Anti-PD-L1 antibody in combination with one or more chemotherapy agents for treating endometrial cancer

Abstract

This disclosure relates to methods, compositions, and combinations for the treatment of endometrial cancer. Specifically, this disclosure relates to a method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, comprising administering one or more chemotherapeutic agents, an anti-PD-L1 antibody or its antigen-binding fragment, and an optional PARP inhibitor to the subject. This disclosure also relates to a combination for use in the treatment of endometrial cancer, comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or its antigen-binding fragment, and an optional PARP inhibitor.

Description

[Technical Field]

[0001] This disclosure relates to methods, compositions, and combinations for the treatment of endometrial cancer. Specifically, this disclosure relates to a method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, comprising administering one or more chemotherapeutic agents, an anti-PD-L1 antibody or its antigen-binding fragment, and an optional PARP inhibitor to the subject. This disclosure also relates to a combination for use in the treatment of endometrial cancer, comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or its antigen-binding fragment, and an optional PARP inhibitor. [Background technology]

[0002] Cancer treatment often involves surgical resection followed by chemotherapy and radiation therapy. Standard treatment regimens vary greatly in their long-term success, as tumor cells can essentially circumvent this by regenerating primary tumor growth and, more importantly, often by disseminating distant metastases. Recent advances in the treatment of cancer, and cancer-related diseases, disorders, and conditions, include the use of combination therapies that combine immunotherapy with more traditional chemotherapy and radiation therapy. In most scenarios, immunotherapy is less toxic than conventional chemotherapy because it utilizes the patient's own immune system to identify and eliminate tumor cells.

[0003] Endometrial cancer is a disease in which malignant cancer cells form in the tissue of the endometrium (the inner lining of the uterus). Endometrial cancer is sometimes called uterine cancer. It is one of the most common malignant tumors of the female reproductive organs, with more than 380,000 new cases reported worldwide in 2018 and an estimated 61,880 new cases diagnosed in the United States in 2019. Prevalence is increasing in developed countries, with the highest incidence observed in the United States, Canada, and Northern and Western Europe. From 2006 to 2015, the incidence increased by approximately 1% per year, and from 2007 to 2016, the mortality increased by approximately 2% per year (American Cancer Society 2019). The main risk factors thought to be associated with the development of endometrial cancer are obesity, diabetes, tamoxifen use, and exposure to excessive estrogen levels associated with reproductive factors (early menarche, late menopause, nulliparity). The growth of the elderly population may also contribute to the increased incidence. Alternative treatment options for recurrent endometrial cancer are limited, and there is a high and unmet need for new therapies. [Overview of the project]

[0004] This disclosure relates to methods, compositions, and combinations for the treatment of endometrial cancer. Specifically, this disclosure relates to a method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, comprising administering one or more chemotherapeutic agents, an anti-PD-L1 antibody or its antigen-binding fragment, and an optional PARP inhibitor to the subject. This disclosure also relates to a combination for use in the treatment of endometrial cancer, comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or its antigen-binding fragment, and an optional PARP inhibitor.

[0005] In one embodiment, the present disclosure provides a method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, comprising administering to the subject (a) a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment and optionally a therapeutically effective dose of a PARP inhibitor.

[0006] In another aspect, the Disclosure provides a combination for use in the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer, the combination comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and optionally a therapeutically effective amount of a PARP inhibitor.

[0007] In another aspect, the Disclosure provides the use of a combination comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor in the manufacture of a pharmaceutical for the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer.

[0008] In a further embodiment, the Disclosure provides a use of a combination in the manufacture of a pharmaceutical for the treatment of ovarian cancer in a subject requiring treatment for ovarian cancer, wherein the combination comprises (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and optionally a therapeutically effective amount of a PARP inhibitor.

[0009] These and other features and advantages of this disclosure will be better understood from the following detailed description together with the attached claims. Note that the claims are defined by their enumeration rather than by a specific consideration of the features and advantages described herein. [Brief explanation of the drawing]

[0010] [Figure 1] The screening process is outlined below. Abbreviations: ICF = Informed Consent Form, MMR = Mismatch Repair. *The use of newly collected tumor samples is permitted only if the sample is collected as part of routine clinical practice. **Patients with an unknown MMR status prior to randomization are considered screening failures and are ineligible. If, due to technical failure, the original MMR test cannot be completed by the end of the 28-day screening period, the patient must be rescreened to allow sufficient time for MMR retesting. Samples must be shipped before signing the primary informed consent, and MMR results must be available prior to randomization. Submission and testing of new samples may only be performed if the original test failed due to technical failure. Refer to the laboratory manual for further details regarding retesting procedures. [Figure 2]The study design diagram is shown. During the chemotherapy phase, the IV trial treatments were administered on the same day in the following order: 1. durvalumab / placebo (1120 mg over 1 hour, or up to 8 hours if infusion interruptions occurred), 2. paclitaxel 175 mg / m2 via IV infusion over 3 hours, 3. carboplatin (via IV infusion over 1 hour, or according to local treatment, AUC5 or AUC6). Maintenance therapy was initiated 3 to 9 weeks after the last chemotherapy infusion. *Disease measurable by RECIST v1.1 after surgery or diagnostic biopsy (FIGO stage III), or with / without disease after surgery or diagnostic biopsy (FIGO stage IV) †Disease measurable or unmeasurable using RECIST v1.1, with little possibility of cure by surgery alone or in combination. ‡Previous adjuvant systemic anticancer therapy was permitted for recurrent disease with a recurrence period of 12 months or more from the last dose to subsequent recurrence. bid, twice daily; EC (endometrial cancer); IV (intravenous); MMR (mismatch repair); PARP (poly(ADP-ribose) polymerase); q3w, every 3 weeks; q4w, every 4 weeks; R, randomization. [Figure 3] A multiplicity control strategy is presented. The presented alpha level is two-sided. *Using the Lan-DeMets consumption function approximating the O'Brien-Fleming approach, 2.5% was allocated overall. H, hypothesis; PFS, progression-free survival; OS, overall survival. [Figure 4A]Progression-free survival (A) and overall survival (B) in the intention-to-treat population are shown, as assessed by the principal investigator according to RECIST, Version 1.1. For PFS analysis, HR and CI were estimated from a Cox proportional hazards model stratified by MMR and disease status. For OS analysis, HR and CI were estimated from an unstratified Cox proportional hazards model. P-values ​​were calculated using a stratified log-rank test. Checkmarks indicate censored observations. Patients without events were censored with the most recent evaluable RECIST assessment. CI (confidence interval); HR (hazard ratio); MMR (mismatch repair); NR (interquartile range); OS (overall survival); PFS (progression-free survival); RECIST (Response Evaluation Criteria in Solid Tumors) = response evaluation criteria in solid tumors. [Figure 4B] Progression-free survival (A) and overall survival (B) in the intention-to-treat population are shown, as assessed by the principal investigator according to RECIST, Version 1.1. For PFS analysis, HR and CI were estimated from a Cox proportional hazards model stratified by MMR and disease status. For OS analysis, HR and CI were estimated from an unstratified Cox proportional hazards model. P-values ​​were calculated using a stratified log-rank test. Checkmarks indicate censored observations. Patients without events were censored with the most recent evaluable RECIST assessment. CI (confidence interval); HR (hazard ratio); MMR (mismatch repair); NR (interquartile range); OS (overall survival); PFS (progression-free survival); RECIST (Response Evaluation Criteria in Solid Tumors) = response evaluation criteria in solid tumors. [Figure 5A]Shows a subgroup analysis of progression-free survival in (A) the doublet group and (B) the triplet group. CI indicates confidence interval; ECOG (Eastern Cooperative Oncology Group), Eastern Cooperative Oncology Group of the United States; FIGO (International Federation of Gynecology and Obstetrics), International Federation of Gynecology and Obstetrics; G grade; HRRm (homologous recombination repair mutation), homologous recombination repair mutation; MMR mismatch repair; PD-L1 (programmed cell death ligand-1) programmed cell death ligand-1; and RoW (rest of world) rest of the world. Stratification factors (MMR status [comparison between functionally normal and deficient], disease status [comparison between newly diagnosed and recurrent], and geographic region [comparison between Asia and the rest of the world]) are based on randomization codes. [Figure 5B] Shows a subgroup analysis of progression-free survival in (A) the doublet group and (B) the triplet group. CI indicates confidence interval; ECOG (Eastern Cooperative Oncology Group), Eastern Cooperative Oncology Group of the United States; FIGO (International Federation of Gynecology and Obstetrics), International Federation of Gynecology and Obstetrics; G grade; HRRm (homologous recombination repair mutation), homologous recombination repair mutation; MMR mismatch repair; PD-L1 (programmed cell death ligand-1) programmed cell death ligand-1; and RoW (rest of world) rest of the world. Stratification factors (MMR status [comparison between functionally normal and deficient], disease status [comparison between newly diagnosed and recurrent], and geographic region [comparison between Asia and the rest of the world]) are based on randomization codes. [Figure 6] Shows enrollment, randomization and intervention. [Figure 7]Shows the sensitivity analysis of progression-free survival evaluated by blinded independent central review. [Figure 8A] Shows progression-free survival as assessed by the investigator in accordance with RECIST Version 1.1 in the (A) dMMR and (B) pMMR subgroups. CI represents confidence interval; dMMR (mismatch repair-deficient), mismatch repair deficiency; pMMR (mismatch repair-proficient), proficient mismatch repair function; and RECIST, Response Evaluation Criteria in Solid Tumors. [Figure 8B] Shows progression-free survival as assessed by the investigator in accordance with RECIST Version 1.1 in the (A) dMMR and (B) pMMR subgroups. CI represents confidence interval; dMMR (mismatch repair-deficient), mismatch repair deficiency; pMMR (mismatch repair-proficient), proficient mismatch repair function; and RECIST, Response Evaluation Criteria in Solid Tumors. [Figure 9] Shows overall survival in the intent-to-treat population. [Figure 10A] Shows progression-free survival as assessed by the investigator in accordance with RECIST Version 1.1 in the (A) PD-L1-positive and (B) PD-L1-negative subgroups. CI, confidence interval; dMMR, mismatch repair deficiency; HR, hazard ratio; MMR, mismatch repair; NR, not reached; PFS, progression-free survival; PD-L1, programmed cell death ligand-1; pMMR, proficient mismatch repair function; RECIST, Response Evaluation Criteria in Solid Tumors. [Figure 10B] Shows progression-free survival as assessed by the investigator in accordance with RECIST Version 1.1 in the (A) PD-L1-positive and (B) PD-L1-negative subgroups. CI, confidence interval; dMMR, mismatch repair deficiency; HR, hazard ratio; MMR, mismatch repair; NR, not reached; PFS, progression-free survival; PD-L1, programmed cell death ligand-1; pMMR, proficient mismatch repair function; RECIST, Response Evaluation Criteria in Solid Tumors. [Figure 11] This document outlines the DUO-E trial design, including patient and endpoint information. [Figure 12A] Patient characteristic data is shown. Federation of Gynaecology and Obstetrics; HRR(m) (homologous recombination repair (mutation)); MMR (mismatch repair); NGS (next-generation sequencing); PD-L1 (programmed death ligand 1); TAP (tumor area proportion). [Figure 12B] Patient characteristic data is shown. Federation of Gynaecology and Obstetrics; HRR(m) (homologous recombination repair (mutation)); MMR (mismatch repair); NGS (next-generation sequencing); PD-L1 (programmed death ligand 1); TAP (tumor area proportion). [Figure 13A] The results for the intent to treat (ITT) population in (A) progression-free survival (PFS), (B) overall survival (OS), (C) objective response rate (ORR), and (D) duration of response (DoR) are shown. [Figure 13B]The results for the intent to treat (ITT) population in (A) progression-free survival (PFS), (B) overall survival (OS), (C) objective response rate (ORR), and (D) duration of response (DoR) are shown. [Figure 13C] The results for the intent to treat (ITT) population in (A) progression-free survival (PFS), (B) overall survival (OS), (C) objective response rate (ORR), and (D) duration of response (DoR) are shown. [Figure 13D] The results for the intent to treat (ITT) population in (A) progression-free survival (PFS), (B) overall survival (OS), (C) objective response rate (ORR), and (D) duration of response (DoR) are shown. [Figure 14A] This report presents the evaluation of secondary endpoints in the ITT population for (A) time to first subsequent therapy or death (TFST), (B) second progression-free survival (PFS2), and (C) time to second subsequent therapy or death (TSST) for both TFST and TSST. [Figure 14B]This report presents the evaluation of secondary endpoints in the ITT population for (A) time to first subsequent therapy or death (TFST), (B) second progression-free survival (PFS2), and (C) time to second subsequent therapy or death (TSST) for both TFST and TSST. [Figure 14C] This report presents the evaluation of secondary endpoints in the ITT population for (A) time to first subsequent therapy or death (TFST), (B) second progression-free survival (PFS2), and (C) time to second subsequent therapy or death (TSST) for both TFST and TSST. [Figure 15A] (A) A post-hoc exploratory analysis of MMR subpopulations in terms of overall survival (OS) for dMMR and (B) pMMR is presented. [Figure 15B] (A) A post-hoc exploratory analysis of MMR subpopulations in terms of overall survival (OS) for dMMR and (B) pMMR is presented. [Figure 16A] Post-hoc exploratory analyses of dMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 16B] Post-hoc exploratory analyses of dMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 16C] Post-hoc exploratory analyses of dMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 16D]Post-hoc exploratory analyses of dMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 16E] Post-hoc exploratory analyses of dMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 16F] Post-hoc exploratory analyses of dMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 17A] Post-hoc exploratory analyses of pMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 17B] Post-hoc exploratory analyses of pMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 17C] Post-hoc exploratory analyses of pMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 17D] Post-hoc exploratory analyses of pMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 17E] Post-hoc exploratory analyses of pMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 17F] Post-hoc exploratory analyses of pMMR subpopulations are shown (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR. [Figure 18A] Pre-specified exploratory analyses of MMR subpopulations for PFS, (A) dMMR, and (B) pMMR are presented. [Figure 18B] Pre-specified exploratory analyses of MMR subpopulations for PFS, (A) dMMR, and (B) pMMR are presented. [Figure 19A] (A) Further results for the ITT population in PFS and (B) OS are shown. [Figure 19B] (A) Further results for the ITT population in PFS and (B) OS are shown. [Figure 20A] Further results from exploratory PFS analyses for the (A) dMMR, (B) pMMR, (C) PD-L1-positive, and (D) PD-L1-negative subgroups are presented. [Figure 20B] Further results from exploratory PFS analyses for the (A) dMMR, (B) pMMR, (C) PD-L1-positive, and (D) PD-L1-negative subgroups are presented. [Figure 20C] Further results from exploratory PFS analyses for the (A) dMMR, (B) pMMR, (C) PD-L1-positive, and (D) PD-L1-negative subgroups are presented. [Figure 20D] Further results from exploratory PFS analyses for the (A) dMMR, (B) pMMR, (C) PD-L1-positive, and (D) PD-L1-negative subgroups are presented. [Modes for carrying out the invention]

[0011] This disclosure relates to methods, compositions, and combinations for the treatment of endometrial cancer. Specifically, this disclosure relates to a method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, comprising administering one or more chemotherapeutic agents, an anti-PD-L1 antibody or its antigen-binding fragment, and an optional PARP inhibitor. This disclosure also relates to a combination for use in the treatment of endometrial cancer, comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or its antigen-binding fragment, and an optional PARP inhibitor.

[0012] When used in accordance with this disclosure, unless otherwise indicated or defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art in which this disclosure pertains. The following references provide general definitions of many of the terms used herein: 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). When used herein, the following terms have the meanings set forth below unless otherwise specified.

[0013] In this disclosure, “comprises,” “comprising,” “containing,” and “having,” etc., may have the meanings attributed to them in U.S. patent law, and “includes,” “including,” etc., and “consisting essentially of” or “consists essentially of” may have the meanings attributed to them in U.S. patent law, and is open-ended and allows for more than described existences, as long as the basic or novel features of the described are not altered by more than described existences, but excludes aspects of the prior art.

[0014] Unless otherwise specified or evident from the context, the term “or” as used herein is understood to be inclusive. Unless otherwise specified or evident from the context, the terms “a,” “an,” and “the” as used herein are understood to be singular or plural. Unless otherwise specifically required by the context, singular terms shall include plural forms, and plural terms shall include singular forms.

[0015] Unless otherwise stated or made clear from the context, the term “about” as used herein is understood to mean within the normal tolerances in the art, for example, within two standard deviations of the mean. “About” can also 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 made clear from the context, all numerical values ​​provided herein are modified by the term “about.”

[0016] Any method, composition, or combination provided herein may be combined with one or more other methods, compositions, or combinations provided herein.

[0017] The ranges provided herein are understood to be abbreviated representations of all values ​​within that range. For example, the range 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.

[0018] As used herein, the term "antibody" refers to a protein capable of specifically binding to an antigen. Conventional or traditional mammalian antibodies comprise a tetramer, which is typically composed of two identical pairs of polypeptide chains, each pair consisting of one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50 to 70 kDa). As used herein, the terms "heavy chain" and "light chain" refer to any immunoglobulin polypeptide that has sufficient variable domain sequences to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically comprises a variable domain of about 100 to 110 or more amino acids that is typically involved in antigen recognition. The carboxy-terminal portion of each chain typically defines a constant domain responsible for effector function. Therefore, in naturally occurring antibodies, a full-length heavy chain immunoglobulin polypeptide comprises a variable domain (V H ) and three constant domains (C H1 , C H2 , and C H3 ), and a hinge region between C H1 and C H2 , wherein the V H domain is at the amino terminus of the polypeptide and the C H3 domain is at the carboxyl terminus. A full-length light chain immunoglobulin polypeptide comprises a variable domain (V L ) and a constant domain (C L ), wherein the V L domain is at the amino terminus of the polypeptide and the C L domain is at the carboxyl terminus.

[0019] Within the full-length light and heavy chains, the variable and constant domains are typically linked by a "J" region of approximately 12 or more amino acids, while the heavy chain also contains a "D" region of approximately 10 or more amino acids. The variable regions of each light / heavy chain pair typically form the antigen-binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of a relatively conserved framework region (FR) linked by three hypervariable regions, also called complementarity-determining regions or CDRs. The CDRs from the two chains of each pair are typically aligned by the framework region, which can enable binding to a specific epitope. From the amino terminus to the carboxyl terminus, both the light and heavy chain variable domains typically contain domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0020] The term "antigen-binding fragment" refers to a portion of an intact antibody and / or the antigen-determining variable domain of an intact antibody. It is known that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, linear antibodies, single-chain antibodies, diabodies, and multispecific antibodies formed from antibody fragments.

[0021] In one embodiment, the present disclosure provides a method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, comprising administering to the subject (a) a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment and optionally a therapeutically effective dose of a PARP inhibitor.

[0022] In one embodiment, the method, composition, and combination include administering to a subject (a) a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment.

[0023] In some embodiments of the method of the present disclosure, step (b) is performed after the completion of step (a).

[0024] In various embodiments of the first embodiment, step (b) may exclude a therapeutically effective amount of a PARP inhibitor. In these embodiments, step (b) includes a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment.

[0025] The number of therapeutic doses planned within each cycle depends on the chemotherapy agent. In some embodiments, each cycle may consist of only one dose. In other embodiments, a cycle may consist of two or more doses.

[0026] In some embodiments, a method for treating endometrial cancer in a subject requiring treatment for endometrial cancer is provided herein, comprising administering to the subject an anti-PD-L1 antibody or its antigen-binding fragment at a dose of about 5 mg / kg to 25 mg / kg. In some embodiments, a method for treating endometrial cancer in a subject requiring treatment for endometrial cancer is provided herein, comprising administering to the subject an anti-PD-L1 antibody or its antigen-binding fragment at a dose of about 10 mg / kg to 20 mg / kg.

[0027] In some embodiments, methods for treating endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, comprising administering to the subjects a fixed dose of an anti-PD-L1 antibody or its antigen-binding fragment at a dose of approximately 800 mg to 1500 mg.

[0028] In some embodiments, methods for treating endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, comprising administering to the subjects an anti-PD-L1 antibody or its antigen-binding fragment at a dose of about 15 mg / kg or 20 mg / kg or a fixed dose of about 1120 mg or 1500 mg.

[0029] In non-limiting embodiments, the anti-PD-L1 antibody is administered using a fixed dose of 1120 mg or 1500 mg (based on an average body weight of 75 kg, which corresponds to a body weight-based dose of 15 mg / kg or 20 mg / kg).

[0030] In some embodiments, methods for treating endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, comprising administering a PARP inhibitor to the subject in a fixed dose of approximately 100 mg to 300 mg.

[0031] In some embodiments, methods for treating endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, comprising administering a fixed dose of 300 mg of a PARP inhibitor to the subjects.

[0032] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment 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 PD1 and CD80 receptors. Disclosures relating to durvalumab can be found in U.S. Patents 8,779,108 and 9,493,565, which are incorporated herein by reference in their entirety.

[0033] The durvalumab and its antigen-binding fragments for use in the methods, compositions, and combinations provided herein include a heavy chain and a light chain, or a heavy chain variable region and a light chain variable region. In some embodiments, the durvalumab or its antigen-binding fragments for use in the methods, compositions, and combinations provided herein include a light chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the durvalumab or its antigen-binding fragments for use in the methods, compositions, and combinations provided herein include a heavy chain variable region and a light chain variable region, the heavy chain variable region including the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and the light chain variable region including the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8. Those skilled in the art can readily identify the Chothia definition, the Abm definition, or other CDR definitions known to those skilled in the art. In some embodiments, durvalumab or its antigen-binding fragments for use in the methods, compositions, and combinations provided herein include variable heavy chain and variable light chain CDR sequences of the 2.14H9OPT antibody disclosed in U.S. Patent No. 8,779,108 and No. 9,493,565.

[0034] Durvalumab light chain (LC) variable region: EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK(Sequence ID 1)

[0035] Durvalumab heavy chain (HC) variable region: EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS(Sequence ID 2)

[0036] Durvalumab heavy chain CDR: HC-CDR1: GFTFSRYWMS (Sequence ID 3) HC-CDR2: NIKQDGSEKYYVDSVKG (Sequence ID 4) HC-CDR3: EGGWFGELAFDY (Sequence ID 5)

[0037] Durvalumab, light chain CDR: LC-CDR1: RASQRVSSSYLA (Sequence ID 6) LC-CDR2: DASSRAT (Sequence ID 7) LC-CDR3: QQYGSLPWT (Sequence ID 8)

[0038] As used herein, the term “PARP inhibitor” means any agent that inhibits the activity of the poly(ADP-ribose) polymerase (PARP) enzyme in cells. PARP helps repair DNA when it is damaged. DNA damage can be caused by a number of things, including exposure to UV light, radiation, certain anticancer drugs, or other substances in the environment. In cancer treatment, blocking PARP can help prevent cancer cells from repairing damaged DNA and thus kill them. In some embodiments, the PARP inhibitor is olaparib (Lynparza®). Disclosures relating to olaparib can be found in European Patent Nos. 1330442 and 1633724, which are incorporated herein by reference in their entirety.

[0039] As used herein, “chemotherapy” or “chemotherapeutic agent” may include any chemotherapeutic agent. In some embodiments, the chemotherapeutic agent comprises one or more platinum-based chemotherapeutic agents. In some embodiments, one or more platinum-based chemotherapeutic agents include carboplatin, cisplatin, oxaliplatin, or a combination thereof. In some embodiments, the chemotherapeutic agent comprises one or more taxane-based chemotherapeutic agents. In some embodiments, one or more taxane-based chemotherapeutic agents include nab-paclitaxel, paclitaxel, docetaxel, cabazitaxel, abraxane, anthracycline (pegylated liposomal doxorubicin), or a combination thereof. In some embodiments, the chemotherapeutic agent comprises one or more platinum-based chemotherapeutic agents in combination with one or more taxane-based chemotherapeutic agents. In various embodiments, the disclosure allows for the substitution of any other chemotherapeutic agent with one or more chemotherapeutic agents at any point during administration. Substitution of chemotherapeutic agents may be carried out for any reason, including, but not limited to, a reaction to or hypersensitivity to one or more chemotherapeutic agents in a subject. In some embodiments, the chemotherapeutic agent includes cisplatin and paclitaxel. In some embodiments, the patient is administered one or more doses of cisplatin, the dose being approximately 25 mg / m². 2 In some embodiments, the patient is administered one or more doses of cisplatin at a dose that produces an area under the curve (AUC) of AUC5 or AUC6. In some embodiments, the patient is administered approximately 25 mg / m². 2 ~100mg / m 2 Administer a dose of cisplatin. In some embodiments, the patient is given one or more doses of paclitaxel, the dose being approximately 175 mg / m². 2 In various embodiments, the dose of the chemotherapeutic agent can be reduced.

[0040] In some embodiments, the number of doses of one or more chemotherapeutic agents is measured in cycles. The number of therapeutic doses planned within each cycle depends on the chemotherapeutic agent. In some embodiments, each cycle may consist of only one dose. In one non-limiting embodiment, a cycle may consist of a single dose administered on day 1 of the cycle. In other embodiments, a cycle may consist of two or more doses. In one non-limiting embodiment, a cycle may consist of two or more doses administered daily or weekly.

[0041] In some embodiments, the number of doses of an anti-PD-L1 antibody or its antigen-binding fragment, and / or a PARP inhibitor, is measured in cycles. The number of therapeutic doses planned within each cycle depends on the antibody or inhibitor. In some embodiments, each cycle may consist of only one dose. In one non-limiting embodiment, a cycle may consist of a single dose administered on day 1 of the cycle. In other embodiments, a cycle may consist of two or more doses. In one non-limiting embodiment, a cycle may consist of two or more doses administered daily or weekly.

[0042] As used herein, the term "subject" may refer to a human patient.

[0043] In some embodiments, the methods, compositions, and combinations disclosed herein are used to treat subjects having endometrial cancer, endometrial neoplastic disorders, or uterine cancer.

[0044] As used herein, the terms “treatment” or “to treat” refer to both therapeutic procedures and preventive or protective measures. Subjects requiring treatment include those with cancer, those prone to developing cancer, or those for whom cancer should be prevented. In some embodiments, the methods, compositions, and combinations disclosed herein can be used for the treatment of endometrial cancer. In other embodiments, subjects requiring treatment include those with tumors, those prone to developing tumors, or those for whom tumors should be prevented. In certain embodiments, the methods, compositions, and combinations disclosed herein can be used for the treatment of tumors. In other embodiments, the treatment of a tumor includes inhibiting tumor growth, promoting tumor reduction, or both inhibiting tumor growth and promoting tumor reduction.

[0045] In some embodiments, the methods, compositions, and combinations disclosed herein result in an increase in progression-free survival (PFS) compared to placebo, standard treatment, or standard treatment plus durvalumab. In some embodiments, the methods, compositions, and combinations disclosed herein result in an increase in overall survival (OS) compared to placebo, standard treatment, or standard treatment plus durvalumab.

[0046] Overall survival (OS) refers to the time from the start of treatment to death from any cause. OS may refer to overall survival within a period such as 2 months, 3 months, 4 months, 6 months, 8 months, 12 months, 18 months, or 24 months. Such a period may be specified, for example, as "OS24," which refers to the number (%) of patients who are alive at 24 months after the start of treatment, per Kaplan-Meier estimate of overall survival at 24 months. In some embodiments, overall survival is measured against patients who received durvalumab and chemotherapy only or chemotherapy only. In other embodiments, overall survival is measured against patients who received no treatment.

[0047] Progression-free survival (PFS) refers to the time from the date of treatment to the date of objective disease progression (RECIST 1.1) or death (by any cause if there is no progression). In some embodiments, the methods, compositions, and combinations of the Disclosure result in a statistically significant and / or clinically meaningful increase in PFS. In some embodiments, the methods, compositions, and combinations of the Disclosure result in a PFS of at least 9 months to at least about 24 months (e.g., at least 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or more than 24 months, and up to about 5 years). In some embodiments, progression-free survival is measured in comparison to patients who received chemotherapy alone or chemotherapy (e.g., platinum doublet chemotherapy) and durvalumab alone. In other embodiments, overall survival is measured in comparison to untreated patients. In various embodiments, the PFS benefit is independent of PD-L1 status (PD-L1 positive or PD-L1 negative).

[0048] As used herein, the terms “administer” or “to administer” mean 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, intra-bursal, intrasternal, intrathecal, intrafocal, or intracranial injection), percutaneous, topical, buccal, rectal, vaginal, nasal, ocular, inhalation, and implantation.

[0049] In some embodiments, an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents are administered intravenously. In some embodiments, a PARP inhibitor is administered orally.

[0050] Methods, compositions, and combinations for treating endometrial cancer, endometrial tumors, uterine cancer, or uterine tumors in subjects requiring treatment of endometrial cancer, endometrial tumors, uterine cancer, or uterine tumors are provided herein. Subjects may be inexperienced with PARP inhibitors and immuno-mediated therapies. As used herein, “endometrial cancer” refers to any cancer or tumor originating from the endometrium or the inner lining of the uterus. Endometrial cancer may also be referred to as uterine cancer.

[0051] Endometrial cancer often presents with abnormal uterine bleeding, and the majority of patients (approximately 75%) are diagnosed early (stage I or II). These patients have a better prognosis with a 5-year OS rate ranging from 74% to 91% (Creasman et al 2006, Siegel et al 2015). The standard treatment for these patients is surgery with or without radiotherapy. Systemic therapy is not frequently administered to these early-stage patients. However, the prognosis is much worse for patients diagnosed with late-stage or advanced endometrial cancer. Endometrial cancer shows strong initial sensitivity to platinum doublet chemotherapy compared to many other solid tumors, with an objective response rate of approximately 51%, but most patients diagnosed with advanced stage disease show disease progression with a median PFS of approximately 12 months (Miller et al 2012, Aghajanian et al 2018). The 5-year overall survival (OS) rate remains low for these patients with advanced disease (57%–66% for stage III and 20%–26% for stage IV disease) (Creasman et al 2006, Siegel et al 2015).

[0052] The severity of endometrial cancer is measured by stage. As used herein, “stage” refers to the international system used to assess the extent to which the cancer has spread. In Stage I, the cancer is confined to the uterus. In Stage II, the cancer has spread to the cervix. In Stage III, the cancer has spread to the vagina, ovaries, and / or lymph nodes. In Stage IV, the cancer has spread to the bladder, rectum, or organs located far from the uterus, such as the lungs or bones. Stages III and IV are considered advanced endometrial cancer. Endometrial cancer as referred herein may be selected from Stage II, III, IV, and recurrent cancer. In one embodiment, endometrial cancer as referred herein is Stage III, IV, or recurrent cancer.

[0053] Endometrial cancer is a heterogeneous disease with diverse molecular patterns. Approximately 20% of endometrial cancer patients have MSI-H or deficient mismatch repair (dMMR) tumors. Mismatch repair is one of the cellular mechanisms for repairing DNA damage resulting from slips during DNA replication by DNA polymerase, primarily from single base pair insertions or deletions (called indels). This type of DNA polymerase error tends to occur in regions of short, repetitive DNA sequences called microsatellites. Therefore, deficient mismatch repair (dMMR) can be detected by observing variations in microsatellite length in normal tissue compared to the length of microsatellites in tumor tissue from the same patient. When there is a high percentage of variation in microsatellite length across the genome, the tumor is said to have a high level of microsatellite instability (MSI-H), which reflects an underlying deficiency in mismatch repair capacity.

[0054] Deficient mismatch repair (dMMR) and its characteristic genetic signature, along with high levels of microsatellite instability (MSI-H) across the genome, define a unique biological subset of cancers characterized by high tumor mutational burden and potential responsiveness to anti-programmed cell death 1 (PD-1)-based immune checkpoint inhibitor immunotherapy. dMMR can result from mutations in, for example, the following MMR proteins (MLH1, PMS2, MSH2, and MSH6) and, optionally, one or a selection (e.g., all) of the V600E mutant BRAF protein. MMR can be determined using the VENTANA MMR IHC panel, which includes the following primary antibodies: VENTANA anti-MLH1 (M1), VENTANA anti-PMS2 (A16-4), VENTANA anti-MLH2 (G219-1129), VENTANA anti-MSH6 (SP93), and VENTANA anti-BRAF V600E (VE1).

[0055] In some embodiments, the methods, compositions, and combinations of the present disclosure are used to treat subjects having endometrial cancer, where the endometrial cancer tumor lacks mismatch repair (dMMR). In some embodiments, the methods, compositions, and combinations of the present disclosure are used to treat subjects having endometrial cancer, where the endometrial cancer tumor does not lack mismatch repair (normal MMR function, pMMR).

[0056] In some embodiments, the methods, compositions, and combinations of the present disclosure include administering to a subject having deficient mismatch repair (dMMR) endometrial cancer (a) a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment.

[0057] In some other embodiments, the methods, compositions, and combinations of the Disclosure include administering to a subject having proficient mismatch repair (pMMR) endometrial cancer (a) a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective dose of a PARP inhibitor.

[0058] In one embodiment, endometrial cancer is unfamiliar with first-line systemic anticancer therapy. In another embodiment, endometrial cancer is unfamiliar with PARP inhibitors and immuno-mediated therapy.

[0059] In other embodiments, the methods, compositions, and combinations of the Disclosure are used to treat subjects having endometrial cancer in which the endometrial tumor is PD-L1 positive (defined as tumor area positive [TAP] ≥ 1%). In other embodiments, the methods, compositions, and combinations of the Disclosure are used to treat subjects having endometrial cancer in which the endometrial tumor is PD-L1 negative.

[0060] A method for treating endometrial cancer in a subject requiring treatment for endometrial cancer is provided herein, comprising administering to the subject (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor. In some embodiments herein, step (b) may be omitted from the therapeutically effective amount of a PARP inhibitor. In these embodiments, step (b) comprises a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment.

[0061] In some embodiments, methods for treating endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, comprising administering to the subject an anti-PD-L1 antibody or its antigen-binding fragment at a dose of about 10 mg to 20 mg / kg (or about 800 mg to 1500 mg, for example, a uniform dose of 1120 mg or 1500 mg) and a PARP inhibitor at a dose of about 100 mg to 300 mg.

[0062] Furthermore, combinations for the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, the combination comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor. In some embodiments herein, combination (b) may omit a therapeutically effective amount of a PARP inhibitor. In these embodiments, combination (b) comprises a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment.

[0063] In some embodiments, the combinations provided herein include an anti-PD-L1 antibody or its antigen-binding fragment in a dose of about 10 mg / kg to 20 mg / kg (or about 800 mg to 1500 mg, for example, a uniform dose of 1120 mg or 1500 mg) and a PARP inhibitor in a dose of about 100 mg to 300 mg.

[0064] The doses of anti-PD-L1 antibodies or their antigen-binding fragments, and PARP inhibitors administered to subjects may vary in part depending on the subject's size (body weight, body surface area, or organ size) and condition (age and overall health status).

[0065] In certain embodiments, the subject is administered one or more doses of anti-PD-L1 antibody or its antigen-binding fragment, the dose being approximately 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, or 15 mg / kg, 20 mg / kg, or 25 mg / kg. In some embodiments, the subject is administered one or more doses of anti-PD-L1 antibody or its antigen-binding fragment, the dose being approximately 15 mg / kg or 20 mg / kg.

[0066] In certain embodiments, a subject is administered one or more uniform doses of anti-PD-L1 antibody or its antigen-binding fragment, with doses being approximately 500 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, and 1100 mg. The doses are 1120 mg, 1125 mg, 1150 mg, 1175 mg, 1180 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, or 1875 mg. In some embodiments, the subject is administered one or more doses of anti-PD-L1 antibody or its antigen-binding fragment, the dose being approximately 1120 mg or 1500 mg.

[0067] In certain embodiments, subjects are administered one or more uniform doses of the PARP inhibitor, the doses being approximately 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, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg. In some embodiments, subjects are administered one or more uniform doses of the PARP inhibitor, the dose being 300 mg. In some embodiments, a PARP inhibitor in a dose of 100 mg to 300 mg is administered twice daily. Thus, the PARP inhibitor can be administered in a daily dose of 200 mg to 600 mg (2 × 100 mg to 300 mg). In other embodiments, the daily dose of the PARP inhibitor can be reduced.

[0068] In one particular non-limiting embodiment, step (a) comprises administering 1120 mg of an anti-PD-L1 antibody or its antigen-binding fragment.

[0069] In one particular non-limiting embodiment, step (b) comprises administering 1500 mg of an anti-PD-L1 antibody or its antigen-binding fragment and 300 mg of a PARP inhibitor.

[0070] As used herein, the terms “simultaneously administered,” “in combination,” or “combination therapy” refer to the simultaneous or sequential administration of multiple compounds or drugs. A first compound or drug may be administered before, simultaneously with, or after the administration of a second compound or drug; a third compound or drug may be administered before, simultaneously with, or after the administration of the first and / or second compound or drug; and a fourth compound or drug may be administered before, simultaneously with, or after the administration of the first, second, and / or third compound or drug. The first, second, third, and fourth compounds or drugs may be administered simultaneously or sequentially on the same day, or sequentially with respect to each other within one, two, three, four, five, six days, one week, two weeks, three weeks, or one month. In some embodiments, the compounds or drugs are administered simultaneously for a period during which each compound or drug is exerting at least some physiological effect and / or retaining efficacy. In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents in step (a) are administered to the subject simultaneously, separately, and / or sequentially (for example, separately and sequentially). In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment and the PARP inhibitor in step (b) are administered to the subject simultaneously, separately, and / or sequentially (for example, separately and sequentially).

[0071] In certain embodiments, the first step of the method disclosed herein (step (a)) or the first component of the combination disclosed herein comprises a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, administered over a treatment period of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 24 weeks, or more than 1 year. In certain embodiments, the first step of the method disclosed herein (step (a)) or the first component of the combination disclosed herein comprises a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, administered over a treatment period of 9 weeks, 10 weeks, or 12 to 18 weeks. In one non-limiting embodiment, step (a) includes administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks for 18 weeks, and one or more chemotherapeutic agents in a certain cycle.

[0072] In certain embodiments, a subsequent step of the method disclosed herein (step (b)) or a subsequent component of the combination disclosed herein comprises a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and optionally a therapeutically effective amount of a PARP inhibitor, administered over a treatment period of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 24 weeks, 6 months, 8 months, 12 months, 14 months, 15 months, 16 months, 18 months, 20 months, or 24 months or longer. In certain embodiments, the anti-PD-L1 antibody or its antigen-binding fragment and the optionally selected PARP inhibitor are administered over a treatment period of 1 month to 24 months or longer. In certain embodiments, an anti-PD-L1 antibody or its antigen-binding fragment and a PARP inhibitor are administered over a treatment period of 24 months. In certain embodiments, step (b) includes administration of a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and a dose of a PARP inhibitor twice daily for at least 12 weeks, or until disease progression.

[0073] In certain embodiments of (a) of the methods, compositions, and combinations of the present disclosure, a therapeutically effective dose of one or more chemotherapeutic agents is administered approximately weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment is administered approximately weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks.

[0074] In one particular embodiment of (a), a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment are administered every three weeks.

[0075] In another specific embodiment of (a), a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment are administered every three weeks for a minimum of three cycles and a maximum of eight cycles. In one non-limiting embodiment of (a), a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment are administered every three weeks for six cycles. In another specific embodiment of (a), a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment are administered every three weeks for a treatment period of nine, ten, or twelve to eighteen weeks.

[0076] In certain embodiments of (b) of the methods, compositions, and combinations of the present disclosure, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment is administered approximately weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks, and a therapeutically effective dose of a PARP inhibitor is administered once daily, twice daily, or three times daily.

[0077] In one particular embodiment of (b), a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment is administered every four weeks.

[0078] In one particular embodiment of (b), a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment is administered every four weeks, and a therapeutically effective dose of a PARP inhibitor is administered twice daily.

[0079] In another specific embodiment of (b), a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment is administered every four weeks for at least 12 weeks or 3 months, up to a maximum of 24 months, and a therapeutically effective dose of a PARP inhibitor is administered twice daily for at least 12 weeks or 3 months, up to a maximum of 24 months.

[0080] In another specific embodiment of (b), a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment is administered every four weeks for at least 12 weeks, or 3 months, and up to 24 months.

[0081] In certain embodiments, a therapeutically effective dose of one or more chemotherapeutic agents is administered over a minimum of 3 cycles and a maximum of 8 cycles. In one non-limiting embodiment, a therapeutically effective dose of one or more chemotherapeutic agents is administered over 6 cycles. In certain embodiments, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment (e.g., durvalumab) is administered over a total of up to approximately 24 months and a total of up to 35 cycles. In certain embodiments, a therapeutically effective dose of a PARP inhibitor (e.g., olaparib) is administered over a total of up to 24 months.

[0082] In certain embodiments, methods, compositions, and combinations for the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, wherein (a) one or more therapeutically effective doses of a chemotherapeutic agent are administered every three weeks for a treatment period of nine, ten, or twelve to eighteen weeks; an anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 1120 mg every three weeks for nine, ten, or twelve to eighteen weeks; and (b) an anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 1500 mg every four weeks, preferably for a total of 24 months; and a PARP inhibitor is administered at a dose of 300 mg twice daily, preferably for a total of 24 months.

[0083] In a particular embodiment, a method, composition, and combination for the treatment of endometrial cancer in a subject requiring treatment for endometrial cancer, comprising (a) 175 mg / m² 2Methods, compositions, and combinations are provided herein, wherein a dose of paclitaxel and a dose of carboplatin with an AUC of 5 or AUC of 6 are administered intravenously every 3 weeks for 9, 10, or 12 to 18 weeks, durvalumab is administered intravenously at a dose of 1120 mg every 3 weeks for 9, 10, or 12 to 18 weeks, followed by (b) durvalumab being administered intravenously at a dose of 1500 mg every 4 weeks, preferably for a total of 24 months, and olaparib is administered orally at a dose of 300 mg twice daily, preferably for a total of 24 months.

[0084] In certain embodiments, methods, compositions, and combinations for the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, wherein step (a) comprises the administration of 3 to 8 doses of an anti-PD-L1 antibody or its antigen-binding fragment and 3 to 8 cycles of one or more chemotherapeutic agents. In one non-limiting embodiment, methods, compositions, and combinations for the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, wherein step (a) comprises the administration of 6 doses of an anti-PD-L1 antibody or its antigen-binding fragment and 6 cycles of one or more chemotherapeutic agents.

[0085] In certain embodiments, methods, compositions, and combinations for the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer are provided herein, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks or 3 months, up to a maximum of 24 months, and optionally administering a PARP inhibitor twice daily for at least 12 weeks or 3 months, up to a maximum of 24 months.

[0086] In certain embodiments of the disclosed methods, compositions and / or combinations, step / combination (a) is administered before step / combination (b). In other embodiments, step / combination (b) is not administered until after the completion of step / combination (a).

[0087] As used herein, the terms “pharmaceutical composition” or “therapeutic composition” refer 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.

[0088] As used herein, the terms “pharmaceutically acceptable carrier” or “physiologically acceptable carrier” refer to one or more formulation materials suitable for achieving or enhancing the delivery of one or more antibodies of this disclosure.

[0089] When used for in vivo administration, the formulations of the present disclosure should be sterile. The formulations of the present disclosure may be sterilized by various sterilization methods, including, for example, sterile filtration or irradiation. In one embodiment, the formulation is sterilized by filtration through a pre-sterilized 0.22 micron filter. Sterile compositions for injection may be formulated in accordance with conventional pharmaceutical practices, such as those described in "Remington: The Science & Practice of Pharmacy," 21st ed., Lippincott Williams & Wilkins, (2005).

[0090] In some embodiments, antibodies can be formulated for administration via specific routes of administration, such as oral, nasal, pulmonary, topical (including oral and sublingual), rectal, vaginal, and / or parenteral administration. As used herein, the terms “parenteral administration” and “administered parenterally” refer to modes of administration other than intestinal and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions. Formulations of the present disclosure suitable for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Antibodies and other active substances may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed (see, for example, U.S. Patents Nos. 7,378,110, 7,258,873, and 7,135,180, and U.S. Patent Application Publications 2004 / 0042972 and 2004 / 0042971).

[0091] The formulations may be provided in unit dosage forms and may be prepared by any method known in the field of pharmacy. The actual dose levels of the active ingredient in the formulations of this disclosure may be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject (e.g., "therapeutic effective dose"). The dosage may also be administered via continuous infusion (e.g., by pump). The dosage may also be route-dependent. For example, subcutaneous administration may require a higher dose than intravenous administration.

[0092] Without limiting the scope of this disclosure, several embodiments of this disclosure are described herein for illustrative purposes.

[0093] Embodiment 1. A method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, comprising administering to the subject (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

[0094] Embodiment 2. A method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, comprising administering to the subject (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment.

[0095] Embodiment 3. The method according to Embodiment 1 or 2, wherein step (b) is performed after the completion of step (a).

[0096] Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

[0097] Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein the PARP inhibitor is olaparib.

[0098] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein an anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 800 mg to 1500 mg.

[0099] Embodiment 7. The method according to Embodiment 6, wherein an anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 1120 mg and / or 1500 mg.

[0100] Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein an anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 10 mg / kg to 20 mg / kg.

[0101] Embodiment 9. The method according to Embodiment 8, wherein an anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 15 mg / kg and / or 20 mg / kg.

[0102] Embodiment 10. The method according to any one of Embodiments 1 to 9, wherein the PARP inhibitor is administered in a dose of 100 mg to 300 mg.

[0103] Embodiment 11. The method according to Embodiment 10, wherein the PARP inhibitor is administered at a dose of 300 mg.

[0104] Embodiment 12. The method according to any one of Embodiments 1 to 11, wherein one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

[0105] Embodiment 13. The method according to any one of Embodiments 1 to 12, wherein paclitaxel is administered at a dose of 175 mg / m2.

[0106] Embodiment 14. The method according to Embodiment 12 or 13, wherein carboplatin is administered in a dose that produces an area under the curve (AUC) of AUC5 or AUC6.

[0107] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein step (a) comprises administering an anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents every 2 to 4 weeks.

[0108] Embodiment 16. The method of Embodiment 15, wherein step (a) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks over a period of 9 to 18 weeks, and one or more chemotherapeutic agents in a cycle.

[0109] Embodiment 17. The method according to any one of Embodiments 1 to 15, wherein step (a) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks, and one or more chemotherapeutic agents in a certain cycle.

[0110] Embodiment 18. The method of Embodiment 17, wherein step (a) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks over a period of 12 to 18 weeks, and one or more chemotherapeutic agents in a cycle.

[0111] Embodiment 19. The method of Embodiment 17, wherein step (a) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks for 18 weeks, and one or more chemotherapeutic agents in a certain cycle.

[0112] Embodiment 20. The method according to any one of Embodiments 1 to 19, wherein step (a) comprises administering 4 to 6 doses of an anti-PD-L1 antibody or its antigen-binding fragment, and 4 to 6 cycles of one or more chemotherapeutic agents.

[0113] Embodiment 21. The method according to any one of Embodiments 1 to 20, wherein step (a) comprises administering 1120 mg of anti-PD-L1 antibody or its antigen-binding fragment.

[0114] Embodiment 22. The method according to Embodiment 21, wherein step (a) includes the administration of 1120 mg of durvalumab.

[0115] Embodiment 23. The method according to Embodiment 22, wherein step (a) includes administration of 1120 mg of durvalumab every three weeks.

[0116] Embodiment 24. The method according to any one of Embodiments 21 to 23, wherein step (a) further comprises administering 175 mg / m2 of paclitaxel, AUC5 or AUC6 of carboplatin, and / or 25 mg / m2 of cisplatin.

[0117] Embodiment 25. The method according to any one of Embodiments 1 to 24, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks, and administering a certain dose of a PARP inhibitor twice daily.

[0118] Embodiment 26. The method according to any one of Embodiments 1 to 25, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks, and administering a certain dose of a PARP inhibitor twice daily.

[0119] Embodiment 27. The method according to any one of Embodiments 1 to 26, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and a dose of a PARP inhibitor twice daily for at least 12 weeks.

[0120] Embodiment 28. The method of Embodiment 27, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and a dose of a PARP inhibitor twice daily for up to 24 months.

[0121] Embodiment 29. The method according to any one of Embodiments 1 to 28, wherein step (b) comprises administering 1500 mg of an anti-PD-L1 antibody or its antigen-binding fragment and 300 mg of a PARP inhibitor.

[0122] Embodiment 30. The method according to Embodiment 29, wherein step (b) includes the administration of 1500 mg of durvalumab and 300 mg of olaparib.

[0123] Embodiment 31. The method according to Embodiment 30, wherein step (b) includes administration of 1500 mg of durvalumab every four weeks and 300 mg of olaparib twice daily.

[0124] Embodiment 32. The method according to any one of Embodiments 2 to 24, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks.

[0125] Embodiment 33. The method according to any one of Embodiments 2 to 24 or 32, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks.

[0126] Embodiment 34. The method according to any one of Embodiments 2-24 or 32-33, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks.

[0127] Embodiment 35. The method of Embodiment 34, wherein step (b) includes administration of a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months.

[0128] Embodiment 36. The method according to any one of Embodiments 2-24 or 32-35, wherein step (b) comprises the administration of 1500 mg of anti-PD-L1 antibody or its antigen-binding fragment.

[0129] Embodiment 37. The method according to Embodiment 36, wherein step (b) includes the administration of 1500 mg of durvalumab.

[0130] Embodiment 38. The method according to Embodiment 37, wherein step (b) includes administration of 1500 mg of durvalumab every four weeks.

[0131] Embodiment 39. The method according to any one of Embodiments 1 to 38, wherein an anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents are administered intravenously.

[0132] Embodiment 40. The method according to any one of Embodiments 1 to 39, wherein the PARP inhibitor is administered orally.

[0133] Embodiment 41. The method according to any one of Embodiments 1 to 40, wherein the antigen-binding fragment in step (a), the anti-PD-L1 antibody or the antigen-binding fragment thereof, and one or more chemotherapeutic agents are administered to the subject simultaneously, separately, and / or sequentially.

[0134] Embodiment 42. The method according to any one of Embodiments 1 to 42, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the PARP inhibitor in step (b) are administered to the subject simultaneously, separately, and / or sequentially.

[0135] Embodiment 43. The method according to any one of Embodiments 1 to 42, wherein the endometrial cancer is advanced endometrial cancer.

[0136] Embodiment 44. The method according to any one of Embodiments 1 to 43, wherein the endometrial cancer is an endometrial cancer tumor lacking mismatch repair (MMR deficiency (dMMR)).

[0137] Embodiment 45. The method according to Embodiment 44, comprising administering to a subject having deficient mismatch repair (dMMR) endometrial cancer (a) a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment.

[0138] Embodiment 46. The method according to any one of Embodiments 1 to 43, wherein the endometrial cancer is an endometrial cancer tumor with normal MMR function (pMMR).

[0139] Embodiment 47. The method according to Embodiment 46, comprising administering to a subject having functionally normal mismatch-repair (pMMR) endometrial cancer (a) a therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective dose of a PARP inhibitor.

[0140] Embodiment 48. The method according to any one of Embodiments 1 to 47, wherein the endometrial cancer is a PD-L1-positive endometrial cancer tumor.

[0141] Embodiment 49. The method according to any one of Embodiments 1 to 47, wherein the endometrial cancer is a PD-L1-negative endometrial cancer tumor.

[0142] Embodiment 50. The method according to any one of Embodiments 1 to 49, wherein the treatment results in an increased progression-free survival in the subject compared to a patient who received durvalumab and chemotherapy alone.

[0143] Embodiment 51. The method according to Embodiment 50, wherein the treatment results in an increase in progression-free survival of at least four months.

[0144] Embodiment 52. The method according to any one of Embodiments 1 to 51, wherein the treatment results in an increase in overall survival in the subject compared to a patient who received durvalumab and chemotherapy alone.

[0145] Embodiment 53. The method according to Embodiment 52, wherein the treatment results in an increase in overall survival by at least four months.

[0146] Embodiment 54. A combination for use in the treatment of endometrial cancer in a subject requiring treatment for endometrial cancer, the combination comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

[0147] Embodiment 55. A combination for use in the treatment of endometrial cancer in a subject requiring treatment for endometrial cancer, the combination comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment.

[0148] Embodiment 56. The combination for use according to Embodiment 54 or 55, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

[0149] Embodiment 57. A combination for use according to any one of Embodiments 54 to 56, wherein the PARP inhibitor is olaparib.

[0150] Embodiment 58. A combination for use according to any one of Embodiments 54 to 57, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 800 mg to 1500 mg.

[0151] Embodiment 59. The combination for use according to Embodiment 58, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 1120 mg and / or 1500 mg.

[0152] Embodiment 60. A combination for use according to any one of Embodiments 54 to 59, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 10 mg / kg to 20 mg / kg.

[0153] Embodiment 61. The combination for use according to Embodiment 60, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg and / or 20 mg / kg.

[0154] Embodiment 62. A combination for use according to any one of Embodiments 54 to 61, wherein the dose of the PARP inhibitor is 100 mg to 300 mg.

[0155] Embodiment 63. The combination for use according to Embodiment 62, wherein the dose of the PARP inhibitor is 300 mg.

[0156] Embodiment 64. A combination for use according to any one of Embodiments 54 to 63, wherein one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

[0157] Embodiment 65. The combination for use according to Embodiment 64, wherein the dose of paclitaxel is 175 mg / m2.

[0158] Embodiment 66. A combination for use according to Embodiment 64 or 65, wherein the dose of carboplatin results in an area under the curve (AUC) of AUC5 or AUC6.

[0159] Embodiment 67(a) is a combination for use according to any one of Embodiments 54 to 66, comprising administration of an anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents every 2 to 4 weeks.

[0160] Embodiment 68. The combination for use described in Embodiment 67, wherein the administration is every 2 to 4 weeks over a period of 9 to 24 weeks.

[0161] Embodiment 69. A combination of use according to Embodiment 67 or 68, wherein the administration is every three weeks or every four weeks.

[0162] Embodiment 70. The combination for use described in Embodiment 69, wherein the administration is every three weeks over a period of 12 to 18 weeks.

[0163] Embodiment 71. The combination for use described in Embodiment 70, wherein the administration is every three weeks for 18 weeks.

[0164] Embodiment 72(a) is a combination for use according to any one of Embodiments 54 to 71, comprising administering an anti-PD-L1 antibody or its antigen-binding fragment in 3 to 6 doses, and one or more chemotherapeutic agents in 4 to 6 doses.

[0165] Embodiment 73(a) is a combination for use according to any one of Embodiments 54 to 72, comprising the administration of an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg.

[0166] Embodiment 74. The combination for use described in Embodiment 73, wherein durvalumab is administered in a dose of 1120 mg.

[0167] Embodiment 75. The combination for use according to Embodiment 73 or 74, wherein durvalumab is administered at a dose of 1120 mg every three weeks.

[0168] Embodiment 76(a) is a combination for use according to any one of Embodiments 73 to 75, further comprising 175 mg / m2 of paclitaxel, AUC5 or AUC6 of carboplatin, and / or 25 mg / m2 of cisplatin.

[0169] Embodiment 77(b) is a combination for use according to any one of Embodiments 54 to 76, comprising an anti-PD-L1 antibody or its antigen-binding fragment administered every 2 to 4 weeks, and a PARP inhibitor administered twice daily.

[0170] Embodiment 78(b) is a combination for use according to any one of Embodiments 54 to 77, comprising an anti-PD-L1 antibody or its antigen-binding fragment administered every four weeks, and a PARP inhibitor administered twice daily.

[0171] Embodiment 79(b) is a combination for use according to any one of Embodiments 54 to 78, comprising the administration of an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1500 mg and a PARP inhibitor at a dose of 300 mg.

[0172] Embodiment 80. The combination for use according to Embodiment 77, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and a dose of a PARP inhibitor twice daily for at least 12 weeks.

[0173] Embodiment 81. The combination for use according to Embodiment 79, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and a dose of a PARP inhibitor twice daily for up to 24 months.

[0174] Embodiment 82(b) is the combination for use described in Embodiment 79, which includes the administration of durvalumab at a dose of 1500 mg and olaparib at a dose of 300 mg.

[0175] Embodiment 83(b) is a combination for use according to any one of Embodiments 79 to 81, comprising administration of durvalumab at a dose of 1500 mg every three weeks and olaparib at a dose of 300 mg twice daily.

[0176] Embodiment 84(b) is a combination for use according to any one of Embodiments 55 to 76, comprising an anti-PD-L1 antibody or its antigen-binding fragment administered every 2 to 4 weeks.

[0177] Embodiment 85(b) is a combination for use according to any one of Embodiments 55-76 or 84, comprising an anti-PD-L1 antibody or its antigen-binding fragment administered every four weeks.

[0178] Embodiment 86(b) is a combination for use according to any one of Embodiments 55-76 or 84-85, comprising the administration of an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1500 mg.

[0179] Embodiment 87. The combination for use according to Embodiment 85, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks.

[0180] Embodiment 88. The combination for use described in Embodiment 87, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for a maximum of 24 months.

[0181] Embodiment 89(b) is a combination for use according to Embodiment 86, comprising the administration of durvalumab at a dose of 1500 mg.

[0182] Embodiment 90(b) is a combination of use according to any one of Embodiments 84-89, comprising administration of durvalumab at a dose of 1500 mg every three weeks.

[0183] Embodiment 91. A combination for use according to any one of Embodiments 54 to 90, wherein an anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents are administered intravenously.

[0184] Embodiment 92. A combination of uses according to any one of Embodiments 54 to 91, wherein the PARP inhibitor is administered orally.

[0185] A combination for use according to any one of embodiments 54 to 92, wherein the anti-PD-L1 antibody or its antigen-binding fragment in embodiment 93(a) and one or more chemotherapeutic agents are administered to the subject simultaneously, separately, and / or sequentially.

[0186] A combination for use according to any one of Embodiments 54 to 93, wherein the anti-PD-L1 antibody or its antigen-binding fragment in Embodiment 94(b) and the PARP inhibitor are administered to the subject simultaneously, separately, and / or sequentially.

[0187] Embodiment 95. A combination of use according to any one of Embodiments 54 to 94, wherein the endometrial cancer is advanced endometrial cancer.

[0188] Embodiment 96. A combination of the uses according to any one of Embodiments 54 to 95, wherein the endometrial cancer is a dMMR (deadly mucosal resection) endometrial cancer tumor.

[0189] Embodiment 97. The combination for use in the treatment of dMMR endometrial cancer in subjects requiring treatment of dMMR endometrial cancer, as described in Embodiment 96, comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment.

[0190] Embodiment 98. A combination of uses according to any one of Embodiments 54 to 95, wherein the endometrial cancer is an endometrial cancer tumor with normal MMR function (pMMR).

[0191] Embodiment 99. The combination for use in the treatment of functionally normal mismatch-repair (pMMR) endometrial cancer in subjects requiring treatment of functionally normal mismatch-repair (pMMR) endometrial cancer, as described in Embodiment 98, comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

[0192] Embodiment 100. A combination for use according to any one of Embodiments 54 to 99, wherein the endometrial cancer is a PD-L1-positive endometrial cancer tumor.

[0193] Embodiment 101. A combination of uses according to any one of Embodiments 54 to 99, wherein the endometrial cancer is a PD-L1-negative endometrial cancer tumor.

[0194] Embodiment 102. A combination for use according to any one of Embodiments 54 to 101, wherein the combination therapy results in an increased progression-free survival in the subject compared to patients who received durvalumab and chemotherapy alone.

[0195] Embodiment 103. A combination of the treatments described in Embodiment 102 for use, wherein the treatment results in an increase in progression-free survival of at least four months.

[0196] Embodiment 104. A combination for use according to any one of Embodiments 54 to 101, wherein the combination therapy results in an increase in overall survival in the subject compared to patients who received durvalumab and chemotherapy alone.

[0197] Embodiment 105. A combination of the treatments described in Embodiment 104 for use, wherein the treatment results in an increase in overall survival of at least four months.

[0198] Embodiment 106. Use of a combination in the manufacture of a pharmaceutical for the treatment of endometrial cancer in a subject requiring treatment for endometrial cancer, wherein the combination comprises (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

[0199] Embodiment 107. Use of a combination in the manufacture of a pharmaceutical for the treatment of endometrial cancer in a subject requiring treatment for endometrial cancer, wherein the combination comprises (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment.

[0200] Embodiment 108. The use according to Embodiment 106 or 107, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

[0201] Embodiment 109. The use according to any one of Embodiments 106 to 108, wherein the PARP inhibitor is olaparib.

[0202] Embodiment 110. The use according to any one of Embodiments 106 to 109, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 800 mg to 1500 mg.

[0203] Embodiment 111. The use according to Embodiment 110, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 1120 mg and / or 1500 mg.

[0204] Embodiment 112. The use according to any one of Embodiments 106 to 111, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 10 mg / kg to 20 mg / kg.

[0205] Embodiment 113. The use according to Embodiment 112, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg and / or 20 mg / kg.

[0206] Embodiment 114. The use according to any one of Embodiments 106 to 113, wherein the dose of the PARP inhibitor is 100 mg to 300 mg.

[0207] Embodiment 115. The use described in Embodiment 114, wherein the dose of the PARP inhibitor is 300 mg.

[0208] Embodiment 116. The use according to Embodiment 114 or 115, wherein one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

[0209] Embodiment 117. The use described in Embodiment 116, wherein the dose of paclitaxel is 175 mg / m2.

[0210] Embodiment 118. The use according to Embodiment 116 or 117, wherein the dose of carboplatin results in an area under the curve (AUC) of AUC5 or AUC6.

[0211] Embodiment 119(a) is the use according to any one of Embodiments 106 to 118, comprising administration of an anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents every 2 to 4 weeks.

[0212] Embodiment 120. The use described in Embodiment 119, wherein the administration is every 2 to 4 weeks over a period of 9 to 24 weeks.

[0213] Embodiment 121. The use according to Embodiment 119 or 120, wherein the administration is every three weeks or every four weeks.

[0214] Embodiment 122. The use described in Embodiment 121, wherein the administration is every three weeks over a period of 12 to 18 weeks.

[0215] Embodiment 123. The use described in Embodiment 122, wherein the administration is every three weeks for 18 weeks.

[0216] Embodiment 124(a) is the use according to any one of Embodiments 106 to 123, wherein Embodiment 124(a) includes the administration of an anti-PD-L1 antibody or its antigen-binding fragment in 3 to 6 doses, and one or more chemotherapeutic agents in 4 to 6 doses.

[0217] Embodiment 125(a) is a use according to any one of Embodiments 106 to 124, wherein Embodiment 125(a) involves the administration of an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg.

[0218] Embodiment 126. The use of durvalumab as described in Embodiment 125, in which durvalumab is administered in a dose of 1120 mg.

[0219] Embodiment 127. The use according to Embodiment 125 or 126, wherein durvalumab is administered in a dose of 1120 mg every three weeks.

[0220] Embodiment 128(a) is the use according to any one of Embodiments 125 to 127, further comprising 175 mg / m2 of paclitaxel, AUC5 or AUC6 of carboplatin, and / or 25 mg / m2 of cisplatin.

[0221] Embodiment 129(b) is the use according to any one of Embodiments 106 to 128, comprising an anti-PD-L1 antibody or its antigen-binding fragment administered every 2 to 4 weeks, and a PARP inhibitor administered twice daily.

[0222] Embodiment 130(b) is the use according to any one of Embodiments 106 to 129, comprising an anti-PD-L1 antibody or its antigen-binding fragment administered every four weeks, and a PARP inhibitor administered twice daily.

[0223] Embodiment 131(b) is a use according to any one of Embodiments 106 to 130, comprising the administration of an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1500 mg and a PARP inhibitor at a dose of 300 mg.

[0224] Embodiment 132. The use according to Embodiment 131, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and a dose of a PARP inhibitor twice daily for at least 12 weeks.

[0225] Embodiment 133. The use according to Embodiment 131, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and a dose of a PARP inhibitor twice daily for up to 24 months.

[0226] Embodiment 134(b) is the use described in Embodiment 131, which includes the administration of durvalumab at a dose of 1500 mg and olaparib at a dose of 300 mg.

[0227] Embodiment 135(b) is a use according to any one of Embodiments 131 to 134, comprising administration of durvalumab at a dose of 1500 mg every three weeks and olaparib at a dose of 300 mg twice daily.

[0228] Embodiment 136(b) is the use according to any one of Embodiments 107 to 128, wherein Embodiment 136(b) comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof administered every 2 to 4 weeks.

[0229] The use according to any one of embodiments 107-128 or 136, wherein embodiment 137(b) comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof administered every four weeks.

[0230] Embodiment 138(b) is a use according to any one of Embodiments 106-128 or 136-137, comprising the administration of an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1500 mg.

[0231] Embodiment 139. The use according to Embodiment 137, wherein step (b) comprises administering a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and a dose of a PARP inhibitor twice daily for at least 12 weeks.

[0232] Embodiment 140. The use according to Embodiment 137, wherein step (b) includes administration of a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months.

[0233] Embodiment 141(b) is the use described in Embodiment 137, which includes the administration of durvalumab at a dose of 1500 mg.

[0234] Embodiment 142(b) is the use according to any one of Embodiments 137 to 141, which includes administration of durvalumab at a dose of 1500 mg every three weeks.

[0235] Embodiment 143. The use according to any one of Embodiments 106 to 142, wherein an anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents are administered intravenously.

[0236] Embodiment 144. The use according to any one of Embodiments 106 to 143, wherein the PARP inhibitor is administered orally.

[0237] The use according to any one of Embodiments 106 to 144, wherein the anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents are administered to the subject simultaneously, separately, and / or sequentially.

[0238] The use according to any one of Embodiments 106 to 145, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the PARP inhibitor in Embodiment 146(b) are administered to the subject simultaneously, separately, and / or sequentially.

[0239] Embodiment 147. The use according to any one of Embodiments 106 to 146, wherein the endometrial cancer is advanced endometrial cancer.

[0240] Embodiment 148. Use according to any one of Embodiments 106 to 147, wherein the endometrial cancer is a dMMR (deadly mucosal resection) endometrial cancer tumor.

[0241] Embodiment 149. Use according to Embodiment 148 in the manufacture of a pharmaceutical for the treatment of deficiency mismatch repair (dMMR) endometrial cancer in subjects requiring treatment of deficiency mismatch repair (dMMR) endometrial cancer, wherein the combination comprises (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment.

[0242] Embodiment 150. The use according to any one of Embodiments 106 to 147, wherein the endometrial cancer is an endometrial cancer tumor with normal MMR function (pMMR).

[0243] Embodiment 151. The use of the pharmaceutical product for the treatment of functional mismatch repair (pMMR) endometrial cancer in subjects requiring treatment of functional mismatch repair (pMMR) endometrial cancer, as described in Embodiment 150, comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

[0244] Embodiment 152. The use according to any one of Embodiments 106 to 151, wherein the endometrial cancer is a PD-L1-positive endometrial cancer tumor.

[0245] Embodiment 153. The use according to any one of Embodiments 106 to 151, wherein the endometrial cancer is a PD-L1-negative endometrial cancer tumor.

[0246] Embodiment 154. The use according to any one of Embodiments 106 to 153, wherein the combination therapy results in an increased progression-free survival in the subject compared to patients who received durvalumab and chemotherapy alone.

[0247] Embodiment 155. The use according to Embodiment 154, wherein the treatment results in an increase in progression-free survival of at least four months.

[0248] Embodiment 156. The use according to any one of Embodiments 106 to 153, wherein treatment with the combination results in increased overall survival in a subject compared to a patient treated with durvalumab and chemotherapy only.

[0249] Embodiment 157. The use according to Embodiment 156, wherein the treatment results in an increase in overall survival of at least 4 months.

Examples

[0250] The following examples illustrate specific embodiments of the present disclosure and various uses thereof. They are set forth for illustrative purposes only and should not be construed as limiting the scope of the present disclosure in any way.

[0251] Example 1: Durvalumab with or without olaparib as maintenance therapy after first-line treatment for advanced and recurrent endometrial cancer (DUO-E) This phase III trial evaluated the efficacy and safety of durvalumab in combination with platinum-based chemotherapy (paclitaxel + carboplatin), followed by maintenance with durvalumab with or without olaparib in patients diagnosed with newly diagnosed advanced or recurrent endometrial cancer.

[0252] Overall Design This is a randomized, double-blind, placebo-controlled, multicenter Phase III trial to evaluate the efficacy, safety, and patient-reported outcomes of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin), followed by maintenance with or without olaparib, in patients with advanced or recurrent endometrial cancer, compared to platinum-based chemotherapy. AstraZeneca believes that the endometrial cancer patient population involved in this trial meets the definition of limited life expectancy for advanced cancer outlined in the ICH S9 guideline, “Non-clinical Evaluation For Anticancer Pharmaceuticals,” and fulfills the requirements outlined in this guideline. The primary endpoint of this trial is progression-free survival (using investigator assessment of scans in accordance with RECIST 1.1). Secondary endpoints include OS, PFS2, ORR, DoR, TFST, TSST, and TDT. See Figure 2 for a summary of the trial design.

[0253] The study includes three groups:

[0254] [Table 1] Abbreviations: IV = intravenous, Q3W = every 3 weeks, Q4W = every 4 weeks.

[0255] Patients are stratified according to MMR expression status (comparison of normal function to deficiency), disease status (comparison of recurrent to newly diagnosed), and geographical region (comparison of Asia to the rest of the world [RoW]). Patients provide tumor samples at screening to determine their MMR status for stratification.

[0256] As part of global recruitment, approximately 699 patients will be randomized in a 1:1:1 ratio to the investigational treatments specified below (N=233 patients per group). If necessary, registration in China will continue after global registration is complete (i.e., the last subjects randomized from non-China sites) to allow for the inclusion of a China cohort consisting of approximately 129 patients randomized in a 1:1:1 ratio from Chinese sites. Any patients from China randomized before global recruitment is complete will be included in the global population.

[0257] Group A (control): Platinum-based chemotherapy (paclitaxel and carboplatin) with durvalumab placebo (IV) during the chemotherapy phase. Patients who achieve and maintain disease control (i.e., complete response [CR], partial response [PR], or stable disease [SD]) during the chemotherapy phase receive durvalumab placebo (IV) and olaparib placebo (tablets) during the maintenance phase.

[0258] Group C (durvalumab + olaparib): Platinum-based chemotherapy (paclitaxel and carboplatin) with durvalumab (IV) during the chemotherapy phase. Patients who achieve and maintain disease control (i.e., CR, PR, or SD) during the chemotherapy phase receive durvalumab (IV) along with olaparib (tablets) during the maintenance phase.

[0259] Patients should be randomized and treatment should begin on day 1. The randomization scheme will be stratified as follows: Tumor tissue mismatch repair (MMR) status: Comparison between patients with MMR-deficient tumors and patients with functionally normal tumors. Tumor MMR status is determined prior to randomization based on the assessment of MMR status in tumor cells from formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples using the Ventana immunohistochemistry (IHC) MMR panel.

[0260] Disease status: Comparison between patients with recurrent disease and newly diagnosed patients. This trial will enroll patients with newly diagnosed stage III / IV cancer and patients with recurrent endometrial cancer. Generally, recurrent disease shows lower response rates to treatment and a worse prognosis compared to newly diagnosed cancer. Furthermore, patients with recurrent cancer may have more comorbidities due to unresolved toxicity from previous anticancer treatments and longer-lasting disease that is more detrimental than newly diagnosed patients. Due to these differences, randomization will incorporate disease status as a stratification factor.

[0261] Stratification by MMR status. Mismatch repair defects, known as MMR loss / deficiency, are observed across various tumor types. In advanced endometrial cancer, approximately 15% of patients have MMR deficiency. Several institutions in the United States have initiated universal tumor testing (MMR or MSI) for all patients with a histologically confirmed diagnosis of endometrial cancer. MMR deficiency can typically be detected by IHC staining as loss of expression of one of the four most common MMR proteins: MutL homolog 1 (MLH1), MutS protein homolog 2 (MSH2), MutS protein homolog 6 (MSH6), and PMS1 protein homolog 2 (PMS2). Loss of expression of any MMR protein by IHC suggests a possible germline mutation in the corresponding MMR gene. Patients with such pathogenic germline MMR mutations develop Lynch syndrome. NCCN guidelines recommend screening for MMR deficiency in all patients with endometrial cancer to identify individuals at risk of Lynch syndrome. As highlighted in the previous section, preliminary data suggest that drugs targeting the PD-1 pathway elicit a significant clinical response in patients with endometrial cancer that is MMR-deficient, and a less significant clinical response in patients with endometrial cancer that is MMR-functioning, thus providing a rationale for stratification based on MMR status.

[0262] Treatment and treatment period Patients should receive platinum-based chemotherapy and durvalumab / placebo for the first six cycles (minimum four cycles). Patients without evidence of disease progression (according to RECIST 1.1) should receive durvalumab / placebo and olaparib / placebo during the maintenance phase.

[0263] Group A (control): During the chemotherapy phase, patients receive platinum-based chemotherapy (paclitaxel and carboplatin) every three weeks (Q3W) for up to six cycles, along with durvalumab placebo (intravenous [IV]) Q3W. After the completion of the chemotherapy phase, patients without objective disease progression receive durvalumab placebo (IV) every four weeks (Q4W) and olaparib placebo (tablets) twice daily (bd) during the maintenance phase until disease progression occurs.

[0264] Group B (durvalumab + placebo): During the chemotherapy phase, patients receive 1120 mg of durvalumab (IV) Q3W along with platinum-based chemotherapy (paclitaxel and carboplatin) Q3W for up to 6 cycles. After the completion of the chemotherapy phase, patients without objective disease progression receive 1500 mg of durvalumab (IV) Q4W and olaparib placebo (tablets) in the maintenance phase (bd) until disease progression occurs.

[0265] Group C (durvalumab + olaparib): During the chemotherapy phase, patients receive platinum-based chemotherapy (paclitaxel and carboplatin) Q3W for up to 6 cycles, along with 1120 mg of durvalumab (IV) Q3W. After the completion of the chemotherapy phase, patients without objective disease progression receive 1500 mg of durvalumab (IV) Q4W and 300 mg of olaparib (tablets) orally in bd doses during the maintenance phase until disease progression occurs.

[0266] Unless there is unacceptable toxicity, withdrawal of consent, or another confirmed discontinuation criterion, the patient shall continue to receive study treatment until radiological disease progression in accordance with RECIST 1.1, as assessed by the investigator (see Appendix G). The general study design is summarized in Figure 2.

[0267] Objectives and Endpoints Objectives and corresponding endpoints are shown in Table 2.

[0268]

Table 2

[0269] Efficacy Evaluation and Analysis CT and MRI Scan Tumor Assessment (RECIST 1.1) Efficacy assessment will be conducted (by AstraZeneca) using RECIST 1.1 assessment based on the evaluation by the investigator. Details of RECIST 1.1 (Eisenhauer et al 2009) are provided in Appendix G. The method of assessment is CT or MRI scanning of the chest, abdomen, and pelvis. The use of positron emission tomography (PET) scanning is described in Appendix G. The same method for assessment of tumor burden must be used at baseline and at each subsequent follow-up assessment. Any other areas involved by disease shall be additionally imaged based on the individual patient's signs and symptoms.

[0270] Radiological examinations performed in conduct of this study must be retained at the site as source data. Anonymized copies of scans will be collected from all patients and sent to the CRO designated by AstraZeneca. The scans will undergo BICR assessment.

[0271] All treatment decisions are based on site evaluation via scan. After the primary PFS analysis, a central review of scans is no longer required, and the principal investigator will be notified when it is no longer necessary to share copies of scans with the CRO performing the central review. However, institutions should continue RECIST 1.1 tumor evaluation until radiological progression and should record RECIST evaluations in the eCRF.

[0272] It is important to adhere as strictly as possible to the evaluation schedule, and the timing of scans should be relative to the date of randomization, regardless of any delays in administration. If a scan is performed outside of the scheduled visit interval and no progression is observed in the patient, all attempts should be made to perform a subsequent scan at the scheduled time. Patients will be evaluated until objective radiological disease progression is observed according to RECIST 1.1, and then followed for second progression and survival, regardless of whether the study treatment is discontinued or delayed and / or a protocol violation occurs, unless the patient withdraws consent.

[0273] Tumor evaluation Patient response to treatment is assessed by determining PFS time and ORR using the RECIST 1.1 criteria. The RECIST 1.1 guidelines, which define measurable, unmeasurable, target lesions (TLs), and non-target lesions (NTLs), as well as objective tumor response criteria, are presented in Appendix G. The overall response classification is based on the assessment of TLs, NTLs, and new lesions.

[0274] For patients with TL at baseline, progression is calculated compared to the point in time when tumor burden was at its lowest (i.e., the sum of the smallest diameters previously recorded in the trial, the lowest point). Tumor response (CR, PR, SD) is calculated compared to baseline tumor measurements obtained before randomization.

[0275] In patients with no evidence of disease (NED) at baseline (i.e., TL and NTL are not applicable [NA]), the RECIST 1.1 outcome at follow-up after complete resection following surgery is NED or PD. Progression is defined by the detection of new lesions on follow-up radiological evaluation (RECIST 1.1).

[0276] For patients with disease that is unmeasurable only at baseline, the classification of objective tumor response is based on the response criteria of RECIST 1.1 (CR, PD, and non-CR / non-PD).

[0277] If there is no clinical progression, or if the principal investigator suspects that progression has occurred, particularly with a response to NTL or the appearance of new lesions, it is desirable to continue randomized treatment and treatment-based evaluation until the next scheduled scan, or earlier if deemed clinically necessary, and to reassess the patient's condition with a new scan. If progression is confirmed by repeated scans, the date of the initial scan should be declared as the date of progression.

[0278] For "obvious progression" to be achieved based on NTL, even if SD or PR exists in the TL, there must be a significant overall deterioration in the NTL level, and the overall tumor burden must have increased sufficiently to warrant discontinuation of therapy. A slight increase in the size of one or more NTLs is usually not sufficient to recognize an obvious progression.

[0279] Reading from the center of the scan An independent review will be conducted of all scans used to assess the tumor in accordance with RECIST 1.1. All imaging assessments, including unscheduled visit scans, will be continuously collected and sent to an AstraZeneca-designated CRO for central analysis. The results of this independent review will not be communicated to the principal investigator, and patient management will be based solely on the results of the RECIST 1.1 assessment conducted by the principal investigator.

[0280] Subgroup analysis Subgroup analyses are performed to assess the consistency of treatment efficacy across potential or expected prognostic factors, including (but not limited to), the following subgroups of the FAS, by comparing PFS (according to RECIST 1.1 using investigator assessment) in the durvalumab + placebo group and the durvalumab + olaparib group compared to the control group. ● MMR status (comparison between those with normal function and those with functional deficiencies) ● Disease status (comparison between recurrent and newly diagnosed cases) ● Region (comparison between Asia and RoW).

[0281] Other baseline variables, including biomarkers, may also be evaluated if there is clinical justification or if a disparity is observed between treatment groups.

[0282] Since all of these analyses are considered to support the PFS analysis, no significant level of adjustments will be made for the subgroup and sensitivity analysis trials.

[0283] overall survival OS is analyzed using a stratified log-rank test, employing the same methodology as described for the primary PFS endpoint. The same stratification factors are used for the primary PFS analysis. If the number of deaths is too small for a significant analysis (fewer than 5 deaths per tier), a pre-specified strategy to account for such situations is applied. Further details are provided in the SAP. The effect of durvalumab + placebo on the control is estimated by HR, along with the corresponding CI and p-value. This is repeated for the comparison of durvalumab + olaparib on the control.

[0284] The OS KM plot is presented for each treatment group for each comparison (durvalumab + placebo versus control and durvalumab + olaparib versus control).

[0285] A summary of the number and percentage of patients who died, patients undergoing survival follow-up, patients who were unable to follow up, and patients who withdrew their consent is provided, along with the median overall survival (OS) for each treatment.

[0286] Dosage and experimental treatment Investigational treatments are defined as any investigational and non-investigational products (including marketed comparator products and placebos) or medical devices intended to be administered to study participants in accordance with the study protocol. In this study, investigational treatments refer to chemotherapy, durvalumab / placebo, and olaparib / placebo. The investigational treatments are summarized in Table 1.

[0287] Patients should receive platinum-based chemotherapy and durvalumab / placebo for the first six cycles (minimum four cycles). Patients with no evidence of disease progression (according to RECIST 1.1) should receive durvalumab / placebo and olaparib / placebo during the maintenance phase.

[0288] During the chemotherapy phase, intravenous experimental treatments should ideally be administered on the same day, in the following order:

[0289] Durvalumab / placebo: A durvalumab dose of 1120 mg (Q3W) should be administered over one hour, but if there are interruptions during the infusion, the total infusion time should not exceed eight hours at room temperature.

[0290] Paclitaxel: 175 mg / m2 administered intravenously over 3 hours.

[0291] Carboplatin: AUC5 or AUC6 after IV infusion over 1 hour (or according to local medical practice).

[0292] durvalumab For ease of use and convenience for both the investigator and the patient, durvalumab is administered at Q3W during the chemotherapy phase to align with the treatment interval of platinum-based chemotherapy, using a fixed dose of 1120 mg (based on an average body weight of 75 kg, which corresponds to a body-based dose of 15 mg / kg Q3W).

[0293] Population PK analysis showed that body weight had a minor impact on the PK of durvalumab, and subsequent modeling demonstrated that body weight-based and fixed-dose regimens yielded similar median steady-state PK concentrations. Based on a median body weight of 75 kg, a fixed dose of 1500 mg Q4W of durvalumab (equivalent to 20 mg / kg Q4W) is currently administered in numerous clinical trials across multiple tumor types. The 1500 mg Q4W dose of durvalumab was convincingly supported by the National Cancer Institute (NCI) Study ESR 14-10366 (hereinafter referred to as the "NCI trial," Lee et al 2017). This dosing regimen, equivalent to a fixed dose of 1120 mg Q3W, was selected for the maintenance phase of this trial to align with other studies.

[0294] The two durvalumab dosing schedules used in this study (1120 mg Q3W during the chemotherapy phase and 1500 mg Q4W during the maintenance phase) are equivalent to administering 10 mg / kg Q2W as recommended on the label.

[0295] If a patient's weight falls below 30 kg (≤30 kg) during the maintenance phase, the patient should receive a weight-based dose equivalent to 20 mg / kg of durvalumab Q4W, after consultation between the principal investigator and the study physician, until their weight improves to above 30 kg (>30 kg). Once improved, the patient should begin a fixed dose of durvalumab 1500 mg Q4W.

[0296] Olaparib Olaparib is administered at the dose approved for use in ovarian and breast cancer, namely 300 mg bd. Dose reductions are permitted according to prescribing information.

[0297] Durvalumab and olaparib combination Durvalumab and olaparib are administered in combination for a range of indications, including ovarian cancer, breast cancer, SCLC, and gastric cancer (MEDIOLA;NCT02734004). The safety and tolerability of olaparib 300 mg bid in combination with durvalumab 1500 mg Q4W have been convincingly supported by the NCI trial (Lee et al 2017).

[0298] [Table 3-1]

[0299] [Table 3-2] Abbreviations: bd = twice a day; GMP (Good Manufacturing Practice) = Good Manufacturing Practice; HDPE (high-density polyethylene) = high-density polyethylene; IP (investigational product) = investigational product; IV (intravenous) = intravenous; IWRS (interactive web response system) = interactive web response system; Q3W = every 3 weeks; Q4W = every 4 weeks; w / v (weight / volume) = weight / volume.

[0300] Chemotherapy agents The chemotherapy agents (paclitaxel and carboplatin) are supplied locally, or, in certain circumstances where local supply is not feasible, AstraZeneca supplies the drugs centrally and labels them in the local language in accordance with regulatory guidelines. In the EU, carboplatin and paclitaxel are considered adjunct drugs in accordance with EU Clinical Trials Guidance 2017.

[0301] Chemotherapy is a "non-investigational drug" because it is a recommended State of Computation (SOC) in international guidelines. Chemotherapy will be administered according to the recommendations for this treatment combination in the international guidelines (NCCN Uterine Neoplasms 2019).

[0302] Platinum-based chemotherapy should be continued for a maximum of 6 cycles. If necessary due to toxicity, a minimum of 4 cycles of platinum-based chemotherapy may be administered. The chemotherapy regimen is as follows: ● Carboplatin (AUC5 or AUC6) Q3W (Note: Dose reduction to AUC5 may be considered for patients who have previously received pelvic radiotherapy) ● Paclitaxel 175 mg / m2 Q3W.

[0303] Each chemotherapy agent will be administered according to local guidelines, and premedication may be provided.

[0304] For recommendations regarding carboplatin administration, please refer to the NCCN guidelines: https: / / www.nccn.org / professionals / OrderTemplates / PDF / appendix_B.pdf. In accordance with NCCN guidance, to avoid overestimation of CrCL and subsequent overestimation of carboplatin dose, creatinine clearance should be estimated using a minimum value of 0.7 mg / dL (equivalent to 62 μmol / L) in patients with low serum creatinine. The carboplatin dose should be calculated using the Calvert formula as shown below. Carboplatin dose (mg) = Target AUC × (GFR + 25) Note: It is recommended that the GFR used in the Calvert formula does not exceed 125 mL / min. For the purposes of this protocol, GFR is considered to correspond to the estimated creatinine clearance.

[0305] Maximum carboplatin dose (mg) = Target AUC (mg / mL × min) × 150 mL / min

[0306] The maximum recommended dose of carboplatin is as follows: ● AUC6 = 900 mg ● AUC5 = 750 mg

[0307] If chemotherapy is permanently discontinued prematurely (before completing 4 cycles) as a result of toxicity or disease progression, all investigational treatment will be discontinued, and the patient will not enter the maintenance phase. Follow-up will continue unless a visit to discontinue investigational treatment is made and the patient withdraws their consent to continue the trial.

[0308] Patients who develop a hypersensitivity reaction to carboplatin should be managed according to standard clinical practice. Patients may be retreated according to local clinical guidance, including prevention of increased hypersensitivity, or using a desensitization protocol. If hypersensitivity prevents further administration of carboplatin, substitution with cisplatin may be considered for the patient, provided that standard clinical practice is in place and chemotherapy is available locally. Cisplatin substitution should be discussed with the AstraZeneca trial physician before implementation.

[0309] Patients who develop a hypersensitivity reaction to paclitaxel should be managed according to standard clinical practice. Depending on the severity of the reaction, patients may be retreated according to local clinical guidance. In cases of recurrent hypersensitivity reactions, despite appropriate premedication to prevent further administration of paclitaxel, the principal investigator may consider omitting paclitaxel from the chemotherapy regimen or replacing it with another taxane (nab-paclitaxel or docetaxel), provided that this is in accordance with local standard clinical practice and that the chemotherapy is locally available.

[0310] Patients who develop chemotherapy-induced peripheral neuropathy should be managed according to standard clinical practice. The dose of chemotherapy may be reduced according to local clinical guidance. If permanent discontinuation of paclitaxel is necessary due to persistent and significant peripheral neuropathy, replacement with docetaxel may be considered for the patient, provided that this is in accordance with local standard clinical practice and that the chemotherapy is locally available.

[0311] Example 2: Durvalumab and olaparib for newly diagnosed advanced or recurrent endometrial cancer method Study design and patients DUO-E was a randomized, double-blind, placebo-controlled, multicenter phase III trial conducted in 22 countries. Eligible patients were 18 years of age or older with newly diagnosed, advanced (International Federation of Gynecology and Obstetrics [FIGO] stage III / IV) or recurrent epithelial endometrial cancer (excluding sarcoma) and who had not received first-line systemic anticancer therapy. For patients with recurrent disease, prior chemotherapy was permitted if administered in an adjuvant setting and at least 12 months had passed between the last chemotherapy dose and subsequent recurrence. DNA MMR status was determined prior to randomization (see Supplemental Appendix). Patients also had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Complete inclusion and exclusion criteria are provided in the Supplemental Appendix.

[0312] Randomized and experimental treatments Patients were randomized in a 1:1:1 ratio to three treatment groups using an interactive voice / web response system (Figure 2), stratified by MMR status (comparison of normal function to deficiency), disease status (comparison of newly diagnosed to relapsed), and geographical region (comparison of Asia to the rest of the world). Patients whose MMR status was unknown before randomization were ineligible.

[0313] Patients entered a chemotherapy phase, followed by a maintenance phase that continued until radiological disease progression (as assessed by the investigator, based on the Response Evaluation Criteria for Solid Tumors [RECIST] version 1.1), unacceptable toxicity, withdrawal of consent, or other discontinuation criteria were met. Only patients who did not experience objective disease progression during the chemotherapy phase and who met other eligibility requirements (see full eligibility criteria below) were permitted to initiate maintenance therapy.

[0314] Patients received platinum-based chemotherapy (carboplatin and paclitaxel at an area under the curve of 5 or 6, at 175 mg per square meter) and placebo intravenously every 3 weeks for 6 cycles, followed by maintenance placebo intravenously every 4 weeks, and placebo tablets twice daily. Platinum-based chemotherapy and durvalumab 1120 mg intravenously every 3 weeks for 6 cycles, followed by maintenance with durvalumab 1500 mg intravenously every 4 weeks, and placebo tablets twice daily; or platinum-based chemotherapy and durvalumab 1120 mg intravenously every 3 weeks for 6 cycles, followed by maintenance with durvalumab 1500 mg intravenously every 4 weeks, and olaparib 300 mg tablets twice daily.

[0315] Determination of DNA mismatch repair (MMR) status DNA MMR status was determined prior to randomization by central testing of MMR status in tumor cells from formalin-fixed paraffin-embedded (FFPE) tumor tissue samples using the Ventana MMR IHC panel (Roche Diagnostics, Rotkreuz, Switzerland).

[0316] In accordance with local regulations, FFPE tumor tissue samples from previously unirradiated tumor lesions were provided for each patient. The FFPE tumor tissue samples could originate from either the local area or a metastatic site, and could be any of the following: ● Tumor samples obtained from cytoreductive surgery (in patients who have already undergone such surgery) ● Biopsy samples obtained for diagnosis (when samples from decompression surgery cannot be used) ● Newly collected tumor samples (when samples are collected as part of routine clinical practice).

[0317] Determination of programmed cell death ligand-1 (PD-L1) status Pre-treatment tumor tissue samples were centrally tested after randomization using VENTANA PD-L1 (SP263) immunohistochemical assay (Roche Diagnostics). PD-L1 expression was determined using a combination of tumor cell and tumor-associated immune cell positivity scoring methods. The tumor area positivity (TAP) score was calculated as the percentage of tumor area occupied by tumor cells and immune cells with PD-L1 staining at any intensity. A TAP score of ≥1% was considered PD-L1 positive, and a TAP score <1% was considered PD-L1 negative.

[0318] Determination of Homologous Recombination Repair Mutation (HRRm) status Baseline tumor tissue samples taken before treatment were used for a pre-randomization homologous recombination repair mutation (HRRm) trial. HRRm status was centrally assessed using the Foundation One CDx NGS assay (Foundation Medicine, Inc., Cambridge, MA). A sample was considered positive if harmful or suspected harmful HRRm was detected in any one of the following pre-specified genes associated with HRR: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. A negative HRRm status (non-HRRm) was defined as a sample without pathogenic mutations in any of the pre-specified genes associated with HRR. Unknown HRRm status included patients recruited in China where HRR trials were not conducted, and patients who withdrew their consent or whose samples were unavailable.

[0319] Eligibility for the maintenance phase To continue in the maintenance phase of the trial, patients must have received a maximum of six cycles of chemotherapy and a minimum of four cycles of platinum-based chemotherapy.

[0320] After completion of chemotherapy, the durvalumab / placebo dosing schedule was changed to 1500 mg every four weeks. The patient also received maintenance therapy with olaparib / placebo after completion of chemotherapy (maintenance therapy was initiated at least three weeks and up to nine weeks after the last chemotherapy infusion).

[0321] Subgroup analysis: Pre-specified subgroup analyses evaluated progression-free survival in the doublet group compared to the control group, the triplet group compared to the control group, and the triplet group compared to the doublet group, according to the following factors: MMR status (comparison of normal function to deficiency), HRRm status (comparison of HRRm, non-HRRm, and unknown), PD-L1 status (PD-L1 positive, PD-L1 negative, and unknown), disease status (comparison of relapsed to newly diagnosed), region (comparison of Asia to the rest of the world), age (comparison of <65 years to 65 years and over), race (comparison of Caucasian, Black / African American, Asian, and others), histology (comparison of endometrioid, serous, and others), ECOG performance status (comparison of 0 to 1), and FIGO stage at initial diagnosis in newly diagnosed patients (comparison of III to IV).

[0322] Efficacy data were summarized and analyzed in the intention-to-treat population (all randomized patients), safety data were summarized in the safety analysis set (all randomized patients who received at least one dose of investigational treatment, i.e., durvalumab / placebo or olaparib / placebo), and for the maintenance phase, safety data were summarized in patients from the safety analysis set who entered the maintenance phase and received at least one dose of olaparib / placebo.

[0323] Primary progression-free survival analyses for each comparison were performed separately using stratified log-rank tests to generate p-values, with hazard ratios and confidence intervals (CIs) estimated using a stratified Cox proportional hazards model. Kaplan-Meier (KM) plots were presented for each treatment group and used to estimate median survival and the proportion of surviving and progression-free patients at 6-month intervals from randomization. Similar methods were used for the analysis of the time to secondary events endpoint.

[0324] result patient From June 2, 2020 to April 20, 2022, 718 patients were randomized: 241, 238, and 239 patients were randomized into the control, doublet, and triplet groups, respectively. Of the randomized patients, 236 patients (97.9%) in the control group, 235 patients (98.7%) in the doublet group, and 238 patients (99.6%) in the triplet group received some form of investigational treatment. Of these, 169 patients (70.1%), 183 patients (76.9%), and 192 patients (80.3%), respectively, initiated the maintenance phase and received olaparib / placebo (Figure 6).

[0325] Patient baseline characteristics were generally well-balanced across treatment groups (Table 4) and representative of patients with newly diagnosed advanced or recurrent endometrial cancer (Table 5). Stratification factors were well-balanced across treatment groups. 80% of patients in each group had tumors with normal MMR function (pMMR), approximately 28% were of Asian origin, and approximately 47% had newly diagnosed disease.

[0326] [Table 4-1]

[0327] [Table 4-2] Abbreviations: ECOG, US East Coast Cancer Clinical Trials Group; FIGO, International Federation of Gynecology and Obstetrics; HRRm, Homologous Recombination Repair Mutation; MMR, Mismatch Repair; PD-L1, Programmed Cell Death Ligand-1; TAP, Tumor Area Positive. a Stratification factors (MMR status [comparison of normal function with deficiency], disease status [comparison of newly diagnosed with relapsed disease], and geographical region [comparison of Asia with non-Asia]) were determined by a randomization code. b This includes China, Hong Kong, India, Japan, South Korea, and Singapore. Two patients from India were mistakenly stratified into the Asian subgroup. c FIGO stages were determined by the electronic case report form format. They are reported as a percentage of the total number of patients in each group. d Characteristics of pathological diseases were collected at the time of the initial diagnosis of the disease under investigation. e MMR status was assessed using the Ventana MMR RxDx panel (Roche Diagnostics, Rotkreuz, Switzerland). f HRRm status was assessed using the Foundation One CDx NGS assay (Foundation Medicine, Inc., Cambridge, MA). A positive HRRm status (HRRm) was defined as a sample with a pathogenic mutation in one of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm status (non-HRRm) was defined as a sample without pathogenic mutations in any of the pre-specified genes. Unknown HRRm status included patients recruited in China where HRR testing was not performed, and patients who withdrew their consent or whose samples were unavailable. gPD-L1 expression was evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics). PD-L1 positivity was defined as TAP ≥ 1%. PD-L1 negativity was defined as TAP < 1%. "Unknown" included patients who withdrew their consent or for whom samples were unavailable. h Only "yes" was reported.

[0328] [Table 5]

[0329] Effectiveness The primary analysis of progression-free survival as assessed by the principal investigator was conducted after 438 out of 718 patients in the intention-to-treat population had experienced disease progression or death (data maturity, 61%) (data cutoff, April 12, 2023). The median follow-up period for censored patients was 12.6 months (range, 0.0–31.6) in the control group, 15.4 months (range, 0.0–29.1) in the doublet group, and 15.4 months (range, 0.0–31.7) in the triplet group.

[0330] In the treatment-intention population, the durvalumab group had a statistically significant 29% lower risk of disease progression or death compared to the control group (HR, 0.71; 95% CI, 0.57–0.89; P=0.003; median PFS of 10.2 over 9.6 months) (Figure 4A, Table 7). The durvalumab + olaparib group had a statistically significant 45% lower risk of disease progression or death compared to the control group (HR, 0.55; 95% CI, 0.43–0.69; P<0.001; median PFS of 15.1 over 9.6 months) (Figure 4A, Table 7). The Kaplan-Meier curves for PFS overlapped up to approximately 6 months, after which there was a clear and sustained separation favorable to both treatment groups compared to the control group (Figure 4A). This delay in separation was expected due to the known delayed therapeutic effect of durvalumab, as well as the fact that olaparib maintenance therapy was initiated only after completion of chemotherapy. The delay in curve separation suggested non-proportionality (P=0.018 and P=0.03 for the comparison of durvalumab to control and durvalumab + olaparib to control, respectively). In the presence of non-proportional hazards, the overall PFS HR should be interpreted as a mean estimate of the observed benefit. Rates and median PFS at specific time points are shown in Table 7.

[0331] In an exploratory analysis of progression-free survival as assessed by the principal investigator in the triplet group compared to the doublet group, the hazard ratio for disease progression or death was 0.78 (95% CI, 0.61–0.99; P=0.045).

[0332] Sensitivity analysis of progression-free survival, assessed by a blinded independent central review, was consistent with the investigator's assessment when comparing the doublet (hazard ratio 0.74; 95% CI 0.58–0.94) and triplet (hazard ratio 0.55; 95% CI 0.42–0.70) compared to the control (Figure 6).

[0333] In a predefined exploratory analysis of investigator-assessed PFS in the durvalumab + olaparib group compared to the durvalumab group, the hazard ratio (HR) was 0.78 (95% CI, 0.61–0.99; 15.1 at a median PFS of 10.2 months) (Table 7).

[0334] Exploratory analyses of progression-free survival in specified subgroups demonstrated consistent therapeutic efficacy, with all observed hazard ratio estimates favoring the doublet and triplet groups compared to the control (Figures 5A-5B). The global interaction trial showed potentially quantitatively different therapeutic efficacy between the doublet and control depending on MMR status and area (Table 6). Analysis by MMR status is reported in Table 7 and Figure 8.

[0335] The first interim analysis of overall survival (OS) was conducted at the time of the primary progression-free survival (PFS) analysis, at which point 199 deaths (28%) had occurred in the treatment-intent population. The median (range) follow-up period for patients whose OS was censored was 18.6 months (0.5–32.9) in the control group, 18.4 months (2.1–33.0) in the durvalumab group, and 18.7 months (1.1–33.4) in the durvalumab plus olaparib group. While the HRs for both comparisons favored the treatment group, neither comparison reached statistical significance in this first interim analysis of OS (durvalumab compared to control: HR, 0.77, 95% CI, 0.56–1.07; P=0.120; durvalumab + olaparib compared to control: HR, 0.59, 95% CI, 0.42–0.83; P=0.003, Figure 4B). In the pre-specified exploratory subgroup analysis of PFS, all observed HR point estimates favored the durvalumab and durvalumab + olaparib groups compared to the control group (Figures 5A–5B). In the dMMR subgroup, the hazard ratio for PFS was 0.42 (95% CI, 0.22–0.80, median PFS at 7 months not reached [NR]) for durvalumab compared to controls, and 0.41 (95% CI, 0.21–0.75, median PFS at 7 months 31.8) for durvalumab plus olaparib compared to controls (Table 7 and Figure 8A). In the pMMR subgroup, the hazard ratio for PFS was 0.77 (95% CI, 0.60–0.97, median PFS at 9.7 months 9.9) for durvalumab compared to controls, and 0.57 (95% CI, 0.44–0.73, median PFS at 9.7 months 15.0) for durvalumab plus olaparib compared to controls (Table 7 and Figure 8B). Table 7 reports a comparison of durvalumab plus olaparib with durvalumab based on MMR status.In subgroup analysis based on PD-L1 status, the PD-L1-positive subgroup (defined as tumor-positive [TAP] ≥ 1%) showed a PFS hazard ratio (HR) of 0.63 (95% CI, 0.48–0.83) for durvalumab compared to controls, with a median PFS of 11.3 at 9.5 months, and a median PFS of 20.8 at 9.5 months for durvalumab plus olaparib compared to controls (Figure 10A). In the PD-L1-negative subgroup (TAP < 1%), the hazard ratio for PFS was 0.89 (95% CI, 0.59–1.34) for durvalumab compared to the control group, with a median PFS of 9.7 compared to 9.9. For durvalumab plus olaparib compared to the control group, the hazard ratio was 0.80 (95% CI, 0.55–1.16) with a median PFS of 10.1 compared to 9.9 (Figure 10B). Details of the duration of the study treatment are provided in Table 8.

[0336] [Table 6] MMR indicates mismatch repair; NA is not applicable; and RECIST response criteria in solid tumors.

[0337] [Table 7-1]

[0338] [Table 7-2] Abbreviations: CI, confidence interval; dMMR, mismatch repair deficiency; NR, not reached; PFS, progression-free survival; MMR, mismatch repair; pMMR, normal mismatch repair function; PD-L1, programmed cell death ligand-1. a The MMR status is determined by a randomized code. b The calculations were performed using the Kaplan-Meier technique. The CI for the median PFS was derived based on the Brookmeyer-Crowley method. cHazard ratios and CIs were estimated from a Cox proportional hazards model stratified by MMR and disease status. Hazard ratios less than 1 indicated a favorable outcome for the target treatment group compared to the comparison group. d Hazard ratios and confidence intervals (CIs) were estimated from an unstratified Cox proportional hazards model. Hazard ratios less than 1 indicated a favorable outcome for the target treatment group compared to the comparison group.

[0339] [Table 8]

[0340] The Phase 3 DUO-E trial demonstrated that durvalumab in combination with first-line carboplatin and paclitaxel, followed by maintenance with durvalumab with or without olaparib, significantly reduced the risk of disease progression or death compared to standard chemotherapy in patients with newly diagnosed advanced or recurrent endometrial cancer (45% risk reduction with olaparib and 29% risk reduction without olaparib). These data confirm the clinical benefit of incorporating immunotherapy with or without a PARP inhibitor into first-line chemotherapy for patients with newly diagnosed advanced or recurrent endometrial cancer, and are the first data to demonstrate that the addition of a PARP inhibitor provides further benefit in this setting.

[0341] In pre-specified exploratory subgroup analyses of PFS, all observed HR point estimates favored durvalumab and durvalumab + olaparib compared to the control group. Analysis by MMR status showed similar clinically meaningful benefits observed in the dMMR subgroup in the durvalumab group compared to the control group (HR, 0.42; 95% CI, 0.22–0.80) and in the durvalumab + olaparib group compared to the control group (HR, 0.41; 95% CI, 0.21–0.75). In the pMMR subgroup, a clinically meaningful benefit was observed in the durvalumab group compared to the control group (HR, 0.77; 95% CI, 0.60–0.97), and the addition of olaparib maintenance to durvalumab suggested further benefits (HR, 0.57; 95% CI, 0.44–0.73 compared to the control). A pre-specified exploratory analysis of durvalumab plus olaparib compared to the durvalumab group suggested a contribution of olaparib in the pMMR subgroup (HR, 0.76, 95% CI, 0.59–0.99 in the pMMR subgroup; HR, 0.97, 95% CI, 0.49–1.98 in the dMMR subgroup). Analysis by PD-L1 status showed that benefits were observed in both the PD-L1-positive subgroup, which showed clinically meaningful improvement in PFS (HR 0.63 [95% CI, 0.48–0.83] for the durvalumab group compared to control, and HR 0.42 [95% CI, 0.31–0.57] for the durvalumab + olaparib group compared to control), and the PD-L1-negative subgroup, which showed less significant improvement (HR 0.89 [95% CI, 0.59–1.34] and 0.80 [95% CI, 0.55–1.16] for the durvalumab group and durvalumab + olaparib group compared to control, respectively).

[0342] In the DUO-E study, the results in the doublet group demonstrated a clinical benefit from the combination therapy of immune checkpoint inhibitors and standard chemotherapy for newly diagnosed advanced or recurrent endometrial cancer.

[0343] Sensitivity analysis of progression-free survival was consistent with the primary analysis. The first interim analysis of overall survival favored the treatment group in support of the primary endpoint.

[0344] The safety profiles in the experimental groups were generally consistent with the known profiles of each individual component of the regimen. Delivery of standard therapy was not impaired by the delivery of any other therapy, and the frequency of chemotherapy discontinuation was similar across the treatment groups.

[0345] Regarding specific or potentially interesting adverse events associated with durvalumab, the events were consistent with the known safety profile of durvalumab in combination with chemotherapy, which is primarily caused by chemotherapy. Regarding particularly interesting adverse events associated with olaparib, the events of myelodysplastic syndrome and acute myeloid leukemia were low and consistent with the known safety profile of olaparib.

[0346] Adding durvalumab to standard first-line platinum-based chemotherapy, followed by maintenance with durvalumab with or without olaparib, significantly improved progression-free survival outcomes in patients with first-line advanced or recurrent endometrial cancer, confirming the clinical benefit of integrating immunotherapy with or without a PARP inhibitor into first-line chemotherapy in this setting. Adding olaparib to maintenance durvalumab further enhanced the clinical benefit. The safety profiles in the experimental group were generally consistent with the known profiles of each individual component of the regimen.

[0347] Olaparib (Lynparza) in combination with durvalumab is indicated for maintenance therapy in adult patients with advanced or recurrent primary endometrial cancer who have normal mismatch repair function (pMMR) and whose disease has not progressed with first-line treatment of durvalumab, carboplatin, and paclitaxel.

[0348] Predefined exploratory subgroup analyses demonstrate that adding olaparib maintenance to the durvalumab-chemotherapy combination improves PFS, potentially enhancing outcomes in pMMR and PD-L1-positive patient populations. While grade 3 or higher adverse events were more prevalent in the durvalumab + olaparib group, the safety profiles in each group were largely consistent with the known profiles of the individual components of the regimen.

[0349] Example 3: Durvalumab + carboplatin / paclitaxel (CP) followed by durvalumab ± olaparib as first-line (1L) treatment for endometrial cancer (EC). Clinical factors for progression-free survival (PFS) in DUO-E. method Patients (pts) with newly diagnosed stage III / IV or relapsed EC were randomized in a 1:1:1 ratio to CP (CP + durvalumab placebo [pbo], followed by durvalumab pbo + olaparib pbo), CP+D (CP + durvalumab, followed by durvalumab + olaparib pbo), or CP+D+O (CP + durvalumab, followed by durvalumab + olaparib). Subgroup analyses of post-hoc exploratory PFS by key clinical factors—age (comparison between <65 years and 65 years and older); BMI (comparison between <25 and ≥25); ECOG PS (comparison between 0 and 1); and ITT and prior chemotherapy, surgery, and radiotherapy (comparison between with and without) in the mismatch repair population are reported.

[0350] result At the primary data cutoff (April 12, 2023), PFS subgroup analyses by age, BMI, ECOG PS, and prior treatment generally showed a benefit for CP+D±O compared to CP in the ITT population (Table 9). PFS subgroup analyses showed a consistent PFS benefit for CP+D compared to CP in patients with dMMR (HR<1.00 in all subgroups). In patients with pMMR, CP+D generally showed a benefit compared to CP, and the addition of olaparib consistently enhanced PFS (HR<1.00 for CP+D+O compared to CP in all subgroups).

[0351] The DUO-E ITT population derived a PFS benefit in CP+D±0 compared to CP across a range of key clinical factors explored in these analyses. In patients with dMMR, a consistent PFS benefit was observed for CP+D compared to CP across key clinical factors. Patients with pMMR benefited from CP+D compared to CP across a range of key clinical factors, and the addition of olaparib consistently enhanced PFS within each subgroup category. These DUO-E subgroup analyses support previous PFS analyses of the ITT and dMMR populations (benefit for CP+D compared to CP), with enhanced benefits in patients with pMMR with the addition of olaparib.

[0352] [Table 9] * Data is missing for two patients in both CP and CP+D, and for one patient in CP+D+O; † Overweight / Obese. e, event; n, patient; N, none; Y, present

[0353] Example 4: For endometrial cancer (EC), first-line treatment (1L) durvalumab + carboplatin / paclitaxel (CP), followed by durvalumab ± olaparib (DUO-E): Objective response rate (ORR), duration of response (DoR), and time to treatment discontinuation or death (TDT) based on mismatch repair (MMR) status. method Patients newly diagnosed with FIGO stage III (measurable disease before randomization [RECIST 1.1]), or stage IV or relapsed EC, and who had not previously received systemic IL treatment, were randomized in a 1:1:1 ratio to receive CP + durvalumab placebo (pbo; 6 cycles), followed by durvalumab pbo + olaparib pbo (CP group); CP + durvalumab (1120 mg IV q3w), then durvalumab (1500 mg IV q4w) + olaparib pbo (CP+D group); or CP + durvalumab, followed by durvalumab + olaparib (300 mg tablet bid; CP+D+O group). ORR, DoR, and TDT were evaluated in the ITT and MMR populations (exploratory).

[0354] result At the primary data cutoff (April 12, 2023), overall, ORRs with CP+D and CP+D+O improved compared to CP (62 and 64 compared to 55%), and median (m)DoR and mTDT were longer for CP+D compared to CP (mDoR: 13.1 [95% CI 6.0~NR], mTDT: 9.9 [8.8~11.2] compared to 8.8 [7.6~9.7]mo), and further increased for CP+D+O (mDoR: 21.3 [8.1~29.9]mo; mTDT: 15.1 [12.5~18.6]mo; Table 10). In patients with MMR deficiency (dMMR), CP+D and CP+D+O improved ORR (71 and 73 compared to 40%), mDoR (NR and 29.9 [95% CI 9.7~29.9] compared to 10.5 [4.6~NR]mo), and mTDT (21.2 [9.3~NR] and 20.6 [13.4~NR] compared to 6.7 [5.1~7.9]mo). In patients with pMMR, ORR was similar across groups, but mDoR and mTDT were longer in CP+D compared to CP (mDoR: 10.6 [95% CI 5.6~NR] compared to 7.6 [5.1~13.1]mo; mTDT: 9.6 [8.1~10.6] compared to 9.3 [8.0~9.9]mo), and further extended in CP+D+O (mDoR: 18.7 [8.0~NR]mo; mTDT: 13.4 [10.6~15.6]mo).

[0355] CP + durvalumab, followed by durvalumab ± olaparib, improved ORR, DoR, and TDT compared to CP (ITT population). In patients with dMMR, CP + D consistently improved ORR, DoR, and TDT compared to CP. In patients with pMMR, CP + D improved mDoR compared to CP, and the addition of olaparib further extended mDoR and mTDT compared to CP + D.

[0356] Example 5: Preliminary analysis of DUO-E results Figure 11 shows the updated DUO-E trial design, including endpoints and patients. †Six cycles of carboplatin and paclitaxel 175 mg / m2 in the area under the concentration-time curve at 5 mg / mL / min or 6 mg / mL / min. bid, twice daily; CP, carboplatin / paclitaxel; D, durvalumab; DCO1, data cutoff 1; FIGO, International Federation of Gynecology and Obstetrics; IV, intravenous; O, olaparib; q3(4)w, every 3(4) weeks; R, randomization; RECIST = response criteria in solid tumors. Figure 12 shows patient characteristics data. International Federation of Gynecology and Obstetrics; HRR(m), homologous recombination repair (mutation); MMR, mismatch repair; NGS, next-generation sequencing; PD-L1, programmed death ligand 1; TAP, tumor area percentage. Percentages may not add up to 100 due to rounding. Ethnic data were missing for six patients; one newly diagnosed patient was FIGO stage I, and one was FIGO stage II. One patient in the CP+D group had an ECOG PS of 2. Stratification factors (MMR status [comparison of normal function to deficiency], disease status [comparison of newly diagnosed to recurrent], and geographical region [comparison of Asia to non-Asia]) followed a randomization code. Two patients with an "unknown" MMR status, as determined by the central laboratory, were randomized as "deficient" via an interactive voice response system based on local trials. "Asia" included China, Hong Kong, India, Japan, Singapore, and South Korea. †MMR status assessed using the Ventana MMR immunohistochemistry panel;‡PD-L1 expression assessed using the Ventana SP263 assay;§HRRm status assessed using the Foundation One CDx NGS assay, including harmful or suspected harmful mutations in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Unknown HRRm status includes patients recruited in China where HRR trials were not conducted, and patients with samples that could not be used for the trials. ECOG PS, performance status of the US East Coast Cancer Clinical Trials Group;

[0357] The results for the ITT group are shown in Figure 13. * The best objective response was determined based on data obtained up to the initiation of any subsequent cancer therapy, and up to the maximum RECIST progression, including RECIST progression, or up to the last RECIST assessment if there was no progression. †Odds of response (complete or partial) were calculated based on the number of patients with measurable disease at baseline. An odds ratio > 1 indicates a favorable outcome for the CP+D or CP+D+O group.‡Time from randomization to the onset of response, §DoR is the time from the first confirmed complete / partial response to the day of progression or the day of PFS censoring. The rate of patients maintaining a response was estimated by the Kaplan-Meier method. IQR (interquartile range); NR, not reached. Secondary endpoints in the ITT population are shown in Figure 14. TFST, PFS2, and TSST rates were estimated by the Kaplan-Meier method. * HR was estimated from a Cox proportional hazards model stratified by MMR and disease status variables. CI was calculated using a profile likelihood approach.

[0358] A post-hoc exploratory analysis of the MMR subpopulation is shown in Figure 15. For the dMMR subpopulation, the median follow-up period for OS was 18.4 (CP), 19.1 (CP+D), and 19.9 months (CP+D+O) in censored patients, and for the pMMR subpopulation, the median follow-up period was 18.6 (CP), 18.2 (CP+D), and 18.4 months (CP+D+O) in censored patients. MMR status was assessed using the Ventana MMR immunohistochemistry panel. OS rates were estimated by the Kaplan-Meier method. * HR and CI were estimated from an unstratified Cox proportional hazards model.

[0359] Figure 16 shows a retrospective exploratory analysis of the dMMR subpopulation. MMR status was assessed using the Ventana MMR immunohistochemistry panel. TFST, PFS2, and TSST rates were estimated by the Kaplan-Meier method. * HR and CI were estimated from an unstratified Cox proportional hazards model. Stratification factors (disease status, MMR status, and geographical area) were determined by randomization codes. HRRm status was assessed using the Foundation One CDx NGS assay and included harmful or suspected harmful mutations in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Unknown HRRm status included patients recruited in China where HRR trials were not conducted, and patients with samples that could not be used for the trials. PD-L1 status in baseline tumor tissue was centrally determined using the Ventana SP263 assay. Expression was assessed using a TAP score calculated based on the percentage of tumor cells or tumor areas with aggregated immune cells exhibiting membrane PD-L1 staining. FIGO stage was determined at the time of initial diagnosis of endometrial cancer under investigation. G, Grade; NC, Not Calculated. The best objective response was determined based on data obtained up to the initiation of any subsequent cancer therapy and up to the maximum RECIST progression, including RECIST progression, or up to the last RECIST assessment if there was no progression. †Odds of response (complete or partial) were calculated based on the number of patients with measurable disease at baseline. An odds ratio > 1 indicates a favorable outcome for the CP+D or CP+D+O group.‡Time from randomization to the onset of response, §DoR is the time from the first confirmed complete / partial response to the day of progression or the day of censoring of PFS. The rate of patients maintaining a response was estimated by the Kaplan-Meier method.

[0360] Figure 17 shows a retrospective exploratory analysis of the pMMR subpopulation. MMR status was assessed using the Ventana MMR immunohistochemistry panel. TFST, PFS2, and TSST rates were estimated by the Kaplan-Meier method. *HR and CI were estimated from an unstratified Cox proportional hazards model. Stratification factors (disease status, MMR status, and geographical area) were determined by randomization codes. HRRm status was assessed using the Foundation One CDx NGS assay and included harmful or suspected harmful mutations in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Unknown HRRm status included patients recruited in China where HRR trials were not conducted, and patients with samples that could not be used for the trials. PD-L1 status in baseline tumor tissue was centrally determined using the Ventana SP263 assay. Expression was assessed using a TAP score calculated based on the percentage of tumor cells or tumor areas with aggregated immune cells exhibiting membrane PD-L1 staining. FIGO stage was determined at the time of initial diagnosis of endometrial cancer under investigation. The best objective response was determined based on data obtained up to the initiation of any subsequent cancer therapy, and up to maximum RECIST progression including RECIST progression, or up to the last RECIST assessment in the case of no progression. †Odds of response (complete or partial) were calculated based on the number of patients with measurable disease at baseline. An odds ratio > 1 indicates a favorable outcome for the CP+D or CP+D+O group.‡Time from randomization to the onset of response, §DoR is the time from the first confirmed complete / partial response to the day of progression or the day of censoring of PFS. The rate of patients maintaining a response was estimated using the Kaplan-Meier method.

[0361] The results for the MMR subpopulation are shown in Figure 18. MMR status was assessed using the Ventana immunohistochemical MMR panel. PFS rates were estimated by the Kaplan-Meier method. *The CI for median PFS was derived based on the Brookmeyer-Crowley method, and HR and CI were estimated from an unstratified Cox proportional hazards model. CI, confidence interval; CP, carboplatin / paclitaxel; D, durvalumab; DCO (data cut-off), data cutoff; dMMR, MMR deficiency; HR, hazard ratio; ITT, intended treatment; NR, not reached; O, olaparib; PFS, progression-free survival; pMMR, normal MMR function.

[0362] Finally, Figures 19-20 show further results from the ITT population and exploratory PFS analysis.

[0363] [Table 10] * In patients with measurable disease at baseline. CI, confidence interval; IQR, interquartile range; ITT, intention to treat; NR, not reached.

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Claims

1. A method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, wherein the subject (a) one or more chemotherapeutic doses and a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, (b) A method comprising administering a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective dose of a PARP inhibitor.

2. A method for treating endometrial cancer in a subject requiring treatment for endometrial cancer, wherein the subject (a) one or more chemotherapeutic doses and a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, (b) A method comprising administering a therapeutically effective dose of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

3. The method according to claim 1 or 2, wherein step (b) is performed after the completion of step (a).

4. The method according to any one of claims 1 to 3, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

5. The method according to any one of claims 1 to 4, wherein the PARP inhibitor is olaparib.

6. The method according to any one of claims 1 to 5, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 800 mg to 1500 mg.

7. The method according to claim 6, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 1120 mg and / or 1500 mg.

8. The method according to any one of claims 1 to 7, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 10 mg / kg to 20 mg / kg.

9. The method according to claim 8, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 15 mg / kg and / or 20 mg / kg.

10. The method according to any one of claims 1 to 9, wherein the PARP inhibitor is administered in a dose of 100 mg to 300 mg.

11. The method according to claim 10, wherein the PARP inhibitor is administered in a dose of 300 mg.

12. The method according to any one of claims 1 to 11, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

13. The aforementioned paclitaxel is 175 mg / m². ２ The method according to any one of claims 1 to 12, administered in the dose of [specified dose].

14. The method according to claim 12 or 13, wherein the carboplatin is administered in a dose that produces an area under the curve (AUC) of AUC5 or AUC6.

15. The method according to any one of claims 1 to 14, wherein step (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents every two to four weeks.

16. The method according to claim 15, wherein step (a) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every two to four weeks over a period of nine to eighteen weeks, and the one or more chemotherapeutic agents in a certain cycle.

17. The method according to any one of claims 1 to 15, wherein step (a) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks, and one or more of the chemotherapeutic agents in a certain cycle.

18. The method according to claim 17, wherein step (a) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks over a period of 12 to 18 weeks, and the one or more chemotherapeutic agents in a certain cycle.

19. The method according to claim 17, wherein step (a) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks for 18 weeks, and the one or more chemotherapeutic agents in a certain cycle.

20. The method according to any one of claims 1 to 19, wherein step (a) comprises administering 4 to 6 doses of the anti-PD-L1 antibody or its antigen-binding fragment, and 4 to 6 cycles of the one or more chemotherapeutic agents.

21. The method according to any one of claims 1 to 20, wherein step (a) comprises administering 1120 mg of the anti-PD-L1 antibody or its antigen-binding fragment.

22. The method according to claim 21, wherein step (a) comprises administering 1120 mg of durvalumab.

23. The method according to claim 22, wherein step (a) comprises administering 1120 mg of durvalumab every three weeks.

24. Step (a) is, 175 mg / m² ２ Paclitaxel, AUC5 or AUC6 carboplatin, and / or 25 mg / m² ２ The method according to any one of claims 21 to 23, further comprising the administration of cisplatin.

25. Step (b) is, The method according to any one of claims 1 to 24, comprising administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks, and administering a certain dose of the PARP inhibitor twice daily.

26. Step (b) is, The method according to any one of claims 1 to 25, comprising administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks, and administering a certain dose of the PARP inhibitor twice daily.

27. The method according to any one of claims 1 to 26, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and a dose of the PARP inhibitor twice daily for at least 12 weeks.

28. The method according to claim 27, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and a dose of the PARP inhibitor twice daily for up to 24 months.

29. Step (b) is, 1500 mg of the anti-PD-L1 antibody or its antigen-binding fragment, and The method according to any one of claims 1 to 28, comprising administering 300 mg of the PARP inhibitor.

30. Step (b) is, 1500 mg of durvalumab, and The method according to claim 29, comprising administration of 300 mg of olaparib.

31. Step (b) is, 1500 mg of durvalumab every four weeks, and The method according to claim 30, comprising administering 300 mg of olaparib twice daily.

32. The method according to any one of claims 2 to 24, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks.

33. The method according to any one of claims 2 to 24 or 32, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks.

34. The method according to any one of claims 2 to 24 or 32 to 33, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks.

35. The method according to claim 34, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for a maximum of 24 months.

36. The method according to any one of claims 2 to 24 or 32 to 35, wherein step (b) comprises administering 1,500 mg of the anti-PD-L1 antibody or its antigen-binding fragment.

37. The method according to claim 36, wherein step (b) comprises administering 1500 mg of durvalumab.

38. The method according to claim 37, wherein step (b) comprises administering 1,500 mg of durvalumab every four weeks.

39. The method according to any one of claims 1 to 38, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents are administered intravenously.

40. The method according to any one of claims 1 to 39, wherein the PARP inhibitor is administered orally.

41. The method according to any one of claims 1 to 40, wherein the antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the one or more chemotherapeutic agents in step (a) are administered to the subject simultaneously, separately, and / or sequentially.

42. The method according to any one of claims 1 to 42, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the PARP inhibitor in step (b) are administered to the subject simultaneously, separately, and / or sequentially.

43. The method according to any one of claims 1 to 42, wherein the endometrial cancer is advanced endometrial cancer.

44. The method according to any one of claims 1 to 43, wherein the endometrial cancer is an endometrial cancer tumor lacking mismatch repair (MMR deficiency (dMMR)).

45. In the aforementioned subjects having deficiency mismatch repair (dMMR) endometrial cancer, (a) one or more chemotherapeutic doses and a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, (b) The method according to claim 44, comprising administering a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

46. The method according to any one of claims 1 to 43, wherein the endometrial cancer is an endometrial cancer tumor in which the MMR function is normal (pMMR).

47. In the aforementioned subjects having endometrial cancer with normal functioning mismatch repair (pMMR), (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) The method according to claim 46, comprising administering a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

48. The method according to any one of claims 1 to 47, wherein the endometrial cancer is a PD-L1-positive endometrial cancer tumor.

49. The method according to any one of claims 1 to 47, wherein the endometrial cancer is a PD-L1-negative endometrial cancer tumor.

50. The method according to any one of claims 1 to 49, wherein the treatment results in an increased progression-free survival in the subject compared to patients who received durvalumab and chemotherapy alone.

51. The method according to claim 50, wherein the treatment results in an increase in progression-free survival of at least four months.

52. The method according to any one of claims 1 to 51, wherein the treatment results in an increase in overall survival in the subject compared to a patient who received durvalumab and chemotherapy alone.

53. The method according to claim 52, wherein the treatment results in an increase in overall survival by at least four months.

54. A combination for use in the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer, wherein the combination is (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) A combination for use comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

55. A combination for use in the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer, wherein the combination is (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) A combination for use comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment.

56. The combination for use according to claim 54 or 55, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

57. The combination for use according to any one of claims 54 to 56, wherein the PARP inhibitor is olaparib.

58. The combination for use according to any one of claims 54 to 57, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 800 mg to 1500 mg.

59. The combination for use according to claim 58, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 1120 mg and / or 1500 mg.

60. The combination for use according to any one of claims 54 to 59, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 10 mg / kg to 20 mg / kg.

61. The combination for use according to claim 60, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg and / or 20 mg / kg.

62. A combination for use according to any one of claims 54 to 61, wherein the dose of the PARP inhibitor is 100 mg to 300 mg.

63. The combination for use according to claim 62, wherein the dose of the PARP inhibitor is 300 mg.

64. The combination for use according to any one of claims 54 to 63, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

65. The dose of paclitaxel is 175 mg / m². ２ The combination for use described in claim 64.

66. The combination for use according to claim 64 or 65, wherein the dose of carboplatin results in an area under the curve (AUC) of AUC5 or AUC6.

67. (a) a combination for use according to any one of claims 54 to 66, comprising administering the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents every two to four weeks.

68. The combination for use according to claim 67, wherein the administration is every 2 to 4 weeks over a period of 9 to 24 weeks.

69. The combination for use according to claim 67 or 68, wherein the administration is every three weeks or every four weeks.

70. The combination for use according to claim 69, wherein the administration is every three weeks over a period of 12 to 18 weeks.

71. The combination for use according to claim 70, wherein the administration is every three weeks for 18 weeks.

72. (a) a combination for use according to any one of claims 54 to 71, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment in 3 to 6 doses, and the one or more chemotherapeutic agents in 4 to 6 doses.

73. (a) a combination for use according to any one of claims 54 to 72, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg.

74. The combination for use according to claim 73, wherein the durvalumab is administered in a dose of 1120 mg.

75. The combination for use according to claim 73 or 74, wherein the durvalumab is administered in a dose of 1120 mg every three weeks.

76. (a) is, 175 mg / m² ２ Paclitaxel, AUC5 or AUC6 carboplatin, and / or 25 mg / m² ２ A combination for use according to any one of claims 73 to 75, further comprising cisplatin.

77. (b) is, The anti-PD-L1 antibody or its antigen-binding fragment is administered every 2 to 4 weeks, and A combination for use according to any one of claims 54 to 76, comprising the PARP inhibitor administered twice daily.

78. (b) is, The anti-PD-L1 antibody or its antigen-binding fragment is administered every four weeks, A combination for use according to any one of claims 54 to 77, comprising the PARP inhibitor administered twice daily.

79. (b) is, The anti-PD-L1 antibody or its antigen-binding fragment in a dose of 1500 mg, and A combination for use according to any one of claims 54 to 78, comprising administering the PARP inhibitor at a dose of 300 mg.

80. The combination for use according to claim 77, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and the PARP inhibitor in a dose twice daily for at least 12 weeks.

81. The combination for use according to claim 79, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and a dose of the PARP inhibitor twice daily for up to 24 months.

82. (b) is, Durvalumab at a dose of 1500 mg, and The combination for use according to claim 79, comprising administration of olaparib at a dose of 300 mg.

83. (b) is, Durvalumab at a dose of 1500 mg every three weeks, and A combination of uses according to any one of claims 79 to 81, comprising administering olaparib at a dose of 300 mg twice daily.

84. (b) The combination for use according to any one of claims 55 to 76, wherein (b) comprises the anti-PD-L1 antibody or its antigen-binding fragment administered every 2 to 4 weeks.

85. (b) The combination for use according to any one of claims 55 to 76 or 84, wherein (b) comprises the anti-PD-L1 antibody or its antigen-binding fragment administered every four weeks.

86. (b) a combination for use according to any one of claims 55 to 76 or 84 to 85, wherein (b) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment in a dose of 1500 mg.

87. The combination for use according to claim 85, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks.

88. The combination for use according to claim 87, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for a maximum of 24 months.

89. (b) The combination for use according to claim 86, wherein (b) comprises administering durvalumab at a dose of 1500 mg.

90. (b) a combination for use according to any one of claims 84 to 89, wherein (b) is an administration of durvalumab at a dose of 1500 mg every three weeks.

91. The combination for use according to any one of claims 54 to 90, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents are administered intravenously.

92. The combination for use according to any one of claims 54 to 91, wherein the PARP inhibitor is administered orally.

93. The combination for use according to any one of claims 54 to 92, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents in (a) are administered to the subject simultaneously, separately, and / or sequentially.

94. The combination for use according to any one of claims 54 to 93, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the PARP inhibitor in (b) are administered to the subject simultaneously, separately, and / or sequentially.

95. The combination for use according to any one of claims 54 to 94, wherein the endometrial cancer is advanced endometrial cancer.

96. The combination for use according to any one of claims 54 to 95, wherein the endometrial cancer is an endometrial cancer tumor lacking mismatch repair (dMMR).

97. The aforementioned combination is (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) The combination for use according to claim 96, comprising a therapeutically effective amount of anti-PD-L1 antibody or an antigen-binding fragment thereof, in the treatment of deficiency mismatch repair (dMMR) endometrial cancer in subjects requiring treatment of deficiency mismatch repair (dMMR) endometrial cancer.

98. The combination for use according to any one of claims 54 to 95, wherein the endometrial cancer is an endometrial cancer tumor with normal MMR function (pMMR).

99. The aforementioned combination is (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) The combination for use according to claim 98 in the treatment of functionally normal mismatch-repaired (pMMR) endometrial cancer in subjects requiring treatment of functionally normal mismatch-repaired (pMMR) endometrial cancer, comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of PARP inhibitor.

100. The combination for use according to any one of claims 54 to 99, wherein the endometrial cancer is a PD-L1-positive endometrial cancer tumor.

101. The combination for use according to any one of claims 54 to 99, wherein the endometrial cancer is a PD-L1-negative endometrial cancer tumor.

102. The combination for use according to any one of claims 54 to 101, wherein the treatment by combination results in an increase in progression-free survival in the subject compared to patients who received durvalumab and chemotherapy alone.

103. The combination for use according to claim 102, wherein the treatment results in an increase in progression-free survival of at least four months.

104. The combination for use according to any one of claims 54 to 101, wherein the treatment by combination results in an increase in overall survival in the subject compared to patients who received durvalumab and chemotherapy alone.

105. The combination for use according to claim 104, wherein the treatment results in an increase in overall survival by at least four months.

106. The use of combinations in the manufacture of pharmaceuticals for the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer, wherein the combination is (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) Use comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

107. The use of combinations in the manufacture of pharmaceuticals for the treatment of endometrial cancer in subjects requiring treatment for endometrial cancer, wherein the combination is (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) Use comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment.

108. The use according to claim 106 or 107, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

109. The use according to any one of claims 106 to 108, wherein the PARP inhibitor is olaparib.

110. The use according to any one of claims 106 to 109, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 800 mg to 1500 mg.

111. The use according to claim 110, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 1120 mg and / or 1500 mg.

112. The use according to any one of claims 106 to 111, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 10 mg / kg to 20 mg / kg.

113. The use according to claim 112, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg and / or 20 mg / kg.

114. The use according to any one of claims 106 to 113, wherein the dose of the PARP inhibitor is 100 mg to 300 mg.

115. The use according to claim 114, wherein the dose of the PARP inhibitor is 300 mg.

116. The use according to claim 114 or 115, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

117. The dose of paclitaxel is 175 mg / m². ２ The use described in claim 116.

118. The use according to claim 116 or 117, wherein the dose of carboplatin results in an area under the curve (AUC) of AUC5 or AUC6.

119. The use according to any one of claims 106 to 118, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents every two to four weeks.

120. The use according to claim 119, wherein the administration is every 2 to 4 weeks over a period of 9 to 24 weeks.

121. The use according to claim 119 or 120, wherein the administration is every three weeks or every four weeks.

122. The use according to claim 121, wherein the administration is every three weeks over a period of 12 to 18 weeks.

123. The use according to claim 122, wherein the administration is every three weeks for 18 weeks.

124. The use according to any one of claims 106 to 123, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment in 3 to 6 doses, and the one or more chemotherapeutic agents in 4 to 6 doses.

125. The use according to any one of claims 106 to 124, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment in a dose of 1120 mg.

126. The use according to claim 125, wherein the durvalumab is administered in a dose of 1120 mg.

127. The use according to claim 125 or 126, wherein the durvalumab is administered in a dose of 1120 mg every three weeks.

128. (a) is, 175 mg / m² ２ Paclitaxel, AUC5 or AUC6 carboplatin, and / or 25 mg / m ２ The use according to any one of claims 125 to 127, further comprising cisplatin.

129. (b) is, The anti-PD-L1 antibody or its antigen-binding fragment is administered every 2 to 4 weeks, and The use according to any one of claims 106 to 128, comprising the PARP inhibitor administered twice daily.

130. (b) is, The anti-PD-L1 antibody or its antigen-binding fragment is administered every four weeks, The use according to any one of claims 106 to 129, comprising the PARP inhibitor administered twice daily.

131. (b) is, The anti-PD-L1 antibody or its antigen-binding fragment in a dose of 1500 mg, and The use according to any one of claims 106 to 130, comprising administering the PARP inhibitor at a dose of 300 mg.

132. The use according to claim 131, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and a dose of the PARP inhibitor twice daily for at least 12 weeks.

133. The use according to claim 131, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and a dose of the PARP inhibitor twice daily for up to 24 months.

134. (b) is, Durvalumab at a dose of 1500 mg, and The use according to claim 131, comprising administering olaparib at a dose of 300 mg.

135. (b) is, Durvalumab at a dose of 1500 mg every three weeks, and The use according to any one of claims 131 to 134, comprising administering olaparib at a dose of 300 mg twice daily.

136. The use according to any one of claims 107 to 128, wherein (b) comprises the anti-PD-L1 antibody or its antigen-binding fragment administered every 2 to 4 weeks.

137. (b) the use according to any one of claims 107 to 128 or 136, wherein (b) comprises the anti-PD-L1 antibody or its antigen-binding fragment administered every four weeks.

138. (b) the use according to any one of claims 106 to 128 or 136 to 137, wherein (b) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment in a dose of 1500 mg.

139. The use according to claim 137, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and a dose of the PARP inhibitor twice daily for at least 12 weeks.

140. The use according to claim 137, wherein step (b) comprises administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for a maximum of 24 months.

141. The use according to claim 137, wherein (b) comprises administering durvalumab at a dose of 1500 mg.

142. (b) the use according to any one of claims 137 to 141, wherein the use comprises administering durvalumab at a dose of 1500 mg every three weeks.

143. The use according to any one of claims 106 to 142, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents are administered intravenously.

144. The use according to any one of claims 106 to 143, wherein the PARP inhibitor is administered orally.

145. The use according to any one of claims 106 to 144, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents in (a) are administered to the subject simultaneously, separately, and / or sequentially.

146. The use according to any one of claims 106 to 145, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the PARP inhibitor in (b) are administered to the subject simultaneously, separately, and / or sequentially.

147. The use according to any one of claims 106 to 146, wherein the endometrial cancer is advanced endometrial cancer.

148. The use according to any one of claims 106 to 147, wherein the endometrial cancer is an endometrial cancer tumor lacking mismatch repair (dMMR).

149. The aforementioned combination is (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) The use according to claim 148 in the manufacture of a pharmaceutical for the treatment of deficiency mismatch repair (dMMR) endometrial cancer in a subject requiring treatment of deficiency mismatch repair (dMMR) endometrial cancer, comprising a therapeutically effective amount of anti-PD-L1 antibody or an antigen-binding fragment thereof.

150. The use according to any one of claims 106 to 147, wherein the endometrial cancer is an endometrial cancer tumor in which the MMR function is normal (pMMR).

151. Manufacturing of pharmaceuticals for the treatment of endometrial cancer with normal function mismatch repair (pMMR) in subjects requiring treatment of endometrial cancer with normal function mismatch repair (pMMR), the combination thereof, (a) one or more chemotherapeutic doses, a therapeutic dose of an anti-PD-L1 antibody or its antigen-binding fragment, and (b) The use according to claim 150, comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of PARP inhibitor.

152. The use according to any one of claims 106 to 151, wherein the endometrial cancer is a PD-L1-positive endometrial cancer tumor.

153. The use according to any one of claims 106 to 151, wherein the endometrial cancer is a PD-L1-negative endometrial cancer tumor.

154. The use according to any one of claims 106 to 153, wherein the combination of treatments results in an increase in progression-free survival in the subjects compared to patients who received durvalumab and chemotherapy alone.

155. The use according to claim 154, wherein the treatment results in an increase in progression-free survival of at least four months.

156. The use according to any one of claims 106 to 153, wherein the combination of treatments results in an increase in overall survival in the subjects compared to patients who received durvalumab and chemotherapy alone.

157. The use according to claim 156, wherein the treatment results in an increase in overall survival by at least four months.

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