] Dosage and administration

[0175] For all cohorts, if applicable, patients received weight-based dosing equivalent to 20 mg / kg durvalumab q4w and 1 mg / kg tremelimumab q4w if their body weight dropped to 30 kg or less (≤30 kg) until their body weight improved to more than 30 kg (>30 kg), at which time patients began receiving a fixed dose of 1500 mg durvalumab plus 75 mg tremelimumab q4w.

[0176] On days with multiple intraperitoneal (IP) injections, IV tremelimumab was administered first, followed by durvalumab and then cisplatin (as appropriate).

[0177] Tremelimumab was administered first; the durvalumab infusion began immediately after the completion of the tremelimumab infusion. The standard infusion time for tremelimumab and durvalumab was 1 hour (±15 minutes); however, if interruptions occurred during the infusion, a total time of more than 8 hours was allowed at room temperature. If clinical issues related to tolerability of the immediate sequential administration arose, the subsequent durvalumab cycle was given up to 1 hour after the completion of the tremelimumab infusion, at the investigator's discretion.

[0178] If durvalumab and chemotherapy were administered on the same day, durvalumab was administered first, followed by chemotherapy (number of infusions according to institutional standards).

[0179] Radiation therapy was administered according to treatment guidelines recommended by the National Comprehensive Cancer Network.

[0180] HNSCC Cohort

[0181] Durvalumab (MEDI4736) monotherapy combined with chemoradiotherapy (Group 1)

[0182] Patients in Group 1 received the following treatment :

[0183] Durvalumab: Patients received 1500 mg of durvalumab (MEDI4736) via IV infusion q4w for 2 years unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met (whichever occurred first).

[0184] Radiotherapy: External beam radiotherapy (1.6 Gy / fraction to 2 Gy / fraction) was administered daily from week 1 to week 7 (5 times per week for approximately 7 weeks of treatment) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first).

[0185] Cisplatin: Patients received 100 mg / m2 via IV infusion every 3 weeks starting in week 1 2 Cisplatin, last dose at week 7 (3 doses), unless unacceptable toxicity, consent withdrawal, or other discontinuation criteria are met (whichever occurs first). Table 2 shows the dosing schedule for the HNSCC cohort.

[0186] Table 2. Dosing regimen for the HNSCC cohort

[0187]

[0188] a Note that the last dose of durvalumab was administered at week 100.

[0189] Note: All administered medications have a dosing window of ±3 days (except Day 1 which will have a dosing window of +3 days).

[0190] Note: Durvalumab dose will be 1500 mg; cisplatin dose will be 100 mg / m 2 ; The radiotherapy dose will be 1.6Gy / fraction to 2Gy / fraction, 5 times a week.

[0191] Cis cisplatin; Durva durvalumab; HNSCC head and neck squamous cell carcinoma.

[0192] NSCLC Cohort

[0193] Durvalumab (MEDI4736) monotherapy combined with chemoradiotherapy (Group 1)

[0194] Patients in Group 1 received the following treatment :

[0195] Durvalumab: Patients received 1500 mg of durvalumab (MEDI4736) via IV infusion q4w until PD unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met (whichever occurred first).

[0196] Radiotherapy: External beam radiotherapy (2 Gy / fraction) was administered daily from week 0 to week 5 (5 fractions per week for approximately 6 weeks of treatment, totaling 60 Gy) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first).

[0197] Cisplatin: Patients received 50 mg / m2 via IV infusion on days 1, 8, 29, and 36 (weeks 0, 1, 4, and 5, respectively). 2 Cisplatin unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met, whichever occurred first.

[0198] Etoposide: Patients received 50 mg / m2 via IV infusion on days 1 to 5 (week 0) and days 29 to 33 (week 4). 2 Etoposide unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met, whichever occurred first.

[0199] Durvalumab (MEDI4736) monotherapy combined with chemoradiotherapy (Group 2)

[0200] Patients in Group 2 received the following treatment :

[0201] Durvalumab: Patients received 1500 mg of durvalumab (MEDI4736) via IV infusion q4w until PD unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met (whichever occurred first).

[0202] Radiotherapy: External beam radiotherapy (2 Gy / fraction) was administered daily from week 0 to week 5 (5 fractions per week for approximately 6 weeks of treatment, totaling 60 Gy) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first).

[0203] Carboplatin: Patients received carboplatin AUC 2 by IV infusion q1w starting at Week 0, received the last dose (6 doses) at Week 5, and then received carboplatin AUC 6 consolidation therapy by IV infusion on Day 43 (Week 6) and Day 64 (Week 9) (Day 1 of a 21-day cycle [q3w], 2 cycles) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first). Consolidation cycles of carboplatin are optional and depend on local practice.

[0204] Paclitaxel: Patients received 45 mg / m2 to 50 mg / m2 paclitaxel via IV infusion q1w starting at week 0, with the last dose (6 doses) at week 5, followed by consolidation therapy with 200 mg / m2 paclitaxel via IV infusion on days 43 (week 6) and 64 (week 9) (day 1 of a 21-day cycle [q3w], 2 cycles) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first). Consolidation cycles of paclitaxel were optional and depended on local practice.

[0205] Durvalumab (MEDI4736) monotherapy combined with chemoradiotherapy (Group 3)

[0206] Patients in Group 3 received the following treatment :

[0207] Durvalumab: Patients received 1500 mg of durvalumab (MEDI4736) via IV infusion q4w until PD unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met (whichever occurred first).

[0208] Radiotherapy: External beam radiotherapy (2 Gy / fraction) was administered daily from week 0 to week 5 (5 fractions per week for approximately 6 weeks of treatment, totaling 60 Gy) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first).

[0209] Carboplatin / cisplatin: Patients received carboplatin AUC 5 or 75 mg / m by IV infusion on Day 1 (Week 0), Day 22 (Week 3), and Day 43 (Week 6) (Day 1 of a 21-day cycle [q3w], 3 cycles) at the discretion of the investigator. 2 Cisplatin unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met, whichever occurred first.

[0210] Pemetrexed: Patients received 500 mg / m2 via IV infusion on Day 1 (Week 0), Day 22 (Week 3), and Day 43 (Week 6) (Day 1 of a 21-day cycle [q3w], 3 cycles) 2 Pemetrexed unless unacceptable toxicity occurs, consent is withdrawn, or other discontinuation criteria are met, whichever occurs first.

[0211] Table 3 shows the dosing regimen for the NSCLC cohort.

[0212]

[0213] SCLC Cohort

[0214] Durvalumab (MEDI4736) monotherapy combined with chemoradiotherapy (Group 1)

[0215] Patients in Group 1 received the following treatment :

[0216] Durvalumab: Patients received 1500 mg of durvalumab (MEDI4736) via IV infusion q4w until PD unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met (whichever occurred first).

[0217] Radiotherapy: Daily external beam radiotherapy (2 Gy / fraction) was started during the first or second chemotherapy cycle; 60 Gy to 70 Gy was given 5 times per week during 6 to 7 weeks of treatment unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first).

[0218] Cisplatin and etoposide: Starting in Week 0, patients received 60 mg / m2 via IV infusion on Days 1 (Week 0), 22 (Week 3), 43 (Week 6), 64 (Week 9), 85 (Week 12), and 106 (Week 15) (Day 1 of a 21-day cycle [q3w] for 4 to 6 cycles based on local guidelines) 2 Up to 80 mg / m 2 Cisplatin, and 100 mg / m2 on days 1 to 3 (week 0), 22 to 24 (week 3), 43 to 45 (week 6), 64 to 66 (week 9), 85 to 87 (week 12), and 106 to 108 (week 15) (days 1 to 3 of a 21-day cycle for cycles 4 to 6 based on local guidelines) 2 Up to 120 mg / m 2Etoposide unless unacceptable toxicity occurs, consent is withdrawn, or other discontinuation criteria are met (whichever occurs first). Patients start with cisplatin, but if they cannot tolerate cisplatin, they have the option of switching to carboplatin (AUC 5). The total cisplatin dose per cycle may be distributed over days 1, 2, and 3 of each chemotherapy cycle in part B if tolerability issues arise and only after consultation with the global medical team.

[0219] Durvalumab (MEDI4736) monotherapy combined with chemoradiotherapy (Group 2)

[0220] Patients in Group 2 received the following treatment :

[0221] Durvalumab: Patients received 1500 mg of durvalumab (MEDI4736) via IV infusion q4w until PD unless unacceptable toxicity occurred, consent was withdrawn, or other discontinuation criteria were met (whichever occurred first).

[0222] Radiotherapy: Daily external beam radiotherapy (1.5 Gy / fraction) was administered starting during the first or second chemotherapy cycle; 10 fractions per week [2 times per day, at least 6 hours apart] for a total of 45 Gy over 3 weeks of treatment unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first).

[0223] Cisplatin and etoposide: Starting in Week 0, patients received 60 mg / m2 to 80 mg / m2 of cisplatin via IV infusion on Days 1 (Week 0), 22 (Week 3), 43 (Week 6), 64 (Week 9), 85 (Week 12), and 106 (Week 15) (Day 1 of a 21-day cycle [q3w] for 4 to 6 cycles based on local guidelines) and etoposide on Days 1 to 3 (Week 0), 2 Patients received 100 mg / m2 to 120 mg / m2 of etoposide on Days 2 to 24 (Week 3), Days 43 to 45 (Week 6), Days 64 to 66 (Week 9), Days 85 to 87 (Week 12), and Days 106 to 108 (Week 15) (Days 1 to 3 of 21-day cycles for cycles 4 to 6, based on local guidelines) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met, whichever occurred first. Patients started with cisplatin, but if they could not tolerate cisplatin, they had the option of switching to carboplatin (AUC 5). The total cisplatin dose per cycle could be distributed over Days 1, 2, and 3 of each chemotherapy cycle in Part B if tolerability issues arose and only after consultation with the global medical team.

[0224] Durvalumab (MEDI4736) + tremelimumab combination therapy combined with chemoradiotherapy (Group 3)

[0225] Patients in Group 3 received the following treatment :

[0226] 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 occurred, consent was withdrawn, or other discontinuation criteria were met (whichever occurred first).

[0227] If the initial dosing regimen of tremelimumab (75 mg q4w) in Group 3 (Schedule 0) was not tolerated, it was adjusted (Schedule-1); 1 dose of tremelimumab was given on day 1 (week 0) and 3 doses q4w were given after chemoradiotherapy. If this regimen was still not tolerated, the tremelimumab regimen was adjusted again (Schedule-2), in which all doses were given after chemoradiotherapy (Table 1). For both Schedule-1 and Schedule-2, maintenance dosing of tremelimumab was started once the initial chemoradiotherapy was completed and at least 48 hours after any recommended PCI, and was administered together with the next scheduled dose of durvalumab.

[0228] Radiotherapy: Daily external beam radiotherapy (2 Gy / fraction) was started during the first or second chemotherapy cycle; 60 Gy to 70 Gy was given 5 times per week during 6 to 7 weeks of treatment unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first).

[0229] Cisplatin and etoposide: Starting in Week 0, patients received 60 mg / m2 to 80 mg / m2 of cisplatin via IV infusion on Days 1 (Week 0), 22 (Week 3), 43 (Week 6), 64 (Week 9), 85 (Week 12), and 106 (Week 15) (Day 1 of a 21-day cycle [q3w] for 4 to 6 cycles based on local guidelines) and etoposide on Days 1 to 3 (Week 0), 2 Patients received 100 mg / m2 to 120 mg / m2 of etoposide on Days 2 to 24 (Week 3), Days 43 to 45 (Week 6), Days 64 to 66 (Week 9), Days 85 to 87 (Week 12), and Days 106 to 108 (Week 15) (Days 1 to 3 of 21-day cycles for cycles 4 to 6, based on local guidelines) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met, whichever occurred first. Patients started with cisplatin, but if they could not tolerate cisplatin, they had the option of switching to carboplatin (AUC 5). The total cisplatin dose per cycle could be distributed over Days 1, 2, and 3 of each chemotherapy cycle in Part B if tolerability issues arose and only after consultation with the global medical team.

[0230] Durvalumab (MEDI4736) + tremelimumab combination therapy combined with chemoradiotherapy (Group 4)

[0231] Patients in Group 4 will receive the following treatments :

[0232] 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 occurred, consent was withdrawn, or other discontinuation criteria were met (whichever occurred first).

[0233] If the initial dosing regimen of tremelimumab (75 mg q4w) in Group 4 (Schedule 0) was not tolerated, it was adjusted (Schedule-1); 1 dose of tremelimumab was given on day 1 (week 0) and 3 doses q4w were given after chemoradiotherapy. If this regimen was still not tolerated, the tremelimumab regimen was adjusted again (Schedule-2), in which all doses would be given after chemoradiotherapy (Table 1). For both Schedule-1 and Schedule-2, maintenance dosing of tremelimumab was started once the initial chemoradiotherapy was completed and at least 48 hours after any recommended PCI, and was administered together with the next scheduled dose of durvalumab.

[0234] Radiotherapy: Daily external beam radiotherapy (1.5 Gy / fraction) was administered starting during the first or second chemotherapy cycle; 10 fractions per week; 2 fractions per day, at least 6 hours apart; a total of 45 Gy over 3 weeks of treatment, unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met (whichever occurred first).

[0235] Cisplatin and etoposide: Starting in Week 0, patients received 60 mg / m2 to 80 mg / m2 of cisplatin via IV infusion on Days 1 (Week 0), 22 (Week 3), 43 (Week 6), 64 (Week 9), 85 (Week 12), and 106 (Week 15) (Day 1 of a 21-day cycle [q3w] for 4 to 6 cycles based on local guidelines) and etoposide on Days 1 to 3 (Week 0), 2 Patients received 100 mg / m2 to 120 mg / m2 of etoposide on Days 2 to 24 (Week 3), Days 43 to 45 (Week 6), Days 64 to 66 (Week 9), Days 85 to 87 (Week 12), and Days 106 to 108 (Week 15) (Days 1 to 3 of 21-day cycles for cycles 4 to 6, based on local guidelines) unless unacceptable toxicity occurred, consent was withdrawn, or other interruption criteria were met, whichever occurred first. Patients started with cisplatin, but if they could not tolerate cisplatin, they had the option of switching to carboplatin (AUC 5). The total cisplatin dose per cycle could be distributed over Days 1, 2, and 3 of each chemotherapy cycle in Part B if tolerability issues arose and only after consultation with the global medical team.

[0236] Table 4 shows the dosing regimen for the SCLC cohort.

[0237]

[0238] b Patients in Groups 1, 2, 3, and 4 will be given 100 mg / m on Days 1 to 3, 22 to 24, 43 to 45, 64 to 66, 85 to 87, and 106 to 108 (Days 1 to 3 of a 21-day cycle, 4 to 6 cycles) according to local guidelines. 2 Up to 120 mg / m 2 Etoposide.

[0239] c Patients should start with cisplatin, but if they cannot tolerate cisplatin, they may choose to switch to carboplatin (AUC 5). The total cisplatin dose per cycle may be distributed over days 1, 2, and 3 of each chemotherapy cycle in Part B if tolerability issues arise and only after consultation with the global medical team.

[0240] d If the initial dosing regimen of tremelimumab (75 mg q4w) in groups 3 and 4 (scheme 0) is not tolerated, it will be adjusted (scheme-1); 1 dose of tremelimumab will be given on day 1 (week 0) and 3 doses q4w will be given after chemoradiotherapy. If this regimen is still not tolerated, the tremelimumab regimen will be adjusted again (scheme-2), in which all doses will be given after chemoradiotherapy (Table 1). For both schemes-1 and -2, maintenance dosing of tremelimumab can be started once the initial chemoradiotherapy is completed and at least 48 hours after any recommended PCI, and should be administered with the next scheduled dose of durvalumab. PCI should be administered according to the National Comprehensive Cancer Network guidelines.

[0241] e Group 3 will be opened only if the regimen in Group 1 is safe and tolerable, and Group 4 will be opened only if the regimen in Group 2 is safe and tolerable.

[0242] f For patients who have received 5 or 6 cycles of chemotherapy.

[0243] Note: All administered medications have a dosing window of ±3 days (except Day 1 which will have a dosing window of +3 days).

[0244] Note: Durvalumab dose will be 1500 mg (q4w); Tremelimumab dose will be 75 mg; Cisplatin dose will be 60 mg / m 2 Up to 80 mg / m 2; Etoposide dose will be 100 mg / m 2 Up to 120 mg / m 2 The radiation dose will be 2 Gy / fraction, 5 times per week (60 Gy to 70 Gy in total) in groups 1 and 3, and 1.5 Gy / fraction, 10 times per week (2 times per day, at least 6 hours apart, 45 Gy in total) in groups 2 and 4.

[0245] result

[0246] HNSCC

[0247] A total of 8 patients were enrolled in the HNSCC cohort. In summary, the safety and tolerability profile of durvalumab + cisplatin + RT was manageable and consistent with the known safety profiles of durvalumab and cisplatin + RT alone. No unexpected safety findings were observed for this combination regimen. Specifically, patients in the HNSCC cohort showed:

[0248] No DLT;

[0249] Seven patients reported CTCAE grade 3 or 4 adverse events, the most common of which were lymphopenia, stomatitis, increased amylase, and leukopenia;

[0250] 2 patients experienced serious adverse events (SAEs) (subdural hemorrhage, acute kidney injury);

[0251] Three patients experienced AEs leading to discontinuation of any study treatment; of these, one led to discontinuation of durvalumab (acute kidney injury—the only fatal AE);

[0252] Five patients experienced immune-mediated adverse events (imAEs); the most common group term categories were hypothyroidism and pancreatitis. No imAEs led to discontinuation or death.

[0253] Efficacy in the HNSCC cohort showed a 71% overall response rate (ORR); disease control rate (DCR) of 86% at 18 weeks and 83% at 48 weeks; disease-free survival of 85.7% at 12 months and 51.4% at 18 and 24 months; and overall survival of 20.1 months.

[0254] NSCLC

[0255] 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 chemoradiation therapy affected the tolerability of standard chemoradiation therapy. Specifically, patients in the NSCLC cohort showed:

[0256] One DLT occurred in Group 1 (Grade 3 AST increase / Grade 4 ALT increase), leading to discontinuation of study treatment;

[0257] 77% and 60% of patients experienced CTC grade 3 / 4 AEs and SAEs; the majority of these events were predictable based on the established toxicity profiles of chemotherapy, radiation, and immunotherapy or due to the patient’s primary tumor location and / or medical history;

[0258] Fatal cardiac events occurred in 4 patients. All patients had a significant history of smoking, and 3 / 4 patients had significant cardiac-related MH. Another 4 patients experienced fatal AEs (acute respiratory failure, pneumonia, PCP pneumonia, sepsis);

[0259] 14 patients experienced AEs leading to discontinuation of any study treatment (n=13, durvalumab), including 8 patients with fatal AEs and 1 patient with a DLT;

[0260] 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;

[0261] 20 patients across 3 treatment groups experienced imAEs; 2 patients experienced imAEs leading to discontinuation

[0262] (hepatic events, pneumonia, no events with fatal outcome).

[0263] The efficacy of the NSCLC cohort showed an ORR for each group, which was 66.7%, 54.5% and 61.9% for groups 1, 2 and 3, respectively. The NSCLC cohort showed a DCR for each group, which was 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 overall mean progression-free survival (mPFS) was 13.4 months, and the 12-month progression-free survival rate was 53.6%. The mPFS of each group was 14.4 months, 12.8 months and 10.8 months for groups 1, 2 and 3, respectively. The 12-month progression-free survival rate of each group was 67.3%, 54.5% and 40.8% for groups 1, 2 and 3, respectively. The median OS was not reached, and the 1-year OS rate of all three groups exceeded 80% (estimated).

[0264] Limited-stage SCLC (LS-SCLC)

[0265] A total of 33 patients were enrolled in the LS-SCLC cohort. Overall, the 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 chemoradiotherapy affected the tolerability of standard chemoradiotherapy.

[0266] Specifically, patients in cohorts 1 and 2 of the LS-SCLC cohort showed:

[0267] No DLT;

[0268] Adverse events of CTCAE grade 3 or 4 and SAEs were reported in 79% and 21% of patients, respectively.

[0269] The most common grade 3 / 4 AEs were hematologic toxicity;

[0270] No fatal AEs;

[0271] Two patients experienced AEs leading to discontinuation of any study treatment (including durvalumab)

[0272] (pneumonia, IgA nephropathy);

[0273] Esophagitis, pneumonitis, and radiation pneumonitis events were mainly grade 1 / 2 in severity. Events were manageable, with only one event leading to treatment discontinuation; no events had fatal outcomes;

[0274] Four patients in the T2 treatment group experienced imAEs (pneumonitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, dermatitis / rash). Only the pneumonitis imAE led to discontinuation. There were no fatal imAEs.

[0275] In SCLC Groups 3 and 4, patients showed:

[0276] In Part A, Group 3 completed recruitment; no DLTs, however Group 4 did not complete recruitment due to study termination. No DLTs were reported in the 3 patients enrolled in Group 4;

[0277] CTCAE grade 3 or 4 adverse events were reported in 76% of patients, with the most common being neutropenia and anemia;

[0278] Four patients experienced SAEs, including two with radiation pneumonitis;

[0279] No fatal AEs;

[0280] Two patients experienced AEs (pneumonitis, radiation pneumonitis) leading to discontinuation of any study treatment (including durvalumab);

[0281] Esophagitis, pneumonitis, and radiation pneumonitis events were mainly grade 1 / 2 in severity. Events were manageable with 2 treatment interruptions; no events had fatal outcomes;

[0282] Three patients experienced imAEs in both treatment groups, all in group 3; the most common group term category was pneumonia; only 1 of these led to discontinuation. There were no fatal imAEs.

[0283] Efficacy in the SCLC cohort showed an ORR of 67%, a median DOR of 13.4 months, a DCR of 96% at 18 weeks and 78% at 48 weeks, an mPFS of 9.3 months, and a PFS12 rate of 41% in both cohorts 1 and 2. The median OS was not reached, and the OS12 rate was estimated to be 90%.

[0284] In cohorts 3 and 4, efficacy in the SCLC cohort showed an ORR of 89%, DCR of 100% at 18 weeks, and 100% at 48 weeks. Overall mPFS and median OS were not reached. The OS12 rate was estimated to be 100%.

Claims

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

2. A method for improving the disease control rate (DCR) of 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.

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

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

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

6. The method according to claim 5, wherein the chemoradiotherapy comprises 2 Gy / time, 5 times a week, for 6 to 7 weeks.

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

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

9. The method according to claim 8, wherein the hyperfractionated radiotherapy comprises 1.5 Gy / time, twice a day, at least 6 hours apart, 10 times a 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 according to any one of claims 1 to 11 , wherein the anti-PD-L1 antibody is durvalumab, avelumab, atezolizumab, or sugemalimab.

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

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

15. The method according to 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 improving the overall response rate (ORR) in a patient with head and neck squamous cell carcinoma (HNSCC), the method comprising treating the patient with a human anti-PD-L1 antibody and chemoradiotherapy simultaneously.

17. A method of improving the disease control rate (DCR) of a patient with HNSCC, the method comprising treating the patient with a human anti-PD-L1 antibody and chemoradiotherapy simultaneously.

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

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

20. The method of claim 19, wherein the chemoradiotherapy comprises 2 Gy / time, 5 times a week for 7 weeks.

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

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

23. The method according to claim 21 or claim 22, wherein the chemoradiotherapy comprises 1.6 Gy / time, 5 times a week for 7 weeks.

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

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

26. The method of any one of claims 16 to 25, wherein treatment with the human anti-PD-L1 antibody comprises administering 1500 mg of the anti-PD-L1 antibody intravenously 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 improving the 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 of improving the disease control rate (DCR) of a patient with SCLC.

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

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

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

33. The combination for use according to claim 32, wherein the chemoradiotherapy comprises 2 Gy / time, 5 times per week, for 6 to 7 weeks.

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

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

36. The combination for use according to claim 35, wherein the hyperfractionated radiotherapy comprises 1.5 Gy / fraction, twice a day, at least 6 hours apart, 10 times a week for 3 weeks.

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

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

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

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

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

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

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

45. A combination for use according to any one of claims 28 to 44, wherein the 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. The combination for use according to 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. The combination for use according to any one of claims 28 to 48, wherein treatment with the anti-CTLA-4 antibody comprises administering 75 mg of the anti-CTLA-4 antibody intravenously to the 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 preparation of a medicament in a method for improving the 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 preparation of a medicament for use in a method for improving the disease control rate (DCR) of a patient with SCLC.

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

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

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

56. Use of a combination comprising a human anti-PD-L1 antibody and concurrent chemoradiotherapy in the preparation of a medicament for treating HNSCC.

Images