Methods, compositions and combinations for treating endometrial cancer

Abstract

The present disclosure relates to methods, compositions, and combinations for treating endometrial cancer. In particular, the disclosure relates to methods of treating endometrial cancer in a subject in need thereof, comprising administering to the subject one or more chemotherapeutic agents, an anti-PD-L1 antibody or antigen-binding fragment thereof, and optionally a PARP inhibitor. The disclosure also relates to combinations for use in the treatment of endometrial cancer comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or antigen-binding fragment thereof, and optionally a PARP inhibitor.

Description

Technical Field

[0001] The present disclosure relates to methods, compositions and combinations for treating endometrial cancer. In particular, the present disclosure relates to methods of treating endometrial cancer in a subject in need thereof, the methods comprising administering to the subject one or more chemotherapeutic agents, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. The present disclosure also relates to combinations for use in treating endometrial cancer, the combinations comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. Background Art

[0002] Treatment of cancer typically requires surgical resection followed by chemotherapy and radiation therapy. The long-term success of standard treatment regimens varies widely because tumor cells are able to essentially escape by regenerating primary tumor growth and, often more importantly, seeding distant metastases. Recent advances in the treatment of cancer and cancer-related diseases, disorders, and conditions include the use of combination therapies combining immunotherapy with more traditional chemotherapy and radiation therapy. In most cases, immunotherapy is less toxic than traditional chemotherapy because it uses 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 lining of the uterus). Endometrial cancer is sometimes referred to as uterine cancer. Endometrial cancer is one of the most common malignancies of the female reproductive tract, with more than 380,000 new cases worldwide in 2018 and an estimated 61,880 new diagnoses in the United States (US) in 2019. Prevalence is increasing in developed countries, with the highest rates 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 rate 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 exposure to excess estrogen levels associated with obesity, diabetes, tamoxifen use, and reproductive factors (early menarche, late menopause, nulliparity). The growing aging population may also play a role in the increase in incidence. Alternative treatment options for recurrent endometrial cancer are limited, and there is a high unmet need for new treatments. Summary of the invention

[0004] The present disclosure relates to methods, compositions and combinations for treating endometrial cancer. In particular, the present disclosure relates to methods of treating endometrial cancer in a subject in need thereof, the methods comprising administering to the subject one or more chemotherapeutic agents, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. The present disclosure also relates to combinations for use in treating endometrial cancer, the combinations comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor.

[0005] In one aspect, the present disclosure provides a method of treating endometrial cancer in a subject in need thereof, the method 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and optionally a therapeutically effective amount of a PARP inhibitor.

[0006] In another aspect, the present disclosure provides a combination for use in treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and optionally a therapeutically effective amount of a PARP inhibitor.

[0007] In another aspect, the present disclosure provides use of a combination in the manufacture of a medicament for treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0008] In another aspect, the present disclosure provides use of a combination in the manufacture of a medicament for treating ovarian cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and optionally a therapeutically effective amount of a PARP inhibitor.

[0009] These and other features and advantages of the present disclosure will be more fully understood from the following detailed description and the appended claims.It should be noted that the scope of the claims is defined by the recitation therein rather than by the specific discussion of the features and advantages set forth in this specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1The screening process is shown. Abbreviations: ICF = informed consent; MMR = mismatch repair. *Newly collected tumor samples are permitted, provided that the sample is collected as part of routine clinical practice **Patients whose MMR status is unknown prior to randomization will be considered screening failures and ineligible. If the initial MMR test cannot be completed by the end of the 28-day screening period due to a technical failure, the patient must be rescreened to ensure adequate time for MMR retesting. Samples must be shipped prior to signing the primary informed consent form and MMR results must be available prior to randomization. New samples may be submitted and tested only if the initial test fails due to a technical failure. Please refer to the laboratory manual for further details on the retesting procedure.

[0011] Figure 2 Figure 2 shows the study design. During the chemotherapy phase, IV study 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 there were infusion interruptions), 2. paclitaxel (175 mg / m2 over 3 hours by IV infusion), 3. carboplatin (AUC5 or AUC6 over 1 hour by IV infusion, or according to local practice). Maintenance therapy was initiated 3–9 weeks after the last chemotherapy infusion. *Measurable disease per RECISTv1.1 after surgery or diagnostic biopsy (FIGO stage III) or with / without disease after surgery or diagnostic biopsy (FIGO stage IV) Measurable or non-measurable disease using RECIST v1.1 in whom the likelihood of cure by surgery alone or in combination is low. Prior adjuvant systemic anticancer therapy was allowed for recurrent disease ≥12 months from the last dose to subsequent relapse. 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, randomized.

[0012] Figure 3 Multiple control strategies are shown. Alpha levels presented are two-sided. *Overall, 2.5% were allocated using the Lan DeMets spending function, approximated by the O'Brien-Fleming method. H, hypothesis; PFS, progression-free survival; OS, overall survival.

[0013] Figure 4A-B shows progression-free survival (A) and overall survival (B) in the intention-to-treat population, as assessed by the investigator according to RECIST, version 1.1. For PFS analysis, HR and CI were estimated by Cox proportional hazards models stratified by MMR and disease status. For OS analysis, HR and CI were estimated by unstratified Cox proportional hazards models. P values ​​were calculated using the stratified log-rank test. Tick marks indicate censored observations. Patients without events were censored at the latest evaluable RECIST assessment. CI, confidence interval; HR, hazard ratio; MMR, mismatch repair; NR, not reached; OS, overall survival; PFS, progression-free survival; RECIST, response evaluation criteria in solid tumors.

[0014] Figure 5A -B shows subgroup analyses of progression-free survival for (A) double-recombination and (B) triple-recombination. CI stands for confidence interval; ECOG stands for Eastern Cooperative Oncology Group; FIGO stands for International Federation of Gynecology and Obstetrics; G stands for grade; HRRm stands for homologous recombination repair mutation; MMR stands for mismatch repair; PD-L1 stands for programmed cell death ligand-1; and RoW stands for rest of the world. Stratification factors (MMR status [perfect vs. defective], disease status [newly diagnosed vs. recurrent], and geographic region [Asia vs. rest of the world]) were according to the randomization code.

[0015] Figure 6 Recruitment, randomization, and intervention are presented.

[0016] Figure 7 Sensitivity analyses of progression-free survival, as assessed by blinded independent central review, are presented.

[0017] Fig. 8A -B shows progression-free survival in the (A) dMMR and (B) pMMR subgroups, as assessed by the investigator according to RECIST, version 1.1. CI stands for confidence interval; dMMR stands for deficient mismatch repair; pMMR stands for proficient mismatch repair; and RECIST stands for Response Evaluation Criteria in Solid Tumors.

[0018] Fig. 9 Overall survival in the intention-to-treat population is shown.

[0019] Fig. 10A-B shows progression-free survival in the (A) PD-L1-positive and (B) PD-L1-negative subgroups, as assessed by the investigators according to RECIST, version 1.1. CI, confidence interval; dMMR, deficient mismatch repair; HR, hazard ratio; MMR, mismatch repair; NR, not reached; PFS, progression-free survival; PD-L1, programmed death-ligand-1; pMMR, proficient mismatch repair; RECIST, response evaluation criteria in solid tumors.

[0020] Fig.11 A summary of the DUO-E study design including patients and endpoints is shown.

[0021] Figures 12A-12B Patient characteristic data are shown. Gynecologic and Obstetrics Alliance; HRR(m), homologous recombination repair (mutation); MMR, mismatch repair; NGS, next generation sequencing; PD-L1, programmed death-ligand 1; TAP, tumor area proportion.

[0022] Figures 13A-13D Results for (A) progression-free survival (PFS) and (B) overall survival (OS), (C) objective response rate (ORR), and (D) duration of response (DoR) in the intention-to-treat (ITT) population are shown.

[0023] Figures 14A-14C Evaluations of the secondary endpoints of (A) time to first subsequent therapy or death (TFST), (B) second progression-free survival (PFS2), and (C) time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST) for the ITT population are shown.

[0024] Figures 15A-15B Post hoc exploratory analyses of overall survival (OS) for the MMR subsets of (A) dMMR and (B) pMMR are shown.

[0025] Figures 16A-16F Post hoc exploratory analyses of (A) TFST, (B) PFS2, (C) TSST, (D) PFS, (E) ORR, and (F) DoR in the dMMR subgroup are shown.

[0026] Figures 17A-17F Post hoc exploratory analyses of (A) TFST, (B) PFS2, (C) TSST, (D) PFS, (E) ORR, and (F) DoR in the pMMR subgroup are shown.

[0027] Figures 18A-18B Prespecified exploratory analyses of PFS in the MMR subpopulation for (A) dMMR and (B) pMMR are shown.

[0028] Figures 19A-19BAdditional results are shown for (A) PFS and (B) OS for the ITT population.

[0029] Figures 20A-20D Additional results of exploratory PFS analyses of (A) dMMR, (B) pMMR, (C) PD-L1 positive, and (D) PD-L1 negative subgroups are shown. DETAILED DESCRIPTION

[0030] The present disclosure relates to methods, compositions and combinations for treating endometrial cancer. In particular, the present disclosure relates to methods of treating endometrial cancer in a subject in need thereof, the methods comprising administering one or more chemotherapeutic agents, anti-PD-L1 antibodies or antigen-binding fragments thereof, and optionally a PARP inhibitor. The present disclosure also relates to combinations for use in treating endometrial cancer, the combinations comprising one or more chemotherapeutic agents, anti-PD-L1 antibodies or antigen-binding fragments thereof, and optionally a PARP inhibitor.

[0031] As used in accordance with the present disclosure, unless otherwise indicated or defined, unless otherwise stated, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs. The following references provide a general definition of multiple terms used in the present disclosure for technical personnel: Singleton et al., Dictionary of Microbiology and Molecular Biology [microbiology and molecular biology dictionary] (2nd edition 1994); The Cambridge Dictionary of Science and Technology [Cambridge Dictionary of Science and Technology] (Walker, 1988); The Glossary of Genetics [genetics vocabulary], 5th edition, R. Rieger et al. (eds), Springer Verlag [Springer Press] (1991); and Hale and Marham, The Harper Collins Dictionary of Biology [Harper Collins Biology Dictionary] (1991). Unless otherwise indicated, as used herein, the following terms have the following meanings assigned to them.

[0032] In the present disclosure, “comprises, comprising,” “containing,” and “having,” etc. may have the meanings ascribed to them by U.S. patent law and may mean “includes, including,” etc.; “consisting essentially of or consists essentially” also has the meaning ascribed to it by U.S. patent law and is open-ended, allowing existence beyond what is described as long as the basic or novel features described are not altered by existence beyond what is described, but excluding prior art aspects.

[0033] Unless expressly stated or obvious from the context, as used herein, the term "or" is understood to be inclusive. Unless expressly stated or obvious from the context, as used herein, the terms "a", "an", and "the" are understood to be singular or plural. Unless otherwise required by context, singular terms shall include plural forms and plural terms shall include the singular.

[0034] Unless expressly stated or obvious from the context, as used herein, the term "about" is understood to mean within the normal tolerance range in the art, such as within 2 standard deviations of the mean. "About" may be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless obvious from the context, all numerical values ​​provided herein are modified by the term about.

[0035] Any method, composition, or combination provided herein may be combined with one or more of any other method, composition, or combination provided herein.

[0036] The ranges provided herein are understood to be shorthand for all values ​​within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0037] As used herein, the term "antibody" refers to a protein that is capable of specifically binding to an antigen. Ordinary or conventional mammalian antibodies comprise tetramers, which are typically composed of two pairs of identical polypeptide chains, each pair consisting of a "light" chain (typically having a molecular weight of about 25 kDa) and a "heavy" chain (typically having a molecular weight of about 50-70 kDa). As used herein, the terms "heavy chain" and "light chain" refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity to a target antigen. The amino terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that are typically responsible for antigen recognition. The carboxyl terminal portion of each chain typically defines a constant domain that is responsible for effector function. Thus, in naturally occurring antibodies, a full-length heavy chain immunoglobulin polypeptide includes a variable domain (V H ) and three constant domains (C H1 , C H2 and C H3 ) and C H1 and C H2 The hinge region between the H The domain is located at the amino terminus of the polypeptide and the C H3 The variable domain is located at the carboxyl terminus, and the full-length light chain immunoglobulin polypeptide includes the variable domain (V L ) and constant domain (C L ), where V L The domain is located at the amino terminus of the polypeptide and the C L The domain is located at the carboxyl terminus.

[0038] In full-length light and heavy chains, variable domains and constant domains are typically connected by a "J" region of about 12 or more amino acids, wherein the heavy chain also includes a "D" region of about 10 or more amino acids. The variable region of each light / heavy chain pair typically forms an antigen binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of a relatively conservative framework region (FR) connected by three hypervariable regions (also referred to as complementary determining regions or CDRs). The CDRs from each pair of two chains are typically aligned by the framework region, which can enable binding to a specific epitope. From amino-terminal to carboxyl-terminal, light and heavy chain variable domains typically all include domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0039] The term "antigen-binding fragment" refers to a portion of an intact antibody and / or refers to the antigen-determining variable domains of an intact antibody. It is known that the antigen-binding function of an antibody can be performed by a fragment of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments, linear antibodies, single-chain antibodies, diabodies, and multispecific antibodies formed from antibody fragments.

[0040] In one aspect, the present disclosure provides a method of treating endometrial cancer in a subject in need thereof, the method 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and optionally a therapeutically effective amount of a PARP inhibitor.

[0041] In one embodiment, the methods, compositions and combinations comprise 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0042] In some embodiments of the methods of the present disclosure, step (b) occurs after step (a) is completed.

[0043] In various embodiments of the first aspect, step (b) may not comprise a therapeutically effective amount of a PARP inhibitor. In these embodiments, step (b) comprises a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0044] The number of therapeutic doses arranged in each cycle depends on the chemotherapeutic agent. In some embodiments, each cycle may contain only 1 dose. In other embodiments, a cycle may contain more than 1 dose.

[0045] In some embodiments, provided herein is a method of treating endometrial cancer in a subject in need thereof, the method comprising administering to the subject an anti-PD-L1 antibody or an antigen-binding fragment thereof at a dose of about 5 mg / kg to 25 mg / kg. In some embodiments, provided herein is a method of treating endometrial cancer in a subject in need thereof, the method comprising administering to the subject an anti-PD-L1 antibody or an antigen-binding fragment thereof at a dose of about 10 mg / kg to 20 mg / kg.

[0046] In some embodiments, provided herein is a method of treating endometrial cancer in a subject in need thereof, the method comprising administering to the subject a fixed dose of about 800 mg to 1500 mg of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0047] In some embodiments, provided herein is a method of treating endometrial cancer in a subject in need thereof, the method comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of about 15 mg / kg or 20 mg / kg or a fixed dose of about 1120 mg or 1500 mg.

[0048] In a non-limiting example, 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, this is equivalent to a weight-based dose of 15 mg / kg or 20 mg / kg).

[0049] In some embodiments, provided herein is a method of treating endometrial cancer in a subject in need thereof, the method comprising administering to the subject a fixed dose of about 100 mg to 300 mg of a PARP inhibitor.

[0050] In some embodiments, provided herein is a method of treating endometrial cancer in a subject in need thereof, the method comprising administering to the subject a fixed dose of 300 mg of a PARP inhibitor.

[0051] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab. ) is a human monoclonal antibody directed against human PD-L1 that is capable of blocking the binding of PD-L1 to both PD1 and CD80 receptors. Disclosures related to durvalumab can be found in U.S. Pat. Nos. 8,779,108 and 9,493,565, which are incorporated herein by reference in their entirety.

[0052] Durvalumab and its antigen-binding fragments for use in the methods, compositions and combinations provided herein comprise a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In some embodiments, Durvalumab or its antigen-binding fragments for use in the methods, compositions and combinations provided herein comprise a light chain variable region and a heavy chain variable region, the light chain variable region comprising an amino acid sequence of SEQ ID NO: 1, and the heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 2. In some embodiments, Durvalumab or its antigen-binding fragments for use in the methods, compositions and combinations provided herein comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a Kabat-defined CDR1, CDR2 and CDR3 sequence of SEQ ID NO: 3-5, and wherein the light chain variable region comprises a Kabat-defined CDR1, CDR2 and CDR3 sequence of SEQ ID NO: 6-8. One of ordinary skill in the art will be able to easily identify Chothia-defined, Abm-defined or other CDR definitions known to one of ordinary skill in the art. In some embodiments, durvalumab or an antigen-binding fragment thereof for use in the methods, compositions and combinations provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H90PT antibody as disclosed in U.S. Pat. Nos. 8,779,108 and 9,493,565.

[0053] Durvalumab light chain (LC) variable region:

[0054] EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQ APRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQ QYGSLPWTFGQGTKVEIK(SEQ ID NO:1)

[0055] Durvalumab heavy chain (HC) variable region:

[0056] EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAP GKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNS LRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS(SEQ IDNO:2)

[0057] Durvalumab heavy chain CDR:

[0058] HC-CDR1: GTFFSRYWMS (SEQ ID NO: 3)

[0059] HC-CDR2:NIKQDGSEKYYVDSVKG(SEQ ID NO:4)

[0060] HC-CDR3:EGGWFGELAFDY(SEQ ID NO:5)

[0061] Durvalumab, light chain CDR:

[0062] LC-CDR1:RASQRVSSSYLA(SEQ ID NO:6)

[0063] LC-CDR2: DASSRAT(SEQ ID NO:7)

[0064] LC-CDR3: QQYGSLPWT(SEQ ID NO:8)

[0065] As used herein, the term "PARP inhibitor" means any agent that inhibits the activity of poly (ADP-ribose) polymerase (PARP) in cells. When DNA is damaged, PARP helps repair that DNA. DNA damage can be caused by many things, including exposure to UV light, radiation, certain anti-cancer drugs, or other substances in the environment. In cancer treatment, blocking PARP can help prevent cancer cells from repairing their damaged DNA, leading to cancer cell death. In some embodiments, the PARP inhibitor is olaparib. Disclosure related to Olaparib can be found in European Patent Nos. 1330442 and 1633724, which are incorporated herein by reference in their entirety.

[0066] 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, the one or more platinum-based chemotherapeutic agents comprise carboplatin, cisplatin, oxaliplatin, or a combination thereof. In some embodiments, the chemotherapeutic agent comprises one or more taxane-based chemotherapeutic agents. In some embodiments, the one or more taxane-based chemotherapeutic agents comprise nab-paclitaxel, paclitaxel, docetaxel, cabazitaxel, abraxane, anthracycline (pegylated liposomal doxorubicin), or a combination thereof. In some embodiments, the chemotherapeutic agent comprises a combination of one or more platinum-based chemotherapeutic agents and one or more taxane-based chemotherapeutic agents. In various embodiments, the present disclosure allows for the substitution of one or more chemotherapeutic agents for any other chemotherapeutic agent at any time during administration. The substitution of chemotherapeutic agents may occur for any reason, including but not limited to the subject's reaction to or hypersensitivity to one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent comprises cisplatin and paclitaxel. In some embodiments, one or more doses of cisplatin are administered to the patient, wherein the dose is about 25 mg / m2 In some embodiments, one or more doses of cisplatin are administered to a patient at a dose that produces an area under the curve (AUC) of 5 or AUC of 6. In some embodiments, about 25 mg / m 2 Up to 100 mg / m 2 In some embodiments, one or more doses of paclitaxel are administered to the patient, wherein the dose is about 175 mg / m 2 In various embodiments, the dose of the chemotherapeutic agent can be reduced.

[0067] In some embodiments, the dosage quantity of one or more chemotherapeutic agents is measured in cycles. The quantity of therapeutic doses arranged in each cycle depends on the chemotherapeutic agent. In some embodiments, each cycle can contain only 1 dosage. In a non-limiting embodiment, a cycle can contain 1 dosage used on the 1st day of the cycle. In other embodiments, a cycle can contain more than 1 dosage. In a non-limiting embodiment, a cycle can contain more than 1 dosage given every day or every week.

[0068] In some embodiments, the number of doses of the anti-PD-L1 antibody or antigen-binding fragment thereof, and / or PARP inhibitor is measured in cycles. The number of therapeutic doses scheduled in each cycle depends on the antibody or inhibitor. In some embodiments, each cycle may contain only 1 dose. In a non-limiting embodiment, a cycle may contain 1 dose administered on day 1 of the cycle. In other embodiments, a cycle may contain more than 1 dose. In a non-limiting embodiment, a cycle may contain more than 1 dose administered daily or weekly.

[0069] As used herein, the term "subject" may be a human patient.

[0070] In some embodiments, the methods, compositions, and combinations disclosed herein are used to treat a subject having endometrial cancer, an endometrial neoplastic disorder, or uterine cancer.

[0071] As used herein, the term "treatment" or "treat" refers to both therapeutic treatment and prophylactic or preventative measures. Subjects in need of treatment include those with cancer and those who are prone to cancer or those who want to prevent cancer. In some embodiments, the methods, compositions and combinations disclosed herein can be used to treat endometrial cancer. In other embodiments, subjects in need of treatment include those with tumors and those who are prone to tumors or those who want to prevent tumors. In certain embodiments, the methods, compositions and combinations disclosed herein can be used to treat tumors. In other embodiments, the treatment of tumors includes inhibiting tumor growth, promoting tumor reduction, or both inhibiting tumor growth and promoting tumor reduction.

[0072] In some embodiments, the methods, compositions and combinations disclosed herein provide an increase in progression-free survival (PFS) relative to placebo or standard of care or standard of care and durvalumab. In some embodiments, the methods, compositions and combinations disclosed herein provide an increase in overall survival (OS) compared to placebo or standard of care or standard of care and durvalumab.

[0073] Overall survival (OS) refers to the time period from the treatment date to the date of death due to any cause. OS can refer to the overall survival rate within a certain time period (such as, for example, 2 months, 3 months, 4 months, 6 months, 8 months, 12 months, 18 months, 24 months, etc.). Such a time period can be identified as, for example, "OS24", which refers to the number of patients (%) who survived 24 months after treatment according to the 24-month overall survival rate of Kaplan-Meyer. In some embodiments, the overall survival is measured compared to patients who only receive durvalumab and chemotherapy or only receive chemotherapy. In other embodiments, the overall survival is measured compared to patients who have not received treatment.

[0074] Progression-free survival (PFS) refers to the time period from the treatment date to the objective disease progression (RECIST 1.1) or the death date (caused by any reason in the absence of progression). In some embodiments, the methods, compositions and combinations disclosed herein provide a (statistically significant and / or clinically significant) increase in PFS. In some embodiments, the methods, compositions and combinations disclosed herein provide at least 9 months to at least about 24 months (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or more than 24 months, and up to about 5 years) of PFS. In some embodiments, compared with patients who only receive chemotherapy or chemotherapy (e.g., platinum-containing doublet chemotherapy) and durvalumab, progression-free survival is measured. In other embodiments, compared with patients who have not received treatment, overall survival is measured. In various embodiments, the PFS benefit is independent of PD-L1 status (PD-L1 positive or PD-L1 negative).

[0075] As used herein, the term "administration" or "administering" refers to providing, contacting and / or delivering one or more compounds by any appropriate route to achieve a desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ocular, via inhalation, and implants.

[0076] In some embodiments, the anti-PD-L1 antibody, or antigen-binding fragment thereof, and one or more chemotherapeutic agents are administered intravenously. In some embodiments, the PARP inhibitor is administered orally.

[0077] Provided herein are methods, compositions and combinations for treating endometrial cancer, endometrial tumors, uterine cancer or uterine tumors in a subject in need thereof. The subject may not have received PARP inhibitors and immune-mediated therapy. As used herein, "endometrial cancer" refers to any cancer or tumor that originates in the endometrium or endometrium. Endometrial cancer may also be referred to as uterine cancer.

[0078] Endometrial cancer usually presents with symptoms of abnormal uterine bleeding, and most (about 75%) patients are diagnosed at an early stage (stage I or II), and these patients have a good prognosis, with 5-year OS rates ranging from 74% to 91% (Creasman et al. 2006, Siegel et al. 2015). The standard treatment for these patients is surgery, with or without radiation therapy. Systemic therapy is not often administered to these early patients. However, for patients diagnosed with or suffering from advanced endometrial cancer, the prognosis is much worse. Although endometrial cancer has a strong initial sensitivity to platinum-containing doublet chemotherapy compared to many other solid tumors, with a response rate of approximately 51%, most patients diagnosed with advanced disease will show disease progression, with a median PFS of approximately 12 months (Miller et al. 2012, Aghajanian et al. 2018). The five-year OS rate for these patients with advanced disease remains low (57% to 66% for stage III and 20% to 26% for stage IV disease) (Creasman et al. 2006, Siegel et al. 2015).

[0079] The severity of endometrial cancer is measured in stages. As used herein, "stage" refers to an international system for assessing the extent of cancer spread. In stage I, the cancer is confined to the uterus. In stage II, the cancer spreads to the cervix. In stage III, the cancer spreads to the vagina, ovaries, and / or lymph nodes. In stage IV, the cancer spreads to the bladder, rectum, or organs away from the uterus, such as the lungs or bones. Stages III and IV are considered to be advanced endometrial cancer. The endometrial cancer mentioned herein can be selected from stage II, stage III, stage IV, and recurrent cancer. In one embodiment, the endometrial cancer mentioned herein is stage III, stage IV, or recurrent cancer.

[0080] Endometrial cancer is a heterogeneous disease with multiple molecular patterns. Approximately 20% of patients with endometrial cancer have MSI-H or defective mismatch repair (dMMR) tumors. Mismatch repair is one of the mechanisms by which cells repair DNA damage, which is mainly caused by single base pair insertions or deletions (called indels) when DNA polymerase slips during DNA replication. This type of DNA polymerase error tends to occur in short, repetitive DNA sequence regions called microsatellites. Therefore, defective mismatch repair (dMMR) can be detected by observing changes in microsatellite length in normal tissue compared to its length in tumor tissue from the same patient. When there is a high rate of variation in microsatellite length throughout the genome, the tumor is considered to have a high level of microsatellite instability (MSI-H), which reflects a potential defect in mismatch repair capacity.

[0081] Defective mismatch repair (dMMR) and its characteristic genetic signature, high levels of microsatellite instability (MSI-H) throughout the genome, define a unique subset of cancer organisms characterized by high tumor mutational burden and potential responsiveness to immune checkpoint inhibitor immunotherapy based on anti-programmed cell death 1 (PD-1). For example, dMMR may occur due to mutations in one or a collection (e.g., all) of the following MMR proteins: MLH1, PMS2, MSH2, and MSH6; and optionally V600E mutant BRAF protein. MMR can be determined using the VENTANA MMR IHC panel. The VENTANA MMR IHC panel 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).

[0082] In some embodiments, the methods, compositions and combinations of the present disclosure are used to treat a subject with endometrial cancer, wherein the endometrial cancer tumor is mismatch repair deficient (dMMR). In other embodiments, the methods, compositions and combinations of the present disclosure are used to treat a subject with endometrial cancer, wherein the endometrial cancer tumor is not mismatch repair deficient (MMR perfect, pMMR).

[0083] In some embodiments, the methods, compositions, and combinations of the present disclosure comprise administering to a subject having deficient mismatch repair (dMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0084] In some other embodiments, the methods, compositions, and combinations of the present disclosure comprise administering to a subject with perfect mismatch repair (pMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0085] In one embodiment, the endometrial cancer has not received a first-line systemic anticancer treatment. In one embodiment, the endometrial cancer has not received a PARP inhibitor and immune-mediated treatment.

[0086] In some embodiments, the methods, compositions and combinations of the present disclosure are used to treat a subject with endometrial cancer, wherein the endometrial cancer tumor is PD-L1 positive (defined as positive tumor area [TAP] ≥ 1%). In other embodiments, the methods, compositions and combinations of the present disclosure are used to treat a subject with endometrial cancer, wherein the endometrial cancer tumor is PD-L1 negative.

[0087] Provided herein are methods for treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. In some embodiments herein, step (b) may not comprise a therapeutically effective amount of a PARP inhibitor. In these embodiments, step (b) comprises a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0088] In some embodiments, provided herein is a method of treating endometrial cancer in a subject in need thereof, the method comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of about 10 mg / kg to 20 mg / kg (or a flat dose of about 800 mg to 1500 mg, such as 1120 mg or 1500 mg) and a PARP inhibitor at a dose of about 100 mg to 300 mg.

[0089] Also provided herein are combinations for treating endometrial cancer in subjects in need thereof, wherein the combinations comprise (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. In some embodiments herein, the combination of (b) may not comprise a therapeutically effective amount of a PARP inhibitor. In these embodiments, the combination of (b) comprises a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0090] In some embodiments, the combination provided herein comprises an anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of about 10 mg / kg to 20 mg / kg (or a flat dose of about 800 mg to 1500 mg, such as 1120 mg or 1500 mg) and a PARP inhibitor at a dose of about 100 mg to 300 mg.

[0091] The dosage of the anti-PD-L1 antibody or antigen-binding fragment thereof and the PARP inhibitor to be administered to a subject may vary depending in part on the size (weight, body surface or organ size) and condition (age and overall health) of the subject.

[0092] In particular embodiments, one or more doses of an anti-PD-L1 antibody or antigen-binding fragment thereof is administered to a subject, wherein the dose is about 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, one or more doses of an anti-PD-L1 antibody or antigen-binding fragment thereof is administered to a subject, wherein the dose is about 15 mg / kg or 20 mg / kg.

[0093] In certain embodiments, one or more fixed doses of an anti-PD-L1 antibody or antigen-binding fragment thereof are administered to a subject, wherein the dose is about 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, 1100 mg, 1120 mg, 1125 mg, 1150 mg, 1175 mg. In some embodiments, the subject is administered one or more flat doses of an anti-PD-L1 antibody or antigen-binding fragment thereof, wherein the dose is about 1120 mg or 1500 mg.

[0094] In particular embodiments, one or more flat doses of the PARP inhibitor are administered to the subject, wherein the dose is about 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, one or more flat doses of the PARP inhibitor are administered to the subject, wherein the dose is 300 mg. In some embodiments, a dose of 100 mg to 300 mg of the PARP inhibitor is administered twice daily. Thus, the PARP inhibitor may be administered at a daily dose of 200 mg to 600 mg (2 x 100 mg to 300 mg). In other embodiments, the daily dose of the PARP inhibitor may be reduced.

[0095] In one particular non-limiting embodiment, step (a) comprises administering 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0096] In a specific non-limiting embodiment, step (b) comprises administering 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and 300 mg of the PARP inhibitor.

[0097] As used herein, the term "co-administration", "combination" or "combination therapy" refers to the simultaneous or sequential administration of multiple compounds or agents. The first compound or agent may be administered before, concurrently with, or after the administration of the second compound or agent; the third compound or agent may be administered before, concurrently with, or after the administration of the first and / or second compound or agent; the fourth compound or agent may be administered before, concurrently with, or after the administration of the first, second, and / or third compound or agent. The first compound or agent, the second compound or agent, the third compound or agent, and the fourth compound or agent may be administered simultaneously or sequentially on the same day, or may be administered sequentially within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 1 month. In some embodiments, the compounds or agents are co-administered during the period during which each compound or agent exerts at least some physiological effect and / or has residual efficacy. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof of step (a), and one or more chemotherapeutic agents are administered to the subject simultaneously, separately, and / or sequentially (e.g., separately and sequentially). In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof of step (b), and the PARP inhibitor are administered to the subject simultaneously, separately, and / or sequentially (eg, separately and sequentially).

[0098] In particular embodiments, the initial step (step (a)) of the methods disclosed herein or the initial components of the combinations disclosed herein comprise a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof administered within a two-week treatment period, within a three-week treatment period, within a four-week treatment period, within a five-week treatment period, within a six-week treatment period, within an eight-week treatment period, within a twelve-week treatment period, within a fourteen-week treatment period, within a sixteen-week treatment period, within an eighteen-week treatment period, within a twenty-four-week treatment period, or within a year or longer treatment period. In particular embodiments, the initial step (step (a)) of the methods disclosed herein or the initial components of the combinations disclosed herein comprise a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof administered within a nine, ten, or twelve to eighteen-week treatment period. In a non-limiting embodiment, step (a) comprises administering a dose of an anti-PD-L1 antibody or antigen-binding fragment thereof and a cycle of one or more chemotherapeutic agents every three weeks for eighteen weeks.

[0099] In certain embodiments, the subsequent step (step (b)) of the methods disclosed herein or the subsequent components of the combinations disclosed herein comprises a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and optionally a therapeutically effective amount of a PARP inhibitor administered within a two week treatment period, within a three week treatment period, within a four week treatment period, within a five week treatment period, within a six week treatment period, within an eight week treatment period, within a twelve week treatment period, within a fourteen week treatment period, within a sixteen week treatment period, within an eighteen week treatment period, within a twenty four week treatment period, within a six month treatment period, within an eighteen month treatment period, within a twelve month treatment period, within a fourteen month treatment period, within a fifteen month treatment period, within a sixteen month treatment period, within an eighteen month treatment period, within a twenty month treatment period, within a twenty four month treatment period, or longer. In certain embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof and the optional PARP inhibitor are administered within a treatment period of one month to twenty four months or longer. In certain embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof and the PARP inhibitor are administered over a twenty-four month treatment period. In certain embodiments, step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for at least 12 weeks, and administering a dose of the PARP inhibitor twice daily for at least 12 weeks, or until disease progression.

[0100] In particular embodiments of (a) of the methods, compositions and combinations of the present disclosure, a therapeutically effective amount of one or more chemotherapeutic agents is administered about every week, 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 amount of an anti-PD-L1 antibody or antigen-binding fragment thereof is administered about every week, 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.

[0101] In a particular embodiment of (a), the therapeutically effective amount of one or more chemotherapeutic agents and the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof are administered every three weeks.

[0102] In another specific embodiment of (a), a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof are administered every three weeks for a minimum of three cycles and a maximum of eight cycles. In a non-limiting embodiment of (a), a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof are administered every three weeks for six cycles. In another specific embodiment of (a), a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof are administered every three weeks for nine, ten, or twelve to eighteen weeks.

[0103] In particular embodiments of (b) of the methods, compositions and combinations of the present disclosure, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof is administered approximately every week, 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 amount of a PARP inhibitor is administered once, twice or three times a day.

[0104] In a particular embodiment of (b), the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every four weeks.

[0105] In a particular embodiment of (b), the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every four weeks; and the therapeutically effective amount of the PARP inhibitor is administered twice a day.

[0106] In another particular embodiment of (b), the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every four weeks for at least 12 weeks or 3 months and up to twenty-four months, and the therapeutically effective amount of the PARP inhibitor is administered twice a day for at least 12 weeks or 3 months and up to twenty-four months.

[0107] In another particular embodiment of (b), the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every four weeks for at least 12 weeks or 3 months and up to twenty-four months.

[0108] In particular embodiments, a therapeutically effective amount of one or more chemotherapeutic agents is administered for a minimum of three cycles and a maximum of eight cycles. In a non-limiting embodiment, a therapeutically effective amount of one or more chemotherapeutic agents is administered for six cycles. In particular embodiments, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof (e.g., durvalumab) is administered for a total of up to about 24 months, for a total of up to 35 cycles. In particular embodiments, a therapeutically effective amount of a PARP inhibitor (e.g., olaparib) is administered for a total of up to 24 months.

[0109] In particular embodiments, provided herein are methods, compositions, and combinations for treating endometrial cancer in a subject in need thereof, wherein (a) a therapeutically effective amount of one or more chemotherapeutic agents is administered every three weeks for nine, ten, or twelve to eighteen weeks, and an anti-PD-L1 antibody, or an antigen-binding fragment thereof, 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 an antigen-binding fragment thereof, is administered at a dose of 1500 mg every four weeks for a possible total of twenty-four months, and a PARP inhibitor is administered at a dose of 300 mg twice daily for a total of twenty-four months.

[0110] In particular embodiments, provided herein are methods, compositions and combinations for treating endometrial cancer in a subject in need thereof, wherein (a) 175 mg / m 2 is administered intravenously every three weeks. 2 The invention relates to the treatment of patients with 2-month course of olaparib who are prescribed paclitaxel at a dose of 1500 mg intravenously and carboplatin at a dose of AUC5 or AUC6 for nine, ten, or twelve to eighteen weeks, and durvalumab at a dose of 1120 mg intravenously every three weeks for nine, ten, or twelve to eighteen weeks; and then (b) durvalumab at a dose of 1500 mg intravenously every four weeks for a total of twenty-four months, and olaparib at a dose of 300 mg orally twice daily for a total of twenty-four months.

[0111] In a particular embodiment, provided herein are methods, compositions, and combinations for treating endometrial cancer in a subject in need thereof, wherein step (a) comprises administering three to eight doses of an anti-PD-L1 antibody, or an antigen-binding fragment thereof, and three to eight cycles of one or more chemotherapeutic agents. In a non-limiting embodiment, provided herein are methods, compositions, and combinations for treating endometrial cancer in a subject in need thereof, wherein step (a) comprises administering six doses of an anti-PD-L1 antibody, or an antigen-binding fragment thereof, and six cycles of one or more chemotherapeutic agents.

[0112] In particular embodiments, provided herein are methods, compositions, and combinations for treating endometrial cancer in a subject in need thereof, wherein step (b) comprises administering a dose of an anti-PD-L1 antibody, or an antigen-binding fragment thereof, every four weeks for at least 12 weeks or 3 months and up to 24 months, and optionally administering a PARP inhibitor at a dose twice daily for at least 12 weeks or 3 months and up to 24 months.

[0113] In certain embodiments of the disclosed methods, compositions and / or combinations, step / combination (a) is applied before step / combination (b). In another embodiment, step / combination (b) is not applied until step / combination (a) is completed.

[0114] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a compound or composition capable of inducing a desired therapeutic effect when appropriately administered to a subject. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one antibody of the present disclosure.

[0115] As used herein, the term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" refers to one or more formulation materials suitable for achieving or enhancing the delivery of one or more antibodies of the disclosure.

[0116] When used for in vivo administration, the formulation of the present disclosure should be sterile. The formulation of the present disclosure can be sterilized by various sterilization methods (including, for example, aseptic filtration or radiation). In one embodiment, the formulation is sterilized by filtration with a 0.22 micron filter sterilized in advance. Sterile compositions for injection can be prepared according to conventional pharmaceutical practices, as described in "Remington: The Science & Practice of Pharmacy [Remington: Pharmaceutical Science and Practice]," 21st edition, Lippincott Williams & Wilkins [Lippincott Williams and Wilkins Press], (2005).

[0117] In some embodiments, the antibody can be formulated for a specific route of administration, such as oral, nasal, pulmonary, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. As used herein, the terms "parenteral administration" and "parenterally administered" refer to modes of administration other than intestinal and topical administration (usually by injection), and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion. Formulations suitable for topical or transdermal administration of the present disclosure include powders, sprays, ointments, pastes, emulsions, lotions, gels, solutions, patches and inhalants. These antibodies and other actives may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required (see, e.g., U.S. Pat. Nos. 7,378,110; 7,258,873; and 7,135,180; U.S. Patent Application Publication Nos. 2004 / 0042972 and 2004 / 0042971).

[0118] These preparations can be presented in unit dosage form and can be prepared by any method known in the pharmaceutical field. The actual dosage level of the active ingredient in the preparation of the present disclosure can be changed so as to obtain an amount of active ingredient (e.g., "therapeutically effective amount") that is effective in achieving the therapeutic response required for a specific subject, composition, and mode of administration and is nontoxic to the subject. The dosage can also be administered via continuous infusion (such as by a pump). The administration dose can also depend on the route of administration. For example, subcutaneous administration may require a higher dosage than intravenous administration.

[0119] Various embodiments of the present disclosure are described herein for purposes of illustration without limiting the disclosure.

[0120] Example 1. A method of treating endometrial cancer in a subject in need thereof, the method 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0121] Example 2. A method of treating endometrial cancer in a subject in need thereof, the method 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0122] Embodiment 3. The method according to embodiment 1 or 2, wherein step (b) occurs after step (a) is completed.

[0123] Embodiment 4. The method according to any one of embodiments 1-3, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab.

[0124] Embodiment 5. The method according to any one of embodiments 1 to 4, wherein the PARP inhibitor is olaparib.

[0125] Embodiment 6. The method according to any one of claims 1 to 5, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 800 mg to 1500 mg.

[0126] Embodiment 7. The method according to embodiment 6, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 1120 mg and / or 1500 mg.

[0127] Embodiment 8. The method according to any one of embodiments 1 to 7, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 10 mg / kg to 20 mg / kg.

[0128] Embodiment 9. The method according to embodiment 8, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 15 mg / kg and / or 20 mg / kg.

[0129] Embodiment 10. The method according to any one of embodiments 1 to 9, wherein the PARP inhibitor is administered at a dose of 100 mg to 300 mg.

[0130] Embodiment 11. The method according to embodiment 10, wherein the PARP inhibitor is administered at a dose of 300 mg.

[0131] Embodiment 12. The method according to any one of embodiments 1 to 11, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

[0132] Embodiment 13. The method according to any one of embodiments 1 to 12, wherein the paclitaxel is administered at a dose of 175 mg / m2.

[0133] Embodiment 14. The method of embodiment 12 or embodiment 13, wherein the carboplatin is administered at a dose that produces an area under the curve (AUC) of 5 or AUC6.

[0134] Embodiment 15. The method according to any one of embodiments 1 to 14, wherein step (a) comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof and the one or more chemotherapeutic agents every two to four weeks.

[0135] Embodiment 16. The method according to embodiment 15, wherein step (a) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof and a cycle of the one or more chemotherapeutic agents every two to four weeks for nine to eighteen weeks.

[0136] Embodiment 17. The method according to any one of embodiments 1 to 15, wherein step (a) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof and a cycle of the one or more chemotherapeutic agents every three weeks.

[0137] Embodiment 18. The method according to embodiment 17, wherein step (a) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof and a cycle of the one or more chemotherapeutic agents every three weeks for twelve to eighteen weeks.

[0138] Embodiment 19. The method according to embodiment 17, wherein step (a) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof and a cycle of the one or more chemotherapeutic agents every three weeks for eighteen weeks.

[0139] Embodiment 20. The method according to any one of embodiments 1 to 19, wherein step (a) comprises administering four to six doses of the anti-PD-L1 antibody or antigen-binding fragment thereof and four to six cycles of the one or more chemotherapeutic agents.

[0140] Embodiment 21. The method according to any one of embodiments 1 to 20, wherein step (a) comprises administering 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0141] Embodiment 22. The method of embodiment 21, wherein step (a) comprises administering 1120 mg of durvalumab.

[0142] Embodiment 23. The method of embodiment 22, wherein step (a) comprises administering 1120 mg of durvalumab every 3 weeks.

[0143] Embodiment 24. The method of 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.

[0144] Embodiment 25. The method according to any one of Embodiments 1 to 24, wherein step (b) comprises: administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks; and administering a dose of the PARP inhibitor twice a day.

[0145] Embodiment 26. The method according to any one of Embodiments 1 to 25, wherein step (b) comprises: administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks; and administering a dose of the PARP inhibitor twice a day.

[0146] Embodiment 27. The method according to any one of Embodiments 1 to 26, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for at least 12 weeks, and administering a dose of the PARP inhibitor twice a day for at least 12 weeks.

[0147] Embodiment 28. The method according to embodiment 27, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for up to 24 months, and administering a dose of the PARP inhibitor twice a day for up to 24 months.

[0148] Embodiment 29. The method according to any one of Embodiments 1 to 28, wherein step (b) comprises administering: 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and 300 mg of the PARP inhibitor.

[0149] Embodiment 30. The method of embodiment 29, wherein step (b) comprises administering: 1500 mg of durvalumab; and 300 mg of olaparib.

[0150] Embodiment 31. The method of embodiment 30, wherein step (b) comprises administering: 1500 mg of durvalumab every 4 weeks; and 300 mg of olaparib twice daily.

[0151] Embodiment 32. The method according to any one of embodiments 2 to 24, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks.

[0152] Embodiment 33. The method according to any one of embodiments 2 to 24 or 32, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks.

[0153] Embodiment 34. The method according to any one of embodiments 2 to 24 or 32-33, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for at least 12 weeks.

[0154] Embodiment 35. The method according to embodiment 34, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for up to 24 months.

[0155] Embodiment 36. The method of any one of embodiments 2 to 24 or 32-35, wherein step (b) comprises administering 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0156] Embodiment 37. The method of embodiment 36, wherein step (b) comprises administering 1500 mg of durvalumab.

[0157] Embodiment 38. The method of embodiment 37, wherein step (b) comprises administering 1500 mg of durvalumab every 4 weeks.

[0158] Embodiment 39. The method according to any one of embodiments 1 to 38, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the one or more chemotherapeutic agents are administered intravenously.

[0159] Embodiment 40. The method according to any one of embodiments 1 to 39, wherein the PARP inhibitor is administered orally.

[0160] Embodiment 41. The method according to any one of Embodiments 1-40, wherein the antigen-binding fragment thereof, the anti-PD-L1 antibody or its antigen-binding fragment in step (a), and the one or more chemotherapeutic agents are administered to the subject simultaneously, separately and / or sequentially.

[0161] Embodiment 42. The method according to any one of Embodiments 1 to 42, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the PARP inhibitor in step (b) are administered to the subject simultaneously, separately and / or sequentially.

[0162] Embodiment 43. The method according to any one of embodiments 1 to 42, wherein the endometrial cancer is advanced endometrial cancer.

[0163] Embodiment 44. The method of any one of embodiments 1 to 43, wherein the endometrial cancer is an endometrial cancer tumor deficient in mismatch repair (MMR-deficient (dMMR)).

[0164] Example 45. The method of Example 44, comprising administering to a subject having deficient mismatch repair (dMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0165] Embodiment 46. The method of any one of embodiments 1 to 43, wherein the endometrial cancer is an MMR-proficient (pMMR) endometrial cancer tumor.

[0166] Example 47. The method of Example 46, comprising administering to a subject having perfect mismatch repair (pMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0167] 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.

[0168] 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.

[0169] Embodiment 50. The method of any one of embodiments 1 to 49, wherein the treatment results in an increase in progression-free survival in the subject compared to patients receiving durvalumab and chemotherapy alone.

[0170] Embodiment 51. The method according to embodiment 50, wherein the treatment results in an increase in progression-free survival of at least 4 months.

[0171] Embodiment 52. The method of any one of embodiments 1 to 51, wherein the treatment results in increased overall survival of the subject compared to patients receiving durvalumab and chemotherapy alone.

[0172] Embodiment 53. The method according to embodiment 52, wherein the treatment results in an increase in overall survival of at least 4 months.

[0173] Embodiment 54. A combination for use in treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0174] Embodiment 55. A combination for use in treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0175] Embodiment 56. The combination for use according to embodiment 54 or embodiment 55, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab.

[0176] Embodiment 57. The combination for use according to any one of embodiments 54 to 56, wherein the PARP inhibitor is olaparib.

[0177] Embodiment 58. The combination for use according to any one of embodiments 54 to 57, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 800 mg to 1500 mg.

[0178] Embodiment 59. The combination for use according to embodiment 58, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 1120 mg and / or 1500 mg.

[0179] Embodiment 60. The combination for use according to any one of embodiments 54 to 59, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 10 mg / kg to 20 mg / kg.

[0180] Embodiment 61. The combination for use according to Embodiment 60, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 15 mg / kg and / or 20 mg / kg.

[0181] Embodiment 62. The 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.

[0182] Embodiment 63. The combination for use according to embodiment 62, wherein the dose of the PARP inhibitor is 300 mg.

[0183] Embodiment 64. The combination for use according to any one of embodiments 54 to 63, wherein the one or more chemotherapeutic agents is paclitaxel and / or carboplatin.

[0184] Embodiment 65. The combination for use according to embodiment 64, wherein the dose of paclitaxel is 175 mg / m2.

[0185] Embodiment 66. The combination for use according to embodiment 64 or embodiment 65, wherein the dose of carboplatin produces an area under the curve (AUC) of 5 or AUC6.

[0186] Embodiment 67. The combination for use according to any one of Embodiments 54 to 66, wherein (a) comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof and the one or more chemotherapeutic agents every two to four weeks.

[0187] Embodiment 68. The combination for use according to embodiment 67, wherein the administration is every two to four weeks for nine to twenty four weeks.

[0188] Embodiment 69. The combination for use according to embodiment 67 or embodiment 68, wherein the administration is every three weeks or every four weeks.

[0189] Embodiment 70. The combination for use according to embodiment 69, wherein the administration is every three weeks for twelve to eighteen weeks.

[0190] Embodiment 71. The combination for use according to embodiment 70, wherein the administration is every three weeks for eighteen weeks.

[0191] Embodiment 72. The combination for use according to any one of Embodiments 54 to 71, wherein (a) comprises administering three to six doses of the anti-PD-L1 antibody or antigen-binding fragment thereof and four to six doses of the one or more chemotherapeutic agents.

[0192] Embodiment 73. The combination for use according to any one of Embodiments 54 to 72, wherein (a) comprises administering a dose of 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0193] Embodiment 74. The combination for use according to embodiment 73, wherein the durvalumab is administered at a dose of 1120 mg.

[0194] Embodiment 75. The combination for use according to embodiment 73 or embodiment 74, wherein the durvalumab is administered at a dose of 1120 mg every 3 weeks.

[0195] Embodiment 76. The combination for use according to any one of embodiments 73 to 75, wherein (a) further comprises: 175 mg / m2 of paclitaxel; AUC5 or AUC6 of carboplatin; and / or 25 mg / m2 of cisplatin.

[0196] Embodiment 77. The combination for use according to any one of Embodiments 54 to 76, wherein (b) comprises: the anti-PD-L1 antibody or antigen-binding fragment thereof administered every two to four weeks; and the PARP inhibitor administered twice daily.

[0197] Embodiment 78. The combination for use according to any one of Embodiments 54 to 77, wherein (b) comprises: the anti-PD-L1 antibody or antigen-binding fragment thereof administered every four weeks; and the PARP inhibitor administered twice daily.

[0198] Embodiment 79. The combination for use according to any one of Embodiments 54 to 78, wherein (b) comprises administering: a dose of 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and a dose of 300 mg of the PARP inhibitor.

[0199] Embodiment 80. The combination for use according to Embodiment 77, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for at least 12 weeks, and administering a dose of the PARP inhibitor twice a day for at least 12 weeks.

[0200] Embodiment 81. The combination for use according to Embodiment 79, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for up to 24 months, and administering a dose of the PARP inhibitor twice daily for up to 24 months.

[0201] Embodiment 82. The combination for use according to Embodiment 79, wherein (b) comprises administering: durvalumab at a dose of 1500 mg; and olaparib at a dose of 300 mg.

[0202] Embodiment 83. The combination for use according to any one of embodiments 79 to 81, wherein (b) comprises administering: durvalumab at a dose of 1500 mg every 3 weeks; and olaparib at a dose of 300 mg twice daily.

[0203] Embodiment 84. The combination for use according to any one of Embodiments 55 to 76, wherein (b) comprises the anti-PD-L1 antibody or antigen-binding fragment thereof administered every two to four weeks.

[0204] Embodiment 85. The combination for use according to any one of Embodiments 55 to 76 or 84, wherein (b) comprises the anti-PD-L1 antibody or antigen-binding fragment thereof administered every four weeks.

[0205] Embodiment 86. The combination for use according to any one of embodiments 55 to 76 or 84-85, wherein (b) comprises administering a dose of 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0206] Embodiment 87. The combination for use according to Embodiment 85, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for at least 12 weeks.

[0207] Embodiment 88. The combination for use according to Embodiment 87, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for up to 24 months.

[0208] Embodiment 89. The combination for use according to Embodiment 86, wherein (b) comprises administering a dose of 1500 mg of durvalumab.

[0209] Embodiment 90. The combination for use according to any one of embodiments 84 to 89, wherein (b) comprises administration of durvalumab at a dose of 1500 mg every 3 weeks.

[0210] Embodiment 91. The combination for use according to any one of embodiments 54 to 90, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the one or more chemotherapeutic agents are administered intravenously.

[0211] Embodiment 92. The combination for use according to any one of embodiments 54 to 91, wherein the PARP inhibitor is administered orally.

[0212] Embodiment 93. The combination for use according to any one of Embodiments 54 to 92, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the one or more chemotherapeutic agents in (a) are administered to the subject simultaneously, separately and / or sequentially.

[0213] Embodiment 94. The combination for use according to any one of Embodiments 54 to 93, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the PARP inhibitor in (b) are administered to the subject simultaneously, separately and / or sequentially.

[0214] Embodiment 95. The combination for use according to any one of embodiments 54 to 94, wherein the endometrial cancer is advanced endometrial cancer.

[0215] Embodiment 96. The combination for use according to any one of embodiments 54 to 95, wherein the endometrial cancer is an endometrial cancer tumor deficient in mismatch repair (dMMR).

[0216] Example 97. A combination for use in treating deficient mismatch repair (dMMR) endometrial cancer in a subject in need thereof according to Example 96, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0217] Embodiment 98. The combination for use according to any one of embodiments 54 to 95, wherein the endometrial cancer is an MMR-proficient (pMMR) endometrial cancer tumor.

[0218] Example 99. A combination for use in treating perfect mismatch repair (pMMR) endometrial cancer in a subject in need thereof according to Example 98, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0219] Embodiment 100. The combination for use according to any one of Embodiments 54 to 99, wherein the endometrial cancer is a PD-L1 positive endometrial cancer tumor.

[0220] Embodiment 101. The combination for use according to any one of Embodiments 54 to 99, wherein the endometrial cancer is a PD-L1 negative endometrial cancer tumor.

[0221] Embodiment 102. The combination for use according to any one of embodiments 54 to 101, wherein treatment with the combination results in an increase in progression-free survival of the subject compared to patients receiving durvalumab and chemotherapy alone.

[0222] Embodiment 103. The combination for use according to embodiment 102, wherein said treatment results in an increase in progression-free survival of at least 4 months.

[0223] Embodiment 104. The combination for use according to any one of embodiments 54 to 101, wherein the subject's overall survival is increased by the combination compared to patients receiving durvalumab and chemotherapy alone.

[0224] Embodiment 105. The combination for use according to embodiment 104, wherein the treatment results in an increase in overall survival of at least 4 months.

[0225] Embodiment 106. Use of a combination in the manufacture of a medicament for treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0226] Embodiment 107. Use of a combination in the manufacture of a medicament for treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0227] Embodiment 108. The use according to Embodiment 106 or Embodiment 107, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab.

[0228] Embodiment 109. The use according to any one of embodiments 106 to 108, wherein the PARP inhibitor is olaparib.

[0229] Embodiment 110. The use according to any one of embodiments 106 to 109, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 800 mg to 1500 mg.

[0230] Embodiment 111. The use according to Embodiment 110, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 1120 mg and / or 1500 mg.

[0231] Embodiment 112. The use according to any one of Embodiments 106 to 111, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 10 mg / kg to 20 mg / kg.

[0232] Embodiment 113. The use according to Embodiment 112, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 15 mg / kg and / or 20 mg / kg.

[0233] 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.

[0234] Embodiment 115. The use according to embodiment 114, wherein the dosage of the PARP inhibitor is 300 mg.

[0235] Embodiment 116. The use according to any one of embodiments 114 to 115, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

[0236] Embodiment 117. The use according to embodiment 116, wherein the dose of paclitaxel is 175 mg / m2.

[0237] Embodiment 118. The use according to embodiment 116 or embodiment 117, wherein the dose of carboplatin produces an area under the curve (AUC) of 5 or AUC6.

[0238] Embodiment 119. The use according to any one of Embodiments 106 to 118, wherein (a) comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof and the one or more chemotherapeutic agents every two to four weeks.

[0239] Embodiment 120. The use according to embodiment 119, wherein the administration is every two to four weeks for nine to twenty four weeks.

[0240] Embodiment 121. The use according to embodiment 119 or embodiment 120, wherein the administration is every three weeks or every four weeks.

[0241] Embodiment 122. The use according to embodiment 121, wherein the administration is every three weeks for twelve to eighteen weeks.

[0242] Embodiment 123. The use according to embodiment 122, wherein the administration is every three weeks for eighteen weeks.

[0243] Embodiment 124. The use according to any one of Embodiments 106 to 123, wherein (a) comprises administering three to six doses of the anti-PD-L1 antibody or antigen-binding fragment thereof and four to six doses of the one or more chemotherapeutic agents.

[0244] Embodiment 125. The use according to any one of Embodiments 106 to 124, wherein (a) comprises administering a dose of 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0245] Embodiment 126. The use according to Embodiment 125, wherein the durvalumab is administered at a dose of 1120 mg.

[0246] Embodiment 127. The use according to Embodiment 125 or Embodiment 126, wherein the durvalumab is administered at a dose of 1120 mg every 3 weeks.

[0247] Embodiment 128. The use according to any one of embodiments 125 to 127, wherein (a) further comprises: 175 mg / m2 of paclitaxel; AUC5 or AUC6 of carboplatin; and / or 25 mg / m2 of cisplatin.

[0248] Embodiment 129. The use according to any one of Embodiments 106 to 128, wherein (b) comprises: the anti-PD-L1 antibody or antigen-binding fragment thereof administered every two to four weeks; and the PARP inhibitor administered twice a day.

[0249] Embodiment 130. The use according to any one of Embodiments 106 to 129, wherein (b) comprises: the anti-PD-L1 antibody or antigen-binding fragment thereof administered every four weeks; and the PARP inhibitor administered twice daily.

[0250] Embodiment 131. The use according to any one of Embodiments 106 to 130, wherein (b) comprises administering: a dose of 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and a dose of 300 mg of the PARP inhibitor.

[0251] Embodiment 132. The use according to Embodiment 131, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and administering a dose of the PARP inhibitor twice a day for at least 12 weeks.

[0252] Embodiment 133. The use according to Embodiment 131, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and administering a dose of the PARP inhibitor twice a day for up to 24 months.

[0253] Embodiment 134. The use according to Embodiment 131, wherein (b) comprises administering: durvalumab at a dose of 1500 mg; and olaparib at a dose of 300 mg.

[0254] Embodiment 135. The use according to any one of embodiments 131 to 134, wherein (b) comprises administering: durvalumab at a dose of 1500 mg every 3 weeks; and olaparib at a dose of 300 mg twice daily.

[0255] Embodiment 136. The use according to any one of Embodiments 107 to 128, wherein (b) comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks.

[0256] Embodiment 137. The use according to any one of Embodiments 107 to 128 or 136, wherein (b) comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks.

[0257] Embodiment 138. The use according to any one of Embodiments 106 to 128 or 136 to 137, wherein (b) comprises administering a dose of 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0258] Embodiment 139. The use according to Embodiment 137, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and administering a dose of the PARP inhibitor twice a day for at least 12 weeks.

[0259] Embodiment 140. The use according to Embodiment 137, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every four weeks for up to 24 months.

[0260] Embodiment 141. The use according to Embodiment 137, wherein (b) comprises administering a dose of 1500 mg of durvalumab.

[0261] Embodiment 142. The use according to any one of embodiments 137 to 141, wherein (b) comprises administering a dose of 1500 mg of durvalumab every 3 weeks.

[0262] Embodiment 143. The use according to any one of Embodiments 106 to 142, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the one or more chemotherapeutic agents are administered intravenously.

[0263] Embodiment 144. The use according to any one of embodiments 106 to 143, wherein the PARP inhibitor is administered orally.

[0264] Embodiment 145. The use according to any one of Embodiments 106 to 144, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the one or more chemotherapeutic agents in (a) are administered to the subject simultaneously, separately and / or sequentially.

[0265] Embodiment 146. The use according to any one of Embodiments 106 to 145, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof and the PARP inhibitor in (b) are administered to the subject simultaneously, separately and / or sequentially.

[0266] Embodiment 147. The use according to any one of embodiments 106 to 146, wherein the endometrial cancer is advanced endometrial cancer.

[0267] Embodiment 148. The use according to any one of embodiments 106 to 147, wherein the endometrial cancer is an endometrial cancer tumor deficient in mismatch repair (dMMR).

[0268] Embodiment 149. Use according to Embodiment 148 in the manufacture of a medicament for treating deficient mismatch repair (dMMR) endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0269] Embodiment 150. The use according to any one of embodiments 106 to 147, wherein the endometrial cancer is an MMR-proficient (pMMR) endometrial cancer tumor.

[0270] Embodiment 151. Use according to Embodiment 150 in the manufacture of a medicament for treating perfect mismatch repair (pMMR) endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0271] 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.

[0272] 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.

[0273] Embodiment 154. The use according to any one of embodiments 106 to 153, wherein treatment with the combination results in an increase in progression-free survival of the subject compared to patients receiving durvalumab and chemotherapy alone.

[0274] Embodiment 155. The use according to Embodiment 154, wherein the treatment results in an increase in progression-free survival of at least 4 months.

[0275] Embodiment 156. The use according to any one of embodiments 106 to 153, wherein treatment with the combination results in increased overall survival of the subject compared to patients receiving durvalumab and chemotherapy alone.

[0276] Embodiment 157. The use according to Embodiment 156, wherein the treatment results in an increase in overall survival of at least 4 months.

[0277] Examples

[0278] 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 in any way as limiting the scope of the present disclosure.

[0279] Example 1: Durvalumab with or without olaparib as maintenance therapy after first-line treatment for advanced and recurrent endometrial cancer (DUO-E)

[0280] A phase III study evaluated the efficacy and safety of durvalumab in combination with platinum-based chemotherapy (paclitaxel + carboplatin) followed by maintenance durvalumab with or without olaparib in patients newly diagnosed with advanced or recurrent endometrial cancer.

[0281] Overall Design

[0282] This is a randomized, double-blind, placebo-controlled, multicenter Phase III study to evaluate the efficacy, safety, and patient-reported outcomes of durvalumab in combination with platinum-based chemotherapy (carboplatin and paclitaxel) followed by maintenance durvalumab with or without olaparib in patients with advanced or recurrent endometrial cancer compared with platinum-based chemotherapy. AstraZeneca believes that the endometrial cancer patient population included in this study falls within the definition of advanced cancer, limited life expectancy as outlined in the ICH S9 guideline “Non-clinical Evaluation For Anticancer Pharmaceuticals” and meets the requirements outlined in the guideline. The primary endpoint of this study will be progression-free survival (per RECIST 1.1, using investigator assessment of scans). Secondary endpoints will include OS, PFS2, ORR, DoR, TFST, TSST, and TDT. For a review of the study design, see Figure 2 .

[0283] The study will include 3 groups:

[0284] Table 1 Study treatments

[0285]

[0286] Abbreviations: IV = intravenous; Q3W = every 3 weeks; Q4W = every 4 weeks.

[0287] Patients will be stratified based on MMR expression status (proficient vs. deficient), disease status (relapsed vs. newly diagnosed), and geographic region (Asia vs. rest of the world [RoW]). Patients will provide tumor samples at screening to determine MMR status for stratification.

[0288] As part of global recruitment, approximately 699 patients will be randomized in a 1:1:1 ratio to the study treatments specified below (N=233 patients per group). If necessary, after the end of global recruitment (i.e., the last subject is randomized from a non-China site), recruitment will continue in China to include a Chinese cohort of approximately 129 patients from Chinese sites who are randomized in a 1:1:1 ratio. Prior to the end of global recruitment, any randomized patients from China will be included in the global cohort.

[0289] Group A(Control): Platinum-based chemotherapy (paclitaxel and carboplatin) and 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 will receive durvalumab placebo (IV) and olaparib placebo (tablets) during the maintenance phase.

[0290] Group C (Durvalumab + Olaparib): Platinum-based chemotherapy (paclitaxel and carboplatin) and durvalumab (IV) in the chemotherapy phase. Patients who achieve and maintain disease control (i.e., CR, PR, or SD) in the chemotherapy phase will receive durvalumab (IV) and olaparib (tablets) in the maintenance phase.

[0291] Patients will be randomized and start treatment on Day 1. The randomization schedule will be stratified according to:

[0292] Mismatch Repair (MMR) Status of Tumor Tissue: Patients with MMR-deficient tumors versus patients with proficient tumors. Tumor MMR status will be determined prior to randomization based on evaluation of MMR status in tumor cells from formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples using the Ventana immunohistochemistry (IHC) MMR panel.

[0293] Disease status : Patients with recurrent disease versus those with newly diagnosed disease. This study will enroll patients newly diagnosed with stage III / IV and recurrent endometrial cancer. In general, recurrent disease has a lower response rate to treatment and a poorer prognosis than newly diagnosed cancer. In addition, patients with recurrent cancer may have unresolved toxicities from prior anticancer therapy and have more comorbidities due to longer disease duration, which makes them more frail than newly diagnosed patients. Because of these differences, randomization will incorporate disease status as a stratification factor.

[0294] Stratification by MMR status.Mismatch repair deficiency, known as MMR loss / deficiency, has been observed in a variety of tumor types. In advanced endometrial cancer, approximately 15% of patients have MMR deficiency. Several institutions in the United States have begun testing all patients with a histologically confirmed diagnosis of endometrial cancer for MMR or MSI (universal tumor testing). MMR deficiency can be detected by IHC staining, typically for loss of expression of any of the 4 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 as determined by IHC indicates the possibility of a germline mutation in the corresponding MMR gene. Patients with such pathogenic germline MMR mutations have Lynch Syndrome. The NCCN guidelines recommend screening all patients with endometrial cancer for MMR deficiency to identify individuals at risk for Lynch syndrome. As described in the previous section, preliminary data suggest that agents targeting the PD-1 pathway produce significant clinical responses in patients with endometrial cancer who have MMR-deficient and, to a lesser extent, MMR-proficient tumors, thus providing a rationale for stratification based on MMR status.

[0295] Treatment and duration of treatment

[0296] Patients should receive platinum-based chemotherapy and durvalumab / placebo in the first 6 cycles (at least 4 cycles). Patients without evidence of PD (according to RECIST 1.1) will receive durvalumab / placebo and olaparib / placebo in the maintenance phase.

[0297] Group A (Control): During the chemotherapy phase, patients will receive platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks (Q3W) for up to 6 cycles, and durvalumab placebo (intravenous [IV]) Q3W. After the chemotherapy phase, patients without objective disease progression will receive durvalumab placebo (IV) every 4 weeks (Q4W) and olaparib placebo (tablets) twice daily (bd) during the maintenance phase until disease progression.

[0298] Group B (Durvalumab + Placebo): During the chemotherapy phase, patients will receive platinum-based chemotherapy (paclitaxel and carboplatin) Q3W for up to 6 cycles, and 1120mg of durvalumab (IV) Q3W. After the chemotherapy phase, patients without objective disease progression will receive 1500mg of durvalumab (IV) Q4W and olaparib placebo (tablets) bd in the maintenance phase until disease progression.

[0299] Group C(Durvalumab + Olaparib): In the chemotherapy phase, patients will receive platinum-based chemotherapy (paclitaxel and carboplatin) Q3W for up to 6 cycles, and 1120mg of durvalumab (IV) Q3W. After the end of chemotherapy, patients without objective disease progression will receive 1500mg of durvalumab (IV) Q4W and 300mg oral olaparib (tablets) bd in the maintenance phase until disease progression.

[0300] Patients should continue to receive study treatment until radiographic disease progression occurs according to RECIST 1.1, as assessed by the investigator (see Appendix G), unless there is unacceptable toxicity, consent is withdrawn, or another stopping criterion is confirmed. Figure 2 In summary.

[0301] Objectives and End Points Objectives and relevant end points are presented in Table 2 .

[0302] Table 2 Study objectives and endpoints

[0303]

[0304] Table 2 Study objectives and endpoints

[0305]

[0306] Table 2 Study objectives and endpoints

[0307]

[0308] a These endpoints may be reported separately in clinical study reports.

[0309] Efficacy Assessment and Analysis

[0310] CT and MRI scan tumor assessment (RECIST1.1)

[0311] Efficacy assessments will be based on investigator evaluation (by AstraZeneca) using RECIST 1.1. Details of RECIST 1.1 (Eisenhauer et al. 2009) are provided in Appendix G. Assessments will be by CT or MRI scans of the chest, abdomen, and pelvis. The use of positron emission tomography (PET) is described in Appendix G. Tumor burden must be assessed using the same method at baseline and at each subsequent follow-up assessment. Any other areas of disease involvement should also be imaged additionally based on the individual patient's signs and symptoms.

[0312] Radiological examinations performed during this study should be retained at the site as source data. Anonymous copies of scans will be collected from all patients and sent to the CRO designated by AstraZeneca; the scans will be evaluated for BICR.

[0313] All treatment decisions will be based on the site's review of scans. After the primary PFS analysis, central review of scans will no longer be required, and investigators will be notified when copies of scans no longer need to be shared with the CRO performing central review. However, sites should continue to perform RECIST 1.1 tumor assessments until radiographic progression and should document RECIST assessments in the eCRF.

[0314] It is important to follow the assessment schedule as closely as possible; scans are timed relative to the randomization date and are independent of any dosing delays. If a scan is performed outside of the scheduled access window and the patient has not progressed, every effort should be made to obtain a follow-up scan at their scheduled time point. Patients will be evaluated until objective radiographic disease progression as determined by RECIST 1.1 and then followed for second progression and survival, regardless of whether study treatment was discontinued or delayed and / or if a protocol violation occurred, unless the patient withdraws consent.

[0315] Tumor evaluation

[0316] The patient's response to treatment will be assessed using the RECIST 1.1 criteria by determining PFS time and ORR. The RECIST 1.1 guidelines defining measurable, non-measurable, target lesions (TL), and non-target lesions (NTL) as well as objective tumor response criteria are presented in Appendix G. The classification of overall response will be based on the assessment of TL, NTL, and new lesions.

[0317] For patients with TL at baseline, progression will be calculated by comparison with the time of minimal tumor burden (ie, the sum of the smallest diameters recorded in the previous study, nadir). Tumor response (CR, PR, SD) will be calculated by comparison with baseline tumor measurements obtained before randomization.

[0318] For patients with no evidence of disease (NED) at baseline (ie, TL and NTL not applicable [NA]), the RECIST 1.1 outcome at follow-up after complete resection following surgery was NED or PD. Progression was defined by detection of new lesions on follow-up radiographic assessment (RECIST 1.1).

[0319] For patients with non-measurable disease at baseline, classification of objective tumor response assessment will be based on RECIST 1.1 response criteria: CR, PD, and non-CR / non-PD.

[0320] In the absence of clinical progression or if the investigator is unsure whether progression has occurred, particularly in the case of response to NTL or appearance of new lesions, it is recommended to continue randomized treatment and treatment assessment until the next scheduled scan or earlier (if clinically indicated) and reassess the patient's status with a new scan. If a repeat scan confirms progression, the date of the initial scan should be declared the date of progression.

[0321] To achieve 'definitive progression' on the basis of NTLs, the overall level of NTLs must have worsened so severely that the overall tumor burden has increased enough to warrant stopping therapy even in the presence of SD or PR in TLs. A modest 'increase' in the size of one or more NTLs is generally insufficient to demonstrate a definitive progression status.

[0322] Scan center read

[0323] All scans used to assess tumors will be reviewed independently according to RECIST 1.1. All imaging assessments, including non-scheduled visit scans, will be collected on an ongoing basis and sent to a CRO designated by AstraZeneca for central analysis. The results of this independent review will not be communicated to the investigator, and patient management will be based solely on the results of the RECIST 1.1 assessment performed by the investigator.

[0324] Subgroup analysis

[0325] Subgroup analyses will be performed by comparing PFS (according to RECIST 1.1, using investigator assessment) in the durvalumab + placebo group versus control and the durvalumab + olaparib group versus control to assess consistency of treatment effects for potential or expected prognostic factors, including (but not limited to) the following subgroups of FAS:

[0326] MMR status (complete vs. defective)

[0327] Disease status (recurrent vs. newly diagnosed)

[0328] Region (Asia vs. RoW).

[0329] Other baseline variables, including biomarkers, may also be assessed if clinical justification exists or imbalance is observed between treatment groups.

[0330] No adjustment was made to the significance levels for subgroup testing and sensitivity analyses, as all of these analyses were considered to support the PFS analysis.

[0331] Overall survival

[0332] The stratified log-rank test will be used to analyze OS using the same method as described for the primary PFS endpoint. The same stratification factors will be used as the primary PFS analysis. If the number of deaths is too small to be meaningfully analyzed (less than 5 deaths per layer), a pre-specified strategy will be applied to explain this situation. Additional details will be recorded in SAP. The effect of durvalumab + placebo relative to the control will be estimated by HR and its corresponding CI and p value. Repeat this operation to compare durvalumab + olaparib relative to the control.

[0333] KM plots of OS will be provided by treatment group for each comparison (durvalumab + placebo vs. control and durvalumab + olaparib vs. control).

[0334] A summary of the number and percentage of patients who have died, remain in survival follow-up, were lost to follow-up, and withdrew consent will be provided, as well as the median OS for each treatment.

[0335] Dosage and Study Treatment

[0336] Study treatment was defined as any one or more investigational products and one or more non-investigational products (including commercially available comparator products and placebo) or one or more medical devices intended to be administered to study participants according to the study protocol. Study treatments in this study were chemotherapy, durvalumab / placebo, and olaparib / placebo. Study treatments are summarized in Table 1.

[0337] Patients should receive platinum-based chemotherapy and durvalumab / placebo in the first 6 cycles (at least 4 cycles). Patients without evidence of PD (according to RECIST 1.1) will receive durvalumab / placebo and olaparib / placebo in the maintenance phase.

[0338] During chemotherapy , intravenous study treatments should ideally be administered on the same day in the following order:

[0339] Durvalumab / Placebo: The 1120 mg (Q3W) dose of Durvalumab should be administered over 1 hour, however if interruptions occur during the infusion, the total infusion time at room temperature should not exceed 8 hours.

[0340] Paclitaxel: 175 mg / m2 over 3 hours by IV infusion.

[0341] Carboplatin: By IV infusion, AUC5 or AUC6 within 1 hour (or according to local practice).

[0342] Durvalumab

[0343] For ease of use and convenience for researchers and patients, durvalumab will be administered Q3W during the chemotherapy phase to coincide with the treatment intervals of platinum-based chemotherapy and will use a fixed dose of 1120 mg (based on an average body weight of 75 kg, this is equivalent to a weight-based dose of 15 mg / kg Q3W).

[0344] Population PK analysis indicated that body weight had little effect on the PK of durvalumab, and subsequent modeling showed that body weight-based and fixed dosing regimens produced similar median steady-state PK concentrations. Based on a median body weight of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg / kg Q4W) is currently administered in many clinical studies of various tumor types. The National Cancer Institute (NCI) study ESR 14-10366 (hereinafter referred to as the "NCI study"; Lee et al. 2017) convincingly supports durvalumab 1500 mg Q4W dosing. This dosing regimen is equivalent to a fixed dose of 1120 mg Q3W and was selected for the maintenance phase of this study to be consistent with other studies.

[0345] The 2 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 10 mg / kg Q2W, as recommended in the label.

[0346] Please note that if the patient's body weight drops to or 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 investigator and the study physician, until the body weight increases to above 30 kg (>30 kg), at which time the patient should start receiving a fixed dose of 1500 mg Q4W durvalumab.

[0347] Olaparib

[0348] Olaparib will be administered at the dose approved for ovarian and breast cancer, which is 300 mg bd. Dose reductions will be permitted, according to the prescribing information.

[0349] Durvalumab and olaparib combination

[0350] Durvalumab and olaparib have been administered in combination in a range of indications, including ovarian cancer, breast cancer, SCLC, and gastric cancer (MEDIOLA; NCT02734004). The NCI study convincingly supported the safety and tolerability of olaparib 300 mg bid in combination with durvalumab 1500 mg Q4W (Lee et al. 2017).

[0351] Table 3 Study treatment under study

[0352]

[0353] Table 3 Study treatment under study

[0354]

[0355] Table 3 Study treatment under study

[0356]

[0357] Abbreviations: bd = twice daily; GMP = good manufacturing practice; HDPE = high-density polyethylene; IP = investigational product; IV = intravenous; IWRS = interactive web response system; Q3W = every 3 weeks; Q4W = every 4 weeks; w / v = weight / volume.

[0358] Chemotherapeutic agents

[0359] The chemotherapy agents (paclitaxel and carboplatin) will be sourced locally or, in some cases, when local procurement is not feasible, AstraZeneca will centrally supply the medicine and label it in the local language in accordance with regulatory guidance. In the EU, carboplatin and paclitaxel are considered adjuvant medical products under the EU Clinical Trials Guidance (EU Guidance 2017).

[0360] Chemotherapy is a “non-study drug” because it is a SoC recommended in international guidelines. Chemotherapy will be administered according to the recommendations for this treatment combination in international guidelines (NCCN Uterine Neoplasms 2019).

[0361] 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 given. Chemotherapy is administered as follows:

[0362] Carboplatin (AUC5 or AUC6) Q3W (note: patients who have received pelvic radiotherapy previously may consider reducing the dose to AUC5)

[0363] Paclitaxel 175 mg / m2 Q3W.

[0364] Each chemotherapy agent will be administered according to local guidelines, and premedication may be provided.

[0365] For carboplatin dosing recommendations, please refer to the NCCN Guidelines https: / / www.nccn.org / professionals / OrderTemplates / PDF / appendix_B.pdf. According to the NCCN Guidelines, in order to avoid overestimation of CrCL and subsequent overestimation of carboplatin dose, a minimum value of 0.7 mg / dL (equivalent to 62 μmol / L) should be used to estimate creatinine clearance in patients with low serum creatinine. The Calvert Formula should be used to calculate the dose of carboplatin as follows:

[0366] Carboplatin dose (mg) = target AUC × (GFR + 25)

[0367] NOTE: It is recommended that the GFR used in the Calvert formula should not exceed 125 mL / min. For the purposes of this protocol, GFR is considered equivalent to estimated creatinine clearance.

[0368] Maximum carboplatin dose (mg) = target AUC (mg / mL × min) × 150 mL / min

[0369] The maximum recommended carboplatin dose is:

[0370] AUC6 = 900 mg

[0371] AUC5 = 750 mg

[0372] If chemotherapy is permanently stopped prematurely (before completion of 4 cycles) due to toxicity or disease progression, all study treatment will be stopped and the patient will not enter the maintenance phase. A study treatment discontinuation visit will be conducted and follow-up will continue unless the patient withdraws consent to continue in the study.

[0373] Patients who develop a hypersensitivity reaction to carboplatin should be managed according to standard clinical practice. Patients may be withdrawn according to local clinical guidelines, including enhanced hypersensitivity prophylaxis or use of a desensitization regimen. If the hypersensitivity reaction prevents further administration of carboplatin, the patient may be considered for cisplatin substitution, provided this is in line with standard clinical practice at the site and only if chemotherapy is sourced locally. The use of cisplatin substitutions should be discussed with the AstraZeneca study physician prior to implementation.

[0374] 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 withdrawn according to local clinical guidelines. In the setting of recurrent hypersensitivity reactions despite adequate premedication that prevents further administration of paclitaxel, investigators may consider omitting paclitaxel from the chemotherapy regimen or substituting it with another taxane (nab-paclitaxel or docetaxel) provided that this is in accordance with standard clinical practice at the site and only if the chemotherapy is of local origin.

[0375] 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 guidelines. If paclitaxel needs to be permanently discontinued due to persistent severe peripheral neuropathy, docetaxel may be considered for the patient, provided this is in accordance with standard clinical practice at the site and only if the chemotherapy is of local origin.

[0376] Example 2: Durvalumab plus olaparib for newly diagnosed advanced or recurrent endometrial cancer

[0377] method

[0378] Trial Design and Patients

[0379] DUO-E was a randomized, double-blind, placebo-controlled, multicenter, phase III trial conducted in 22 countries. Eligible patients were ≥18 years of age with newly diagnosed advanced (International Federation of Gynecology and Obstetrics [FIGO] stage III / IV) or recurrent endometrial cancer (excluding sarcomas) of epithelial histology and had not received first-line systemic anticancer therapy. For patients with recurrent disease, prior chemotherapy was allowed if it had been administered in the adjuvant setting and there was a time interval of ≥12 months between the last chemotherapy dose and the subsequent relapse. DNA MMR status was determined before randomization (see the Supplementary Appendix). Patients also had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Full inclusion and exclusion criteria are provided in the Supplementary Appendix.

[0380] Randomization and Study Treatment

[0381] Patients were randomly assigned 1:1:1 to three treatment groups using an interactive voice / web response system. Figure 2 ), stratified by MMR expression status (proficient vs deficient), disease status (newly diagnosed vs relapsed), and geographic region (Asia vs rest of the world). Patients with unknown MMR status prior to randomization were not eligible.

[0382] Patients entered the chemotherapy phase and subsequently the maintenance phase, which lasted until radiographic disease progression (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1, investigator-assessed), unacceptable toxicity, withdrawal of consent, or meeting other stopping criteria. Only patients who did not have objective disease progression during the chemotherapy phase and met other eligibility requirements (see full eligibility criteria below) were allowed to start maintenance therapy.

[0383] Patients received platinum-based chemotherapy (carboplatin with an area under the curve of 5 or 6 and 175 mg / m2 intravenously every 3 weeks) 2 paclitaxel) plus placebo for 6 cycles, followed by maintenance placebo intravenously every 4 weeks plus placebo tablets twice daily; platinum-based chemotherapy plus durvalumab 1120 mg intravenously every 3 weeks for 6 cycles, followed by maintenance durvalumab 1500 mg intravenously every 4 weeks plus placebo tablets twice daily; or platinum-based chemotherapy plus durvalumab 1120 mg intravenously every 3 weeks for 6 cycles, followed by maintenance durvalumab 1500 mg intravenously every 4 weeks plus olaparib 300 mg tablets twice daily.

[0384] Determination of DNA mismatch repair (MMR) status

[0385] DNA MMR status was determined prior to randomization via 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).

[0386] According to local regulations, FFPE tumor tissue samples from previously non-irradiated tumor lesions were provided to each patient. FFPE tumor tissue samples could be from local or metastatic sites and could be any of the following:

[0387] Tumor samples obtained from cytoreductive surgery (in patients who have already undergone this surgery)

[0388] Biopsy specimen obtained at diagnosis (if a specimen from cytoreductive surgery is not available)

[0389] • Newly collected tumor samples (if samples are collected as part of routine clinical practice).

[0390] Determination of programmed death ligand-1 (PD-L1) status

[0391] Pretreatment tumor tissue samples were centrally tested after randomization using the VENTANA PD-L1 (SP263) immunohistochemistry assay (Roche Diagnostics). PD-L1 expression was determined using a combined tumor cell and tumor-associated immune cell positive scoring method. The positive tumor area (TAP) score was calculated as the proportion of tumor area occupied by tumor cells and immune cells at any intensity as determined using PD-L1 staining. A sample was considered PD-L1 positive if the TAP score was ≥1%, and PD-L1 negative if the TAP score was <1%.

[0392] Determination of homologous recombination repair mutation (HRRm) status

[0393] Pre-treatment baseline tumor tissue samples were used for homologous recombination repair mutation (HRRm) testing after randomization. HRRm status was centrally assessed using Foundation One CDx NGS assay (Foundation Medicine, Inc., Cambridge, MA). The sample was considered positive if harmful or suspected harmful HRRm was detected in any of the following pre-specified genes associated with HRR: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Negative HRRm status (non-HRRm) is defined as a sample without a pathogenic mutation in any of the pre-specified genes associated with HRR. Unknown HRRm status includes patients recruited in China who were not tested for HRR and patients who withdrew from the consent form or withdrew from the consent form due to sample unavailability.

[0394] Maintenance Phase Eligibility

[0395] Patients received a maximum of 6 cycles of chemotherapy and had to receive a minimum of 4 cycles of platinum-based chemotherapy to continue into the maintenance phase of the study.

[0396] After completion of chemotherapy, the durvalumab / placebo dosing schedule was changed to 1500 mg every 4 weeks. After completion of chemotherapy, patients also received maintenance olaparib / placebo (maintenance therapy started a minimum of 3 weeks and a maximum of 9 weeks after the last day of chemotherapy infusion).

[0397] Subgroup analysis:Prespecified subgroup analyses evaluated progression-free survival with respect to the doublet group versus the control group, the triplet group versus the control group, and the triplet group versus the doublet group according to the following factors: MMR status (perfect versus defective), HRRm status (HRRm versus non-HRRm versus unknown), PD-L1 status (PD-L1-positive, PD-L1-negative, unknown), disease status (relapsed versus newly diagnosed), region (Asia versus rest of the world), age (<65 years versus ≥65 years), race (white versus black / African American versus Asian versus other), histology (endometrioid versus serous versus other), ECOG performance status (0 versus 1), and FIGO stage at initial diagnosis in newly diagnosed patients (III versus IV).

[0398] Efficacy data were summarized and analyzed in the intention-to-treat population (all randomized patients), and safety data were summarized in the safety analysis set (all randomized patients who received at least one dose of study treatment, i.e., durvalumab / placebo or olaparib / placebo); 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.

[0399] The primary progression-free survival analysis was performed separately for each comparison using the stratified log-rank test to generate p values, and the stratified Cox proportional-hazards model was used to estimate the hazard ratio and confidence interval (CI). Kaplan–Meier (KM) plots were presented by treatment group and used to estimate the median survival time and the proportion of patients alive and progression-free at the 6-month interval after randomization. Similar methods were used for the analysis of the secondary time-to-event end points.

[0400] result

[0401] patient

[0402] From June 2, 2020, to April 20, 2022, 718 patients were randomized: 241, 238, and 239 patients were randomly assigned to the control, doublet, and triplet groups, respectively. Of these, 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 any study treatment, and 169 (70.1%), 183 (76.9%), and 192 (80.3%), respectively, started the maintenance phase and received olaparib / placebo ( Figure 6 ).

[0403] Baseline patient characteristics were generally balanced across treatment groups (Table 4) and were representative of patients with newly diagnosed advanced or recurrent endometrial cancer (Table 5). Stratification factors were balanced across treatment groups: 80% of patients in each group had MMR-proficient (pMMR) tumors, approximately 28% were of Asian origin, and approximately 47% had newly diagnosed disease.

[0404] Table 4. Baseline characteristics of patients.

[0405]

[0406]

[0407] Abbreviations: ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; HRRm, homologous recombination repair mutation; MMR, mismatch repair; PD-L1, programmed death-ligand-1; TAP, tumor area.

[0408] a Stratification factors (MMR status [perfect vs. deficient], disease status [newly diagnosed vs. relapsed], and geographic region [Asian vs. non-Asian]) were according to the randomization code.

[0409] b These included China, India, Japan, the Republic of Korea, and Singapore. Two patients from India were incorrectly classified into the Asian subgroup.

[0410] c FIGO period was determined using electronic case report forms. Reported as a percentage of the total number of patients in each group.

[0411] d Pathology-related disease characteristics were collected at the time of primary diagnosis of the disease under investigation.

[0412] e MMR status was assessed using the Ventana MMR RxDx panel (Roche Diagnostics, Rothkleitz, Switzerland).

[0413] fHRRm status was evaluated using Foundation One CDx NGS assay (Foundation Medicine, Cambridge, Massachusetts). Positive HRRm status (HRRm) is defined as a sample with a pathogenic mutation in any of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L. Negative HRRm status (non-HRRm) is defined as a sample without a pathogenic mutation in any of the pre-specified genes. Unknown HRRm status includes patients recruited in China who were not tested for HRR and patients who withdrew consent or withdrew consent due to sample unavailability.

[0414] g PD-L1 expression was assessed using the Ventana SP263 immunohistochemistry assay (Roche Diagnostics). PD-L1 positivity was defined as TAP ≥ 1%. PD-L1 negativity was defined as TAP < 1%. Unknown included patients who withdrew consent or due to sample unavailability.

[0415] h Only 'yes' is reported.

[0416] Table 5. Representativeness of study participants.

[0417]

[0418]

[0419] effect

[0420] The primary analysis of investigator-assessed progression-free survival was performed after 438 of 718 patients in the intention-to-treat population had disease progression or death (data maturity, 61%). The median follow-up for censored patients was 12.6 months (range, 0.0 to 31.6) in the control group, 15.4 months (range, 0.0 to 29.1) in the doublet group, and 15.4 months (range, 0.0 to 31.7) in the triplet group.

[0421] In the intention-to-treat population, the durvalumab group showed a statistically significant 29% reduction in the risk of disease progression or death relative to control (HR, 0.71; 95% CI, 0.57 to 0.89; P = .003; median PFS 10.2 vs 9.6 months) ( Figure 4A; Table 7). The durvalumab + olaparib group showed a statistically significant 45% reduction in the risk of disease progression or death relative to the control (HR, 0.55; 95% CI, 0.43 to 0.69; P < .001; median PFS 15.1 vs 9.6 months) ( Figure 4A ; Table 7). The PFS Kaplan-Meier curves overlapped until approximately 6 months, after which a clear and sustained separation occurred in favor of both study treatment groups compared with the control group ( Figure 4A ). This delayed separation is expected to be due to the known delayed treatment effect of durvalumab and the fact that olaparib maintenance therapy was started only after chemotherapy was completed. The delay in the separation of the curves indicates disproportionality (P = .018 and P = .03 for durvalumab relative to control and durvalumab + olaparib relative to control, respectively). In the presence of non-proportional hazards, the overall PFS HR should be interpreted as the average estimate of the observed benefit. The ratios and median PFS values ​​at specific time points are shown in Table 7.

[0422] In an exploratory analysis of investigator-assessed progression-free survival in the triplet group versus the doublet group, the hazard ratio for disease progression or death was 0.78 (95% CI, 0.61 to 0.99; P=0.045).

[0423] Sensitivity analyses of progression-free survival assessed by blinded independent central review were consistent with investigator-assessed results in the comparisons of the doublet arm versus control (hazard ratio, 0.74; 95% CI, 0.58 to 0.94) and the triplet arm versus control (hazard ratio, 0.55; 95% CI, 0.42 to 0.70). Figure 6 ).

[0424] In a predefined exploratory analysis of investigator-assessed PFS in the durvalumab plus olaparib group versus the durvalumab group, the HR was 0.78 (95% CI, 0.61 to 0.99; median PFS 15.1 versus 10.2 months) ( Table 7 ).

[0425] Exploratory analyses of progression-free survival in predefined subgroups showed a consistent treatment effect, with all observed hazard ratio point estimates favoring the double arm versus control and the triple arm versus control ( Figure 5A -B). Global interaction tests showed that there may be quantitative differences in the treatment effects for the comparison of double recombinants relative to controls according to MMR status and region (Table 6). The analysis by MMR status is reported in Table 7 and Figure 8.

[0426] The first interim analysis for OS was performed at the time of the primary PFS analysis, at which time 199 deaths (28%) had occurred in the intention-to-treat population. The median (range) duration of follow-up for patients censored for OS 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. The HRs for both comparisons favored the study group; however, neither comparison reached statistical significance at the time of the first interim analysis for OS (durvalumab versus control: HR, 0.77, 95% CI, 0.56 to 1.07; P = .120; durvalumab plus olaparib versus control: HR, 0.59, 95% CI, 0.42 to 0.83; P = .003, Figure 4B ).

[0427] In prespecified exploratory subgroup analyses of PFS, all observed HR point estimates favored durvalumab and durvalumab plus olaparib relative to control ( Figure 5A In the dMMR subgroup, the HR for PFS with durvalumab versus control was 0.42 (95% CI, 0.22 to 0.80, median PFS not reached [NR] versus 7.0 months), and the HR for PFS with durvalumab plus olaparib versus control was 0.41 (95% CI, 0.21 to 0.75, median PFS 31.8 versus 7.0 months) ( Table 7 and Fig. 8A In the pMMR subgroup, the HR for PFS with durvalumab versus control was 0.77 (95% CI, 0.60 to 0.97, median PFS 9.9 versus 9.7 months), and the HR for PFS with durvalumab plus olaparib versus control was 0.57 (95% CI, 0.44 to 0.73, median PFS 15.0 versus 9.7 months) ( Table 7 and Figure 8B Comparisons of durvalumab plus olaparib versus durvalumab by MMR status are reported in Table 7. In subgroup analyses by PD-L1 status, in the PD-L1-positive subgroup (defined as positive tumor area [TAP] ≥ 1%), the HR for PFS with durvalumab versus control was 0.63 (95% CI, 0.48 to 0.83), with a median PFS of 11.3 versus 9.5 months, and the HR for PFS with durvalumab plus olaparib versus control was 0.42 (95% CI, 0.31 to 0.57), with a median PFS of 20.8 versus 9.5 months ( Fig. 10AIn the PD-L1-negative subgroup (TAP < 1%), the HR for PFS with durvalumab versus control was 0.89 (95% CI, 0.59 to 1.34), with a median PFS of 9.7 versus 9.9 months, and the HR for PFS with durvalumab plus olaparib versus control was 0.80 (95% CI, 0.55 to 1.16), with a median PFS of 10.1 versus 9.9 months ( Fig. 10B ). Details on the duration of study treatment are provided in Table 8.

[0428] Table 6. Interaction tests based on investigator-assessed progression-free survival (RECIST, version 1.1).

[0429]

[0430]

[0431] MMR stands for mismatch repair; NA stands for not applicable; and RECIST stands for Response Evaluation Criteria in Solid Tumors.

[0432]

[0433]

[0434]

[0435] The phase 3 DUO-E trial showed that for patients newly diagnosed with advanced or recurrent endometrial cancer, durvalumab combined with first-line carboplatin and paclitaxel followed by maintenance durvalumab with or without olaparib resulted in a significantly lower risk of disease progression or death than standard chemotherapy (45% risk reduction with olaparib and 29% risk reduction without olaparib). These data confirm the clinical benefit of combining immunotherapy with or without a PARP inhibitor to first-line chemotherapy for patients newly diagnosed with advanced or recurrent endometrial cancer and are the first to demonstrate further benefit from adding a PARP inhibitor in this setting.

[0436] In prespecified exploratory subgroup analyses of PFS, all observed HR point estimates favored the durvalumab and durvalumab plus olaparib groups relative to control. Analyses by MMR status showed that in the dMMR subgroup, similar clinically meaningful benefits were observed in the durvalumab group relative to control (HR, 0.42; 95% CI, 0.22 to 0.80) and the durvalumab plus olaparib group relative to control (HR, 0.41; 95% CI, 0.21 to 0.75). In the pMMR subgroup, clinically meaningful benefits were observed in the durvalumab group relative to control (HR, 0.77; 95% CI, 0.60 to 0.97), and the addition of maintenance olaparib to durvalumab showed further benefit (HR relative to control, 0.57; 95% CI, 0.44 to 0.73). Prespecified exploratory analyses of durvalumab plus olaparib versus durvalumab showed that the contribution of olaparib was in the pMMR subgroup (HR in the pMMR subgroup, 0.76, 95% CI, 0.59 to 0.99; HR in the dMMR subgroup, 0.97, 95% CI, 0.49 to 1.98). Analysis by PD-L1 status indicated that benefit was observed for both the PD-L1-positive subgroup, which showed a clinically meaningful improvement in PFS (HR for durvalumab relative to control, 0.63 [95% CI, 0.48 to 0.83], and HR for durvalumab plus olaparib relative to control, 0.42 [95% CI, 0.31 to 0.57]), and the PD-L1-negative subgroup, which showed a smaller improvement (HR for durvalumab and durvalumab plus olaparib relative to control, 0.89 [95% CI, 0.59 to 1.34] and 0.80 [95% CI, 0.55 to 1.16], respectively).

[0437] In DUO-E, results from the dual arm showed clinical benefit of the combination of an immune checkpoint inhibitor and standard chemotherapy for newly diagnosed advanced or recurrent endometrial cancer.

[0438] Sensitivity analyses of progression-free survival were consistent with the primary analysis. The first interim analysis of overall survival favored the study group in support of the primary endpoint.

[0439] The safety profiles of the experimental groups were generally consistent with the known profiles of each individual component of the regimen. The provision of standard-of-care treatment was not affected by the provision of any other treatment, and the frequency of chemotherapy discontinuations was similar in all groups.

[0440] For adverse events of special or potential interest related to durvalumab, these events were consistent with the known safety profile of durvalumab in combination with chemotherapy, which was primarily driven by chemotherapy. For adverse events of special interest related to olaparib, events for myelodysplastic syndrome and acute myeloid leukemia were low and consistent with the known safety profile of olaparib.

[0441] The addition of durvalumab to standard first-line platinum-based chemotherapy followed by maintenance 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 combining immunotherapy with or without a PARP inhibitor to first-line chemotherapy in this setting. The addition of olaparib to maintenance durvalumab further enhanced the clinical benefit. The safety profiles in the experimental groups were generally consistent with the known profiles of each individual component of the regimen.

[0442] Lynparza in combination with durvalumab is indicated for the maintenance treatment of adult patients with mismatch repair-proficient (pMMR) primary advanced or recurrent endometrial cancer whose disease has not progressed on first-line treatment with durvalumab in combination with carboplatin and paclitaxel.

[0443] Predefined exploratory subgroup analyses showed that improving PFS with the addition of maintenance olaparib to the combination of durvalumab plus chemotherapy improved outcomes in the pMMR and PD-L1-positive patient population. Although the incidence of grade 3 or higher AEs was higher in the durvalumab plus olaparib group, the safety profile of each group was generally consistent with the known profiles of the individual components of the regimen.

[0444] Example 3: Durvalumab + Carboplatin / Paclitaxel (CP) followed by Durvalumab ± Olaparib as First-line (1L) Treatment for Endometrial Cancer (EC): Progression-Free Survival (PFS) Determined by Clinical Factors in DUO-E

[0445] method

[0446] Patients (pts) newly diagnosed with stage III / IV or recurrent EC were randomized 1:1:1 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 pbo). Post hoc exploratory PFS subgroup analyses by key clinical factors, age (<65 vs. ≥65 years); BMI (<25 vs. ≥25); ECOGPS (0 vs. 1); and prior chemotherapy, surgery, and radiation therapy (yes vs. no) in the ITT and mismatch repair populations were reported.

[0447] result

[0448] At the primary data cutoff date (April 12, 2023), PFS subgroup analyses by age, BMI, ECOGPS, and prior treatment generally showed a benefit of CP+D±O over CP in the ITT population (Table 9). PFS subgroup analyses showed a consistent PFS benefit of CP+D over CP in dMMR pts (HR < 1.00 for all subgroups). In pMMRpts, CP+D generally showed a benefit over CP, and the addition of olaparib consistently improved PFS (HR < 1.00 for CP+D+O over CP for all subgroups).

[0449] Across a range of key clinical factors explored in these analyses, the DUO-E ITT population achieved a PFS benefit with CP+D±O versus CP. In dMMR pts, a consistent PFS benefit of CP+D versus CP was observed across key clinical factors. pMMR pts benefited from CP+D versus CP across a range of key clinical factors, with the addition of olaparib consistently improving PFS in each subgroup category. These DUO-E subgroup analyses support previous PFS analyses of the ITT and dMMR populations (benefit of CP+D versus CP), and the benefit in pMMRpts was enhanced with the addition of olaparib.

[0450] Table 9.

[0451]

[0452]

[0453]

[0454] *Data for 2 pts in CP and CP+D and 1 pt in CP+D+O were missing; Overweight / obesity.

[0455] e, event; n, patient; N, no; Y, yes

[0456] Example 4: First-line (1L) durvalumab + carboplatin / paclitaxel (CP) followed by durvalumab ± olaparib (DUO-E) for endometrial cancer (EC): objective response rate (ORR), duration of response (DoR), and time to treatment discontinuation or death (TDT) by mismatch repair (MMR) status

[0457] method

[0458] PTs newly diagnosed with FIGO stage III (measurable disease before randomization [RECIST 1.1]) or stage IV or recurrent EC who had not received prior systemic 1L therapy were randomized 1:1:1 to CP + durvalumab placebo (pbo; 6 cycles), followed by durvalumab pbo + olaparib pbo (CP group); CP + durvalumab (1120 mg IV q3w), followed by 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 (exploratory) were evaluated in the ITT and MMR populations.

[0459] result

[0460] At the primary data cutoff date (April 12, 2023), ORR was improved by CP+D and CP+D+O relative to CP (62% and 64% vs. 55%); median (m)DoR and mTDT were longer with CP+D relative to CP (mDoR: 13.1 [95% CI 6.0–NR] vs. 7.7 [5.1–13.5] months [mo]; mTDT: 9.9 [8.8–11.2] vs. 8.8 [7.6–9.7] mo) and were further increased with CP+D+O (mDoR: 21.3 [8.1–29.9] mo; mTDT: 15.1 [12.5–18.6] mo; Table 10). In MMR-deficient (dMMR) pts, CP+D and CP+D+O improved ORR (71% and 73% vs. 40%), mDoR (NR and 29.9 [95% CI 9.7–29.9] vs. 10.5 [4.6–NR] mo), and mTDT (21.2 [9.3–NR] and 20.6 [13.4–NR] vs. 6.7 [5.1–7.9] mo) relative to CP. In pMMR pts, ORR was similar in each group, but mDoR and mTDT were longer with CP+D versus CP (mDoR: 10.6 [95% CI 5.6–NR] versus 7.6 [5.1–13.1] mo; mTDT: 9.6 [8.1–10.6] versus 9.3 [8.0–9.9] mo), and further prolonged by CP+D+O (mDoR: 18.7 [8.0–NR] mo; mTDT: 13.4 [10.6–15.6] mo).

[0461] CP+durvalumab followed by durvalumab±olaparib improved ORR, DoR, and TDT relative to CP (ITT population). In dMMRpt, CP+D continuously improved ORR, DoR, and TDT relative to CP. In pMMRpt, CP+D improved mDoR relative to CP, and the addition of olaparib further prolonged mDoR and mTDT relative to CP+D.

[0462] Example 5: Interim analysis of DUO-E results

[0463] Updated DUO-E study design, including endpoints and patients, in Fig.11 Shown in. Six cycles of carboplatin, with an area under the concentration-time curve of 5 or 6 mg / mL / min, and paclitaxel 175 mg / m2. 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 evaluation criteria in solid tumors. Figure 12 shows patient characteristics data. 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 proportion. Percentages may not total 100% due to rounding. Ethnicity data were missing for 6 patients; 1 newly diagnosed patient was FIGO stage I and 1 was FIGO stage II; 1 patient in the CP+D group had an ECOGPS of 2. Stratification factors (MMR status [perfective vs deficient], disease status [newly diagnosed vs relapsed], and geographic region [Asian vs non-Asian]) were based on randomization code. Two patients with MMR status ‘unknown’ were randomized to ‘deficient’ based on a locally tested interactive voice response system, as determined by the central laboratory. ‘Asia’ included China, India, Japan, Singapore, and South Korea; Status was evaluated using the Ventana MMR immunohistochemistry panel; Expression was assessed using the Ventana SP263 assay; §HRRm status was assessed using the Foundation One CDx NGS assay and included deleterious or suspected deleterious 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 who did not undergo HRR testing and patients whose samples could not be tested. ECOGPS, Eastern Cooperative Oncology Group performance status;

[0464] Results for the ITT population are shown in Figure 13. *Best objective response was determined based on data obtained before initiation of any subsequent cancer therapy, up to and including RECIST progression or the last RECIST assessment in the absence of progression. Calculated based on the number of patients with measurable disease at baseline; Odds of remission (complete or partial). Odds ratio > 1 favors CP+D or CP+D+O groups; Time from randomization to start of response; §DoR is the time from first confirmed complete / partial response to date of progression or PFS review date. The rate of patients maintaining response was estimated by the Kaplan–Meier method. IQR, interquartile range; NR, not reached. Secondary endpoints for the ITT population are shown in Figure 14. TFST, PFS2, and TSST rates were estimated by the Kaplan–Meier method. *HR was estimated by Cox proportional hazards model stratified by MMR and disease status variables. CI was calculated using the profile likelihood method.

[0465] Post hoc exploratory analysis of the MMR subgroup is shown in Figure 15. For the dMMR subgroup, the median follow-up duration of OS of the censored patients was 18.4 months (CP), 19.1 months (CP+D), and 19.9 months (CP+D+O); for the pMMR subgroup, the median follow-up duration of the censored patients was 18.6 months (CP), 18.2 months (CP+D), and 18.4 months (CP+D+O). MMR status was evaluated using the Ventana MMR immunohistochemistry panel. OS rates were estimated by the Kaplan-Meier method. *HR and CI were estimated by unstratified Cox proportional hazard models.

[0466] Figure 16 shows a post hoc exploratory analysis of the dMMR subgroup. MMR status was evaluated using the Ventana MMR immunohistochemistry panel. TFST, PFS2, and TSST rates were estimated by the Kaplan-Meier method. *HR and CI were estimated by an unstratified Cox proportional hazard model. Stratification factors (disease status, MMR status, and geographic region) were based on randomization codes. HRRm status was evaluated using Foundation One CDx NGS assays 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 includes patients recruited in China who were not tested for HRR, and patients whose samples could not be tested. The PD-L1 status in baseline tumor tissue was centrally determined using the Ventana SP263 assay. Expression was assessed using the TAP score, which is calculated based on the proportion of tumor area occupied by tumor cells or immune cells as determined using membrane PD-L1 staining. FIGO stage was determined at the time of initial diagnosis of the endometrial cancer studied. G, grade; NC, not calculated. Best objective response was determined based on data obtained before the initiation of any subsequent cancer therapy and up to and including RECIST progression or the last RECIST assessment in the absence of progression. Calculated based on the number of patients with measurable disease at baseline; Odds of remission (complete or partial). Odds ratio > 1 favors CP+D or CP+D+O groups; The time from randomization to the onset of response; §DoR is the time from the first confirmation of complete / partial response to the date of progression or PFS review date. The rate of patients maintaining response was estimated by the Kaplan–Meier method.

[0467] Figure 17 shows a post hoc exploratory analysis of the pMMR subgroup. MMR status was evaluated using the Ventana MMR immunohistochemistry combination. TFST, PFS2 and TSST rates were estimated by the Kaplan-Meier method. *HR and CI were estimated by an unstratified Cox proportional hazard model. Stratification factors (disease status, MMR status and geographic region) were based on the randomization code. HRRm status was evaluated using Foundation One CDx NGS assays, 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 includes patients recruited in China who were not tested for HRR, and patients whose samples could not be tested. The PD-L1 status in baseline tumor tissue was determined centrally using the Ventana SP263 assay. Expression was assessed using the TAP score, which is calculated based on the proportion of tumor area occupied by tumor cells or immune cells, as determined using membrane PD-L1 staining. FIGO stage was determined at the time of initial diagnosis of the endometrial cancer studied. Best objective response was determined based on data obtained before the initiation of any subsequent cancer therapy, up to and including RECIST progression or the last RECIST assessment in the absence of progression. Calculated based on the number of patients with measurable disease at baseline; Odds of remission (complete or partial). Odds ratio > 1 favors CP+D or CP+D+O groups; The time from randomization to the onset of response; §DoR is the time from the first confirmation of complete / partial response to the date of progression or PFS review date. The rate of patients maintaining response was estimated by the Kaplan–Meier method.

[0468] For the MMR subpopulation, the results are shown in Figure 18. MMR status was assessed using the Ventana immunohistochemistry MMR panel. PFS rates were estimated by the Kaplan–Meier method. *CI for median PFS was based on the Brookmeyer–Crowley method; and CIs were estimated by unstratified Cox proportional hazards models. CI, confidence interval; CP, carboplatin / paclitaxel; D, durvalumab; DCO, data cutoff; dMMR, MMR-deficient; HR, hazard ratio; ITT, intention-to-treat; NR, not reached; O, olaparib; PFS, progression-free survival; pMMR, MMR-proficient.

[0469] Finally, Figures 19-20 show additional results from the ITT population and exploratory PFS analyses.

[0470]

[0471] References:

[0472] 1. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase 3trial. Lancet 2019; 394 (10212): 1929-1939. (In eng).DOI:10.1016 / s0140-6736(19)32222-6.

[0473] 2. Johnson ML, Cho BC, Luft A, et al. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study. Journal of Clinical Oncology 2023;41(6):1213-1227.DOI:10.1200 / jco.22.00975.

[0474] 3.Oh DY,Lee KH,Lee DW,et al.Gemcitabine and cisplatin plus durvalumabwith or without tremelimumab in chemotherapy-naive patients with advancedbiliary tract cancer:an open-label,single-centre,phase 2study.LancetGastroenterol Hepatol 2022;7(6):522-532.DOI:10.1016 / S2468-1253(22)00043-7.

[0475] 1.Siegel RL,Miller KD,Fuchs HE,Jemal A.Cancer statistics,2022.CACancer J Clin 2022;72(1):7-33.(In eng).DOI:10.3322 / caac.21708.

[0476] 2.NCCN.NCCN Clinical Practice Guidelines in Oncology(NCCN ).Uterine neoplasms.Version 1.2023.Plymouth Meeting,PA:National ComprehensiveCancerNetwork,2022.

[0477] 3.Aghajanian C,Filiaci V,Dizon DS,et al.A phase II study of frontlinepaclitaxel / carboplatin / bevacizumab,paclitaxel / carboplatin / temsirolimus, orixabepilone / carboplatin / bevacizumab in advanced / recurrent endometrialcancer.Gynecol Oncol 2018;150(2):274-281.DOI:10.1016 / j.ygyno.2018.05.018.

[0478] 4.Miller D,Filiaci V,Fleming G,et al.Late-Breaking Abstract 1:Randomized phase III noninferiority trial of first line chemotherapy formetastatic or recurrent endometrial carcinoma:a Gynecologic Oncology Groupstudy.Gynecol Oncol 2012;125(3):771.DOI:10.1016 / j.ygyno.2012.03.034.

[0479] 5.Pectasides D,Xiros N,Papaxoinis G,et al.Carboplatin andpaclitaxelin advanced or metastatic endometrial cancer.Gynecol Oncol2008;109(2):250-4.DOI:10.1016 / j.ygyno.2008.01.028.

[0480] 6.AndréT,Berton-Rigaud D,Curigliano G,et al.549PProgression-freesurvival(PFS)and overall survival(OS)in patients(pts)with mismatch repairdeficient(dMMR)solid tumors treated withdostarlimab in the GARNET study.AnnOncol 2022;33:S799-800;abstract.DOI:10.1016 / j.annonc.2022.07.677.

[0481] 7.Antill Y,Kok PS,Robledo K,et al.Clinical activity ofdurvalumab forpatients with advanced mismatch repair-deficient andrepair-proficientendometrial cancer.A nonrandomized phase 2 clinicaltrial.J Immunother Cancer2021;9(6):e002255.DOI:10.1136 / jitc-2020-002255.

[0482] 8.Marabelle A,Le DT,Ascierto PA,et al.Efficacy ofpembrolizumab inpatients with noncolorectal high microsatelliteinstability / mismatch repair-deficient cancer:results from the Phase IIKEYNOTE-158 study.J Clin Oncol2020;38(1):1-10.DOI:10.1200 / JCO.19.02105.

[0483] 9.Makker V,Colombo N,Casado Herráez A,et al.LenvatinibplusPembrolizumab for Advanced Endometrial Cancer.New EnglandJournal of Medicine2022;386(5):437-448.DOI:10.1056 / NEJMoa2108330.

[0484] 10.Mirza MR,Chase DM,Slomovitz BM,et al.Dostarlimab forprimaryadvanced or recurrent endometrial cancer.N Engl J Med2023;388:2145-2158.DOI:10.1056 / NEJMoa2216334.

[0485] 11.Eskander RN,Sill MW,Beffa L,et al.Pembrolizumab pluschemotherapyin advanced endometrial cancer.N Engl J Med2023;388(23):2159-2170.DOI:10.1056 / NEJMoa2302312.

[0486] 12.Stewart RA,PiliéPG,Yap TA.Development of PARP andImmune-CheckpointInhibitor Combinations.Cancer Research2018;78(24):6717-6725.DOI:10.1158 / 0008-5472.Can-18-2652.

[0487] 13.Li A,Yi M,Qin S,Chu Q,Luo S,Wu K.Prospects forcombining immunecheckpoint blockade with PARP inhibition.J HematolOncol 2019;12(1):98.DOI:10.1186 / s13045-019-0784-8.

[0488] 14.Wanderley CWS,Correa TS,Scaranti M,Cunha FQ,Barroso-SousaR.Targeting PARP1 to Enhance Anticancer CheckpointImmunotherapy Response:Rationale and Clinical Implications.FrontImmunol 2022;13:816642.DOI:10.3389 / fimmu.2022.816642.

[0489] 15.Lee EK,Konstantinopoulos PA.Combined PARP and ImmuneCheckpointInhibition in Ovarian Cancer.Trends Cancer2019;5(9):524-528.DOI:10.1016 / j.trecan.2019.06.004.

[0490] 16.AstraZeneca.Global Policy:bioethics.(www.astrazeneca.com / content / dam / az / PDF / 2019 / Bioethics%20Policy%20final.pdf).

Claims

1. A method of treating endometrial cancer in a subject in need thereof, the method 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

2. A method of treating endometrial cancer in a subject in need thereof, the method 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

3. The method of claim 1 or 2, wherein step (b) occurs after step (a) is completed.

4. The method according to any one of claims 1-3, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof is administered at a dose of 800 mg to 1500 mg.

7. The method of claim 6, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at 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 antigen-binding fragment thereof is administered at a dose of 10 mg / kg to 20 mg / kg.

9. The method of claim 8, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at 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 at a dose of 100 mg to 300 mg.

11. The method of claim 10, wherein the PARP inhibitor is administered at 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 method according to any one of claims 1 to 12, wherein the paclitaxel is administered at 175 mg / m 2 dosage administration.

14. The method of claim 12 or claim 13, wherein the carboplatin is administered at a dose that produces an area under the curve (AUC) of 5 or AUC6.

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

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

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

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

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

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

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

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

23. The method of claim 22, wherein step (a) comprises administering 1120 mg of durvalumab every 3 weeks.

24. The method according to any one of claims 21 to 23, wherein step (a) further comprises administering: 175 mg / m 2 of paclitaxel; Carboplatin at AUC5 or AUC6; and / or 25 mg / m 2 of cisplatin.

25. The method according to any one of claims 1 to 24, wherein step (b) comprises: A dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every two to four weeks; and a dose of the PARP inhibitor is administered twice daily.

26. The method according to any one of claims 1 to 25, wherein step (b) comprises: A dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every four weeks; and a dose of the PARP inhibitor is administered twice daily.

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

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

29. The method according to any one of claims 1 to 28, wherein step (b) comprises administering: 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and 300 mg of this PARP inhibitor.

30. The method of claim 29, wherein step (b) comprises administering: 1500 mg of durvalumab; and 300mg of olaparib.

31. The method of claim 30, wherein step (b) comprises administering: 1500 mg of durvalumab every 4 weeks; and 300 mg of olaparib twice a day.

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

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

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

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

36. The method of any one of claims 2 to 24 or 32-35, wherein step (b) comprises administering 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

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

38. The method of claim 37, wherein step (b) comprises administering 1500 mg of durvalumab every 4 weeks.

39. The method of any one of claims 1 to 38, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof 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 thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, 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 antigen-binding fragment thereof and the PARP inhibitor in step (b) are administered to the subject simultaneously, separately and / or sequentially.

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

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

45. The method of claim 44, comprising administering to a subject having deficient mismatch repair (dMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

46. ​​The method of any one of claims 1 to 43, wherein the endometrial cancer is an MMR-proficient (pMMR) endometrial cancer tumor.

47. The method of claim 46, comprising administering to a subject having perfect mismatch repair (pMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

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

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

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

51. The method of claim 50, wherein the treatment results in an increase in progression-free survival of at least 4 months.

52. The method of any one of claims 1 to 51, wherein the treatment results in increased overall survival of the subject compared to patients receiving durvalumab and chemotherapy alone.

53. The method of claim 52, wherein the treatment results in an increase in overall survival of at least 4 months.

54. A combination for use in treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

55. A combination for use in treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

56. The combination for use according to claim 54 or claim 55, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 antigen-binding fragment thereof is 15 mg / kg and / or 20 mg / kg.

62. The 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 is paclitaxel and / or carboplatin.

65. The combination for use according to claim 64, wherein the dose of paclitaxel is 175 mg / m 2 .

66. The combination for use according to claim 64 or claim 65, wherein the dose of carboplatin produces an area under the curve (AUC) of 5 or AUC6.

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

68. The combination for use according to claim 67, wherein administration is every two to four weeks for nine to twenty four weeks.

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

70. The combination for use according to claim 69, wherein administration is every three weeks for twelve to eighteen weeks.

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

72. The combination for use according to any one of claims 54 to 71, wherein (a) comprises administering three to six doses of the anti-PD-L1 antibody or antigen-binding fragment thereof and four to six doses of the one or more chemotherapeutic agents.

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

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

75. The combination for use according to claim 73 or claim 74, wherein the durvalumab is administered at a dose of 1120 mg every 3 weeks.

76. A combination for use according to any one of claims 73 to 75, wherein (a) further comprises: 175 mg / m 2 of paclitaxel; Carboplatin at AUC5 or AUC6; and / or 25 mg / m 2 of cisplatin.

77. A combination for use according to any one of claims 54 to 76, wherein (b) comprises: The anti-PD-L1 antibody or antigen-binding fragment thereof is administered every two to four weeks; and The PARP inhibitor is administered twice daily.

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

79. A combination for use according to any one of claims 54 to 78, wherein (b) comprises administering: A dose of 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and The dose was 300 mg of the PARP inhibitor.

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

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

82. The combination for use according to claim 79, wherein (b) comprises administering: Durvalumab at a dose of 1500 mg; and The dose was 300 mg of olaparib.

83. A combination for use according to any one of claims 79 to 81, wherein (b) comprises administering: Durvalumab at a dose of 1500 mg every 3 weeks; and Olaparib was given at a dose of 300 mg twice daily.

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

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

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

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

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

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

90. The combination for use according to any one of claims 84 to 89, wherein (b) comprises administration of durvalumab at a dose of 1500 mg every 3 weeks.

91. The combination for use according to any one of claims 54 to 90, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 deficient in mismatch repair (dMMR).

97. The combination of claim 96 for use in treating deficient mismatch repair (dMMR) endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

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

99. The combination according to claim 98 for use in treating perfect mismatch repair (pMMR) endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a 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 treatment with the combination results in an increase in progression-free survival in the subject compared to patients receiving 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 4 months.

104. The combination for use according to any one of claims 54 to 101, wherein treatment with the combination results in increased overall survival of the subject compared to patients receiving durvalumab and chemotherapy alone.

105. The combination for use according to claim 104, wherein the treatment results in an increase in overall survival of at least 4 months.

106. Use of a combination in the manufacture of a medicament for treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

107. Use of a combination in the manufacture of a medicament for treating endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

108. The use according to claim 106 or claim 107, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof is 800 mg to 1500 mg.

111. The use according to claim 110, wherein the dose of the anti-PD-L1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 any one of claims 114 to 115, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

117. The use according to claim 116, wherein the dose of paclitaxel is 175 mg / m 2 .

118. The use of claim 116 or claim 117, wherein the dose of carboplatin produces an area under the curve (AUC) of 5 or AUC6.

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

120. The use according to claim 119, wherein the administration is every two to four weeks for nine to twenty four weeks.

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

122. The use according to claim 121, wherein the administration is every three weeks for twelve to eighteen weeks.

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

124. The use of any one of claims 106 to 123, wherein (a) comprises administering three to six doses of the anti-PD-L1 antibody or antigen-binding fragment thereof and four to six doses of the one or more chemotherapeutic agents.

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

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

127. The use according to claim 125 or claim 126, wherein the durvalumab is administered at a dose of 1120 mg every 3 weeks.

128. The use according to any one of claims 125 to 127, wherein (a) further comprises: 175 mg / m 2 of paclitaxel; Carboplatin at AUC5 or AUC6; and / or 25 mg / m 2 of cisplatin.

129. The use according to any one of claims 106 to 128, wherein (b) comprises: The anti-PD-L1 antibody or antigen-binding fragment thereof is administered every two to four weeks; and The PARP inhibitor is administered twice daily.

130. The use according to any one of claims 106 to 129, wherein (b) comprises: The anti-PD-L1 antibody or antigen-binding fragment thereof is administered every four weeks; and The PARP inhibitor is administered twice daily.

131. The use according to any one of claims 106 to 130, wherein (b) comprises administering: A dose of 1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and The dose was 300 mg of the PARP inhibitor.

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

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

134. The use according to claim 131, wherein (b) comprises administering: Durvalumab at a dose of 1500 mg; and The dose was 300 mg of olaparib.

135. The use according to any one of claims 131 to 134, wherein (b) comprises administering: Durvalumab at a dose of 1500 mg every 3 weeks; and Olaparib was given at a dose of 300 mg twice daily.

136. The use of any one of claims 107 to 128, wherein (b) comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks.

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

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

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

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

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

142. The use according to any one of claims 137 to 141, wherein (b) comprises administering a dose of 1500 mg of durvalumab every 3 weeks.

143. The use according to any one of claims 106 to 142, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 antigen-binding fragment thereof 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 deficient in mismatch repair (dMMR).

149. Use according to claim 148 in the manufacture of a medicament for treating deficient mismatch repair (dMMR) endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an 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 MMR-proficient (pMMR) endometrial cancer tumor.

151. Use according to claim 150 in the manufacture of a medicament for treating perfect mismatch repair (pMMR) endometrial cancer in a subject in need thereof, 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 an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a 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 of any one of claims 106 to 153, wherein treatment with the combination results in an increase in progression-free survival of the subject compared to patients receiving 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 4 months.

156. The use of any one of claims 106 to 153, wherein treatment with the combination results in increased overall survival of the subject compared to patients receiving durvalumab and chemotherapy alone.

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

Images