Methods, compositions, and combinations for the treatment of ovarian cancer

Abstract

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

Description

[Technical Field]

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

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

[0003] Ovarian cancer is one of the deadliest gynecological malignancies in developed countries. In the United States alone, approximately 23,000 women are diagnosed with the disease each year, and nearly 14,000 women die from it. Despite advances in cancer treatment, the mortality rate from ovarian cancer has remained virtually unchanged over the past 20 years.

[0004] Ovarian cancer is the second most common gynecological cancer in the United States and causes more deaths than any other cancer of the female reproductive system. Unfortunately, there are no screening options for ovarian cancer, so the disease is often detected in the later stages of progression, and patients are most frequently diagnosed with stage 3 ovarian cancer. Stage 3 cancer means that ovarian cancer cells have spread or grown to the surrounding pelvic organs, and therefore the disease is not confined to the ovary or fallopian tube. Because ovarian cancer is diagnosed in the later stages and is invasive, the 5-year survival rate is only about 39%. Current treatment options remain inadequate. [Overview of the project]

[0005] This disclosure relates to methods, compositions, and combinations for the treatment of ovarian cancer. Specifically, this disclosure relates to a method for treating ovarian cancer in a subject requiring treatment for ovarian cancer, comprising administering one or more chemotherapeutic agents, an anti-VEGF antibody or antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and optionally a PARP inhibitor to the subject. This disclosure also relates to a combination for use in the treatment of ovarian cancer, comprising one or more chemotherapeutic agents, an anti-VEGF antibody or antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and optionally a PARP inhibitor.

[0006] In one embodiment, the present disclosure provides a method for treating ovarian cancer in a subject requiring treatment for ovarian cancer, comprising administering to the subject (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and optionally a therapeutically effective amount of a PARP inhibitor.

[0007] In another aspect, the present disclosure provides a combination for the treatment of ovarian cancer in a subject needing treatment for ovarian cancer, the combination comprising: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF 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, a therapeutically effective amount of an anti-VEGF antibody or an antigen-binding fragment thereof, and optionally a therapeutically effective amount of a PARP inhibitor.

[0008] In a further aspect, the present disclosure provides the use of a combination in the manufacture of a medicament for the treatment of ovarian cancer in a subject needing treatment for ovarian cancer, the combination comprising: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF 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, a therapeutically effective amount of an anti-VEGF 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 together with the accompanying claims. It should be noted that the claims are defined by the recitations therein, rather than by specific considerations of the features and advantages described herein.

Brief Description of the Drawings

[0010] [Figure 1]The study design diagram is shown. Medication and schedule: Bevacizumab (15 mg / kg IV q3w); durvalumab (1120 mg IV q3w); olaparib (300 mg po bid); chemotherapy: paclitaxel 175 mg / m2 IV q3w and carboplatin IV q3w with AUC5 or AUC6. Progression-free survival (PFS) interim analysis DCO: December 5, 2022. Use of bevacizumab follows local clinical practice; number of cycles 2-6; genomic instability score of 42 or higher as assessed by the Myriad MyChoice CDx assay. AUC, Area under the curve; bev, Bevacizumab; bid, Twice daily; CTx, Chemotherapy; DCO, Data cutoff; durva, Durvalumab; FIGO, International Federation of Gynecology and Obstetrics; HRD, Homologous recombination deficiency; ITT, Intention to treat; IV, Intravenous; ola, Olaparib; OS, Overall survival; PC, Paclitaxel / Carboplatin; po, Oral; q3w, Every 3 weeks; R, Randomization; RECIST, Response Evaluation Criteria for Solid Tumors. [Figure 2]The study design diagram is shown along with the endpoints. Medication and schedule: Bevacizumab (15 mg / kg IV q3w); durvalumab (1120 mg IV q3w); olaparib (300 mg po bid); chemotherapy: paclitaxel 175 mg / m2 IV q3w and carboplatin IV q3w with AUC5 or AUC6. PFS interim analysis DCO: December 5, 2022. *Use of bevacizumab depends on local practice; †Number of cycles 2-6; ‡Genome instability score of 42 or higher as assessed by Myriad MyChoice CDx assay. AUC, Area under the curve; bev, Bevacizumab; bid, Twice daily; CTx, Chemotherapy; DCO, Data cutoff; durva, Durvalumab; FIGO, International Federation of Gynecology and Obstetrics; HRD, Homologous recombination deficiency; ITT, Intention to treat; IV, Intravenous; ola, Olaparib; OS, Overall survival; PC, Paclitaxel / Carboplatin; po, Oral; q3w, Every 3 weeks; R, Randomization; RECIST, Response Evaluation Criteria for Solid Tumors. [Figure 3] Multiple testing and PFS interim analysis are presented. For each PFS comparison, alpha is controlled at each point in time of the interim and final analyses using individually designed spending functions. FA: Final analysis; IA: Interim analysis. [Figure 4] Patient characteristics are shown. Due to rounding, percentages may not add up to 100. *One patient in Arm 2 had an unknown FIGO stage. †Includes mixed epithelial type, carcinosarcoma, and other histological types;‡Genomic instability assessed using Myriad MyChoice CDx assay and cutoff 42;ECOG, US East Coast Cancer Clinical Trials Group. [Figure 5]The patient distribution is shown. Patients who discontinued one or more study treatments were able to continue receiving the remaining study treatments. Due to rounding, percentages may not add up to 100%. *Total time from the first dose to the last non-zero dose + 20 days, death, or DCO, whichever comes first; *Total time from the first dose to the last non-zero dose, death, or DCO, whichever comes first; ‡Carboplatin or cisplatin substitute; §Paclitaxel or nab-paclitaxel, docetaxel, or pegylated liposomal doxorubicin substitute; [Table 1] Patients whose PFS (Progression-Free Situation) tracking was discontinued. [Figure 6] This shows progression-free survival in the HRD-positive subgroup for Arm 3 versus Arm 1. *Censored patients; †Median and proportion estimated by KM method; ‡24-month PFS rate is unstable. Median PFS for Arm 3 is unstable. §HR and CI were estimated from stratification. Cox proportional hazards model. P-values ​​obtained from stratified log-rank text. Model stratified by timing and outcome of cytoreductive surgery; CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier. [Figure 7] This shows progression-free survival in the ITT population in an arm-3 vs. arm-1 ratio. *Censored patients; †Median and proportion estimated by the KM method; ‡24-month PFS rate is unstable. §HR and CI were estimated from stratified Cox proportional hazards models. Models stratified by timing and outcome of cytoreductive surgery, as well as geographical region. P-values ​​obtained from stratified log-rank texts. [Figure 8] This shows progression-free survival in the ITT population. Censored patients; †Median and proportion estimated by the KM method; ‡24-month PFS rate is unstable. §HR and CI were estimated from stratified Cox proportional hazards models. Models stratified by timing and outcome of cytoreductive surgery, as well as geographical region. P-values ​​obtained from stratified log-rank texts. [Figure 9]This shows subgroup analysis of PFS based on HRD status. Panel A shows the HRD-positive subgroup, and Panel B shows the HRD-negative subgroup. *Median and proportion were estimated by the KM method. †24-month PFS rates are unstable. Median PFS in arms 3 and 2 of the HRD-positive subgroup is unstable. ‡HR and CI were estimated from an unstratified Cox proportional hazards model. [Figure 10] This shows a subgroup analysis (ITT population) of PFS arm 3 vs arm 1. Consistency of treatment effects between subgroups, estimated from an unstratified Cox proportional hazards model, is also shown. PD-L1 expression was primarily assessed by Ventana SP263 immunohistochemical assay. Tumor area positivity PD-L1 expression (TAP5): High defined as ≥5%; Low defined as <5%; Unknown defined as samples where PD-L1 expression was unavailable. PD-L1, programmed death ligand 1. [Figure 11] A summary of safety events is presented. This includes AEs that occurred or worsened from the day of the first dose (overall) of durvalumab / placebo or olaparib / placebo (maintenance phase) until the initiation of the first subsequent anticancer therapy after the last dose of the study treatment, or until the end of the safety follow-up period. *Includes events from the first dose of durvalumab / olaparib / placebo until the end of the study. †As assessed by the principal investigator;‡Based on actions taken for AEs and CRFs for at least one treatment. For durvalumab / placebo, dose changes include skipping or delaying administration, or interrupting infusion;§Either dose reduction or interruption;AEs, adverse events;AML, acute myeloid leukemia;CRF, case report form;MDS, myelodysplastic syndrome. [Figure 12] Any adverse event occurring in 20% or more of the treatment is included. This includes AEs that occur or worsen from the day of the first dose of durvalumab / placebo or olaparib / placebo (overall) or the first dose of olaparib / placebo (maintenance phase) until the initiation of the first subsequent anticancer therapy after the last dose of the study treatment, or until the end of the safety follow-up period. *Any grade of AE other than alopecia that occurred in association with the maintenance phase and had an overall incidence of 20% or more in any arm. [Figure 13] Adverse events of grade 3 or higher occur in 5% or more of the cases. This includes AEs that occur or worsen from the day of the first dose of durvalumab / placebo or olaparib / placebo (overall) or the first dose of olaparib / placebo (maintenance phase) until the initiation of the first subsequent anticancer therapy after the last dose of the study treatment, or until the end of the safety follow-up period. *Grade 3 or higher AEs that occur in association with the maintenance phase and have an overall incidence of 5% or more in any arm. [Figure 14A] (A) Distribution of clinical trial participants at the time of the interim / first progression-free survival analysis (DCO) (December 5, 2022) and (B) distribution of participants at the time of the final progression-free survival analysis (DCO) (September 18, 2023). In either treatment arm, no patients were still receiving paclitaxel or carboplatin at the time of DCO. DCO: data cutoff; ITT: intention to treat. [Figure 14B] (A) Distribution of clinical trial participants at the time of the interim / first progression-free survival analysis (DCO) (December 5, 2022) and (B) distribution of participants at the time of the final progression-free survival analysis (DCO) (September 18, 2023). In either treatment arm, no patients were still receiving paclitaxel or carboplatin at the time of DCO. DCO: data cutoff; ITT: intention to treat. [Figure 15]The study design is as follows: Patients received a minimum of 4 cycles and a maximum of 6 cycles of carboplatin / paclitaxel. Patients who had undergone prior surgery received cycle 1 of carboplatin / paclitaxel within 8 weeks of surgery. Interval decompression surgery was ideally performed within 14 days (and within 28 days) after day 21 of cycle 3 of carboplatin / paclitaxel; bevacizumab administration was mandatory in cycle 2, but was omitted immediately before interval decompression surgery in cycle 3. If carboplatin / paclitaxel was initiated within 4 weeks after interval decompression surgery, bevacizumab was omitted from the first cycle after interval decompression surgery. During cycle 1 of chemotherapy, patients received intravenous carboplatin at AUC5 or AUC6 and intravenous paclitaxel at 175 mg / m2. Cycle 1 may include intravenous bevacizumab at 15 mg / kg, depending on local practice. From Cycle 2 onward, patients received paclitaxel 175 mg / m2, q3w + carboplatin, AUC5 or AUC6 for q3w (total 6 cycles), and bevacizumab 15 mg / kg, q3w + durvalumab placebo, followed by subsequent maintenance bevacizumab 15 mg / kg, q3w (total 15 months) + durvalumab placebo + olaparib placebo (control arm); carboplatin / paclitaxel + bevacizumab + intravenous The following treatments were administered: durvalumab 1,120 mg for 3 weeks, followed by maintenance bevacizumab + durvalumab 1,120 mg for 3 weeks (total 24 months) + olaparib placebo (durvalumab arm); or carboplatin / paclitaxel + bevacizumab + durvalumab, followed by maintenance bevacizumab + durvalumab + olaparib 300 mg twice daily (total 24 months) (durvalumab + olaparib arm). AUC: Area under serum concentration-time curve; BRCA: BRCA1 and / or BRCA2; FIGO: International Federation of Gynecology and Obstetrics; PARP: Poly(ADP-ribose) polymerase; q3w: Every 3 weeks; R: Randomization; tBRCAm: Tumor BRCA mutation. [Figure 16A]The interim PFS analysis (DCO: December 5, 2022) for (A) the non-tBRCAm HRD-positive group and (B) the treatment-intention group is shown, as well as the final PFS analysis (DCO: September 18, 2023) for (C) the non-tBRCAm HRD-positive group and (D) the treatment-intention group. [Figure 16B] The interim PFS analysis (DCO: December 5, 2022) for (A) the non-tBRCAm HRD-positive group and (B) the treatment-intention group is shown, as well as the final PFS analysis (DCO: September 18, 2023) for (C) the non-tBRCAm HRD-positive group and (D) the treatment-intention group. [Figure 16C] The interim PFS analysis (DCO: December 5, 2022) for (A) the non-tBRCAm HRD-positive group and (B) the treatment-intention group is shown, as well as the final PFS analysis (DCO: September 18, 2023) for (C) the non-tBRCAm HRD-positive group and (D) the treatment-intention group. [Figure 16D] The interim PFS analysis (DCO: December 5, 2022) for (A) the non-tBRCAm HRD-positive group and (B) the treatment-intention group is shown, as well as the final PFS analysis (DCO: September 18, 2023) for (C) the non-tBRCAm HRD-positive group and (D) the treatment-intention group. [Figure 17] Interim PFS analysis is shown. BRCA, BRCA1 and / or BRCA2; HRD, homologous recombination deficiency; ITT, intention to treat; non-tBRCAm, non-tumor BRCAm; OS, overall survival; PFS, progression-free survival. [Figure 18]This shows pre-specified subgroup analyses of interim PFS (DCO: December 5, 2022) in the durvalumab + olaparib arm versus the control arm. Consistency of treatment efficacy between subgroups estimated from an unstratified Cox proportional hazards model. *Gross residual disease after prior surgery or planned IDS. †tHRRm status was assessed using the Myriad tumor histological gene panel. Positive HRRm status was defined as specimens with pathogenic mutations in any of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. Negative HRRm status (non-HRRm) was defined as specimens without pathogenic mutations in any of the pre-specified genes. ‡PD-L1 expression was primarily evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics, Rotkreuz, Switzerland). High TAP5 was defined as ≥5%; low TAP5 as <5%; and TAP5 unknown as samples for which PD-L1 expression was unavailable. DCO: Data cutoff; ECOG: US East Coast Cancer Clinical Trials Group; HR: Hazard ratio; HRD: Homologous recombination deficiency; HRRm: Homologous recombination repair mutation; IDS: Interval debulking surgery; PFS: Progression-free survival; RoW: Other regions of the world; TAP: Tumor-positive PD-L1 expression; tHRRm: Tumor homologous recombination repair mutation. [Figure 19A]Pre-specified subgroup analyses of (A) final progression-free survival (DCO: September 18, 2023) in the durvalumab + olaparib arm versus the control arm, (B) intermediate progression-free survival (DCO: December 5, 2022), and (C) final progression-free survival (DCO: September 18, 2023) in the durvalumab arm versus the control arm are shown. Consistency of treatment efficacy between subgroups estimated from an unstratified Cox proportional hazards model. * Macroscopic residual disease after prior surgery or planned IDS. † Tumor HRRm status was assessed using the Myriad tumor histological gene panel. A positive HRRm state was defined as a specimen having a pathogenic mutation in one of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm state (non-HRRm) was defined as a specimen without pathogenic mutations in any of the pre-specified genes. ‡PD-L1 expression was primarily evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics, Rothkreuz, Switzerland). High TAP5 was defined as ≥5%; low TAP5 was defined as <5%; and TAP5 unknown was defined as a specimen for which PD-L1 expression was unavailable. DCO, data cutoff; ECOG, US East Coast Cancer Clinical Trials Group; HR, hazard ratio; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IDS, interval decompression surgery; PD-L1, programmed death ligand 1; RoW, other regions of the world; TAP, tumor-positive PD-L1 expression. [Figure 19B]Pre-specified subgroup analyses of (A) final progression-free survival (DCO: September 18, 2023) in the durvalumab + olaparib arm versus the control arm, (B) intermediate progression-free survival (DCO: December 5, 2022), and (C) final progression-free survival (DCO: September 18, 2023) in the durvalumab arm versus the control arm are shown. Consistency of treatment efficacy between subgroups estimated from an unstratified Cox proportional hazards model. * Macroscopic residual disease after prior surgery or planned IDS. † Tumor HRRm status was assessed using the Myriad tumor histological gene panel. A positive HRRm state was defined as a specimen having a pathogenic mutation in one of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm state (non-HRRm) was defined as a specimen without pathogenic mutations in any of the pre-specified genes. ‡PD-L1 expression was primarily evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics, Rothkreuz, Switzerland). High TAP5 was defined as ≥5%; low TAP5 was defined as <5%; and TAP5 unknown was defined as a specimen for which PD-L1 expression was unavailable. DCO, data cutoff; ECOG, US East Coast Cancer Clinical Trials Group; HR, hazard ratio; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IDS, interval decompression surgery; PD-L1, programmed death ligand 1; RoW, other regions of the world; TAP, tumor-positive PD-L1 expression. [Figure 19C]Pre-specified subgroup analyses of (A) final progression-free survival (DCO: September 18, 2023) in the durvalumab + olaparib arm versus the control arm, (B) intermediate progression-free survival (DCO: December 5, 2022), and (C) final progression-free survival (DCO: September 18, 2023) in the durvalumab arm versus the control arm are shown. Consistency of treatment efficacy between subgroups estimated from an unstratified Cox proportional hazards model. * Macroscopic residual disease after prior surgery or planned IDS. † Tumor HRRm status was assessed using the Myriad tumor histological gene panel. A positive HRRm state was defined as a specimen having a pathogenic mutation in one of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm state (non-HRRm) was defined as a specimen without pathogenic mutations in any of the pre-specified genes. ‡PD-L1 expression was primarily evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics, Rothkreuz, Switzerland). High TAP5 was defined as ≥5%; low TAP5 was defined as <5%; and TAP5 unknown was defined as a specimen for which PD-L1 expression was unavailable. DCO, data cutoff; ECOG, US East Coast Cancer Clinical Trials Group; HR, hazard ratio; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IDS, interval decompression surgery; PD-L1, programmed death ligand 1; RoW, other regions of the world; TAP, tumor-positive PD-L1 expression. [Figure 20A]The PFS2 analysis (DCO: September 18, 2023) in (A) the treatment-intent population and (B) the non-tBRCAm HRD-positive population, and the interim OS analysis (DCO: September 18, 2023) in (C) the treatment-intent population and (D) the non-tBRCAm HRD-positive population are shown. Median values ​​were estimated by the Kaplan-Meier method. In A, B, and C, HR and CI were estimated from unstratified Cox proportional hazards models. In D, HR and CI were estimated from stratified Cox proportional hazards models (stratified by timing of cytoreductive surgery and outcome). P-values ​​in C from unstratified log-rank text. BRCA, BRCA1 and / or BRCA2; CI, confidence interval; DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; NR, not reached; OS, overall survival; PFS2, second disease progression; tBRCAm, tumor BRCAm [Figure 20B] The PFS2 analysis (DCO: September 18, 2023) in (A) the treatment-intent population and (B) the non-tBRCAm HRD-positive population, and the interim OS analysis (DCO: September 18, 2023) in (C) the treatment-intent population and (D) the non-tBRCAm HRD-positive population are shown. Median values ​​were estimated by the Kaplan-Meier method. In A, B, and C, HR and CI were estimated from unstratified Cox proportional hazards models. In D, HR and CI were estimated from stratified Cox proportional hazards models (stratified by timing of cytoreductive surgery and outcome). P-values ​​in C from unstratified log-rank text. BRCA, BRCA1 and / or BRCA2; CI, confidence interval; DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; NR, not reached; OS, overall survival; PFS2, second disease progression; tBRCAm, tumor BRCAm [Figure 20C]The PFS2 analysis (DCO: September 18, 2023) in (A) the treatment-intent population and (B) the non-tBRCAm HRD-positive population, and the interim OS analysis (DCO: September 18, 2023) in (C) the treatment-intent population and (D) the non-tBRCAm HRD-positive population are shown. Median values ​​were estimated by the Kaplan-Meier method. In A, B, and C, HR and CI were estimated from unstratified Cox proportional hazards models. In D, HR and CI were estimated from stratified Cox proportional hazards models (stratified by timing of cytoreductive surgery and outcome). P-values ​​in C from unstratified log-rank text. BRCA, BRCA1 and / or BRCA2; CI, confidence interval; DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; NR, not reached; OS, overall survival; PFS2, second disease progression; tBRCAm, tumor BRCAm [Figure 20D] The PFS2 analysis (DCO: September 18, 2023) in (A) the treatment-intent population and (B) the non-tBRCAm HRD-positive population, and the interim OS analysis (DCO: September 18, 2023) in (C) the treatment-intent population and (D) the non-tBRCAm HRD-positive population are shown. Median values ​​were estimated by the Kaplan-Meier method. In A, B, and C, HR and CI were estimated from unstratified Cox proportional hazards models. In D, HR and CI were estimated from stratified Cox proportional hazards models (stratified by timing of cytoreductive surgery and outcome). P-values ​​in C from unstratified log-rank text. BRCA, BRCA1 and / or BRCA2; CI, confidence interval; DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; NR, not reached; OS, overall survival; PFS2, second disease progression; tBRCAm, tumor BRCAm [Figure 21A]This report shows (A) intermediate PFS (DCO: December 5, 2022), (B) final PFS (DCO: September 18, 2023), (C) PFS2 (DCO: September 18, 2023), and (D) intermediate OS (DCO: September 18, 2023) in patients with HRD-negative tumors. Median values ​​were estimated by the Kaplan-Meier method; HR and CI were estimated from an unstratified Cox proportional hazards model. DCO: data cutoff; HR: hazard ratio; HRD: homologous recombination deficiency; OS: overall survival; PFS: progression-free survival; PFS2: second disease progression. [Figure 21B] This report shows (A) intermediate PFS (DCO: December 5, 2022), (B) final PFS (DCO: September 18, 2023), (C) PFS2 (DCO: September 18, 2023), and (D) intermediate OS (DCO: September 18, 2023) in patients with HRD-negative tumors. Median values ​​were estimated by the Kaplan-Meier method; HR and CI were estimated from an unstratified Cox proportional hazards model. DCO: data cutoff; HR: hazard ratio; HRD: homologous recombination deficiency; OS: overall survival; PFS: progression-free survival; PFS2: second disease progression. [Figure 21C] This report shows (A) intermediate PFS (DCO: December 5, 2022), (B) final PFS (DCO: September 18, 2023), (C) PFS2 (DCO: September 18, 2023), and (D) intermediate OS (DCO: September 18, 2023) in patients with HRD-negative tumors. Median values ​​were estimated by the Kaplan-Meier method; HR and CI were estimated from an unstratified Cox proportional hazards model. DCO: data cutoff; HR: hazard ratio; HRD: homologous recombination deficiency; OS: overall survival; PFS: progression-free survival; PFS2: second disease progression. [Figure 21D]This report shows (A) intermediate PFS (DCO: December 5, 2022), (B) final PFS (DCO: September 18, 2023), (C) PFS2 (DCO: September 18, 2023), and (D) intermediate OS (DCO: September 18, 2023) in patients with HRD-negative tumors. Median values ​​were estimated by the Kaplan-Meier method; HR and CI were estimated from an unstratified Cox proportional hazards model. DCO: data cutoff; HR: hazard ratio; HRD: homologous recombination deficiency; OS: overall survival; PFS: progression-free survival; PFS2: second disease progression. [Figure 22A] (A) Final PFS in the non-tBRCAm HRD-positive group and (B) in the non-tBRCAm ITT group. [Figure 22B] (A) Final PFS in the non-tBRCAm HRD-positive group and (B) in the non-tBRCAm ITT group. [Figure 23A] (A) Intermediate OS in the non-tBRCAm HRD-positive group and (B) Intermediate OS in the non-tBRCAm ITT group. [Figure 23B] (A) Intermediate OS in the non-tBRCAm HRD-positive group and (B) Intermediate OS in the non-tBRCAm ITT group. [Figure 24A] Unstratified subgroup analyses of (A) PFS and (B) intermediate OS in the HRD-negative population are shown. [Figure 24B] Unstratified subgroup analyses of (A) PFS and (B) intermediate OS in the HRD-negative population are shown. [Figure 25] This section provides updated safety information for DCO2. [Figure 26] The flowcharts for the final PFS analysis and the intermediate OS analysis are shown. [Figure 27]The final PFS analysis for the non-tBRCAm HRD-positive population is presented. Median values ​​were estimated by the Kaplan-Meier method. HR and CI were estimated from a stratified Cox proportional hazards model (stratified by timing and outcome of cytoreductive surgery). P-values ​​were obtained from the stratified log-rank test. The median (range) follow-up periods for PFS in censored patients were 28.8 (0.0–40.8) months, 21.2 (0.0–41.5) months, and 25.6 (0.0–41.7) months for the control arm, durvalumab arm, and durvalumab + olaparib arm, respectively, at the time of the primary PFS analysis, and 38.4 (0.0–51.6) months, 33.1 (0.0–50.8) months, and 34.6 (0.0–51.3) months, respectively, at the time of the final PFS analysis. BRCA, BRCA1 and / or BRCA2; DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; non-tBRCAm, non-tumor BRCAm; NR, not reached; OS, overall survival; PFS, progression-free survival. [Figure 28]This shows a pre-specified subgroup analysis of final PFS in the non-tBRCAm ITT population, comparing the durvalumab + olaparib arm with the control arm. Consistency of treatment efficacy between subgroups, estimated from an unstratified Cox proportional hazards model. *Gross residual disease after prior surgery or planned IDS. †tHRRm status was assessed using the MyChoice® CDx assay. A positive HRRm status was defined as a specimen with a harmful or suspected harmful mutation in any of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm status (non-HRRm) was defined as a specimen without any harmful or suspected harmful mutations in any of the pre-specified genes. ‡PD-L1 expression was primarily evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics, Rothkreuz, Switzerland). High TAP5 was defined as ≥5%; low TAP5 as <5%; and TAP5 unknown as samples for which PD-L1 expression was unavailable. DCO: Data cutoff; ECOG: US East Coast Cancer Clinical Trials Group; HR: Hazard ratio; HRD: Homologous recombination deficiency; HRRm: Homologous recombination repair mutation; IDS: Interval debulking surgery; ITT: Intention to treat; PFS: Progression-free survival; TAP: Percentage of tumor area; tHRRm: Tumor homologous recombination repair mutation. [Figure 29] This shows the distribution of clinical trial participants at the time of the final PFS / interim OS analysis DCO (September 18, 2023). *No patients in any treatment arm were still receiving paclitaxel or carboplatin at the time of DCO. DCO, data cutoff; ITT, intention to treat; OS, overall survival; PFS, progression-free survival. [Figure 30]This shows a pre-specified subgroup analysis of primary PFS in the non-tBRCAm ITT population, comparing the durvalumab + olaparib arm with the control arm. Consistency of treatment efficacy between subgroups was estimated from an unstratified Cox proportional hazards model. *Patients with macroscopic residual disease after prior surgery or planned IDS. †tHRRm status was assessed using the MyChoice® CDx assay. A positive HRRm status was defined as a specimen with a harmful or suspected harmful mutation in any of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm status (non-HRRm) was defined as a specimen without any harmful or suspected harmful mutations in any of the pre-specified genes. ‡PD-L1 expression was primarily evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics, Rothkreuz, Switzerland). High TAP5 was defined as ≥5%; low TAP5 as <5%; and unknown TAP5 was defined as a sample for which PD-L1 expression was unavailable. BRCA, BRCA1 and / or BRCA2; DCO, data cutoff; ECOG, US East Coast Cancer Clinical Trials Group; HR, hazard ratio; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IDS, interval debulking surgery; ITT, intention to treat; non-tBRCAm, non-tumor BRCAm; PFS, progression-free survival; TAP, percentage of tumor area; tHRRm, tumor homologous recombination repair mutation. [Figure 31A] Further results of PFS2 analysis for (A) non-tBRCAm HRD positive and (B) non-tBRCAm ITT are shown. [Figure 31B] Further results of PFS2 analysis for (A) non-tBRCAm HRD positive and (B) non-tBRCAm ITT are shown. [Figure 32A] Further results of PFS analysis for (A) non-tBRCAm HRD positive and (B) non-tBRCAm ITT are shown. [Figure 32B]Further results of PFS analysis for (A) non-tBRCAm HRD positive and (B) non-tBRCAm ITT are shown. [Figure 33] Further results from unstratified subgroup analysis of the HRD-negative population in PFS2 are presented. [Modes for carrying out the invention]

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

[0012] When used in accordance with this disclosure, unless otherwise indicated or defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art in which this disclosure pertains. The following references provide general definitions of many of the terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). When used herein, the following terms have the meanings set forth below unless otherwise specified.

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

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

[0015] Unless otherwise stated or made clear from the context, the term “about” as used herein is understood to mean within the normal tolerances in the art, for example, within two standard deviations of the mean. “About” can also be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise made clear from the context, all numerical values ​​provided herein are modified by the term “about.”

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

[0017] The ranges provided in this specification are to be understood as being shorthand for all of the values within the range. For example, a range of 1 to 50 is to be understood as including any number, combination of numbers, or sub-ranges from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0018] As used herein, the term "antibody" refers to a protein that can specifically bind to an antigen. Normal or conventional mammalian antibodies include a tetramer, which typically consists of two identical pairs of polypeptide chains, each pair consisting of one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). As used herein, the terms "heavy chain" and "light chain" refer to any immunoglobulin polypeptide having a variable domain sequence sufficient to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100-110 or more amino acids typically involved in antigen recognition. The carboxyl-terminal portion of each chain typically defines a constant domain responsible for effector functions. Thus, in a naturally occurring antibody, a full-length heavy-chain immunoglobulin polypeptide includes a variable domain (V H ) and three constant domains (C H1 , C H2 , and C H3 ), as well as a hinge region between C H1 and C H2 . The V H domain is at the amino terminus of the polypeptide, the C H3 domain is at the carboxyl terminus, and a full-length light-chain immunoglobulin polypeptide includes a variable domain (V L ) and a constant domain (C L ), with the V L domain at the amino terminus of the polypeptide and C LThe domain is located at the carboxyl terminus.

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

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

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

[0022] In some embodiments of the method of the present disclosure, step (b) is performed after the completion of step (a).

[0023] In various embodiments of the first embodiment, step (b) may exclude a therapeutically effective amount of a PARP inhibitor. In these embodiments, step (b) includes a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment.

[0024] In some embodiments, the method further comprises administering to the subject a therapeutically effective dose of one or more chemotherapeutic agents, or a therapeutically effective dose of one or more chemotherapeutic agents and an anti-VEGF antibody or its antigen-binding fragment, prior to step (a). In some embodiments, the method further comprises administering to the subject a therapeutically effective dose of one or more chemotherapeutic agents, or a therapeutically effective dose of one or more chemotherapeutic agents and an anti-VEGF antibody or its antigen-binding fragment, prior to step (a). The number of therapeutic doses planned within each cycle depends on the chemotherapeutic agents. In some embodiments, each cycle may consist of only one dose. In other embodiments, a cycle may consist of more than one dose.

[0025] In some embodiments, a method for treating ovarian cancer in a subject requiring treatment for ovarian cancer is provided herein, comprising administering an anti-VEGF antibody or its antigen-binding fragment to the subject at a dose of 5 mg / kg to 25 mg / kg. In other embodiments, a method for treating ovarian cancer in a subject requiring treatment for ovarian cancer is provided herein, comprising administering an anti-VEGF antibody or its antigen-binding fragment to the subject at a dose of 5 mg / kg to 20 mg / kg.

[0026] In some embodiments, methods for treating ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, comprising administering to the subjects a fixed dose of 800 mg to 1500 mg of an anti-VEGF antibody or its antigen-binding fragment.

[0027] In one non-limiting embodiment, the anti-VEGF antibody is administered at a fixed dose of 1120 mg (based on an average body weight of 75 kg, which corresponds to a body weight-based dose of 15 mg / kg).

[0028] In some embodiments, methods for treating ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, comprising administering an anti-VEGF antibody or its antigen-binding fragment to the subject at a dose of 15 mg / kg.

[0029] In some embodiments, a method for treating ovarian cancer in a subject requiring treatment for ovarian cancer is provided herein, comprising administering an anti-PD-L1 antibody or its antigen-binding fragment to the subject at a dose of 5 mg / kg to 25 mg / kg. In some embodiments, a method for treating ovarian cancer in a subject requiring treatment for ovarian cancer is provided herein, comprising administering an anti-PD-L1 antibody or its antigen-binding fragment to the subject at a dose of 10 mg / kg to 20 mg / kg.

[0030] In some embodiments, methods for treating ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, comprising administering to the subjects a fixed dose of 800 mg to 1500 mg of an anti-PD-L1 antibody or its antigen-binding fragment.

[0031] In some embodiments, methods for treating ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, comprising administering to the subjects an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 15 mg / kg or a fixed dose of 1120 mg.

[0032] In one non-limiting embodiment, the anti-PD-L1 antibody is administered at a fixed dose of 1120 mg (based on an average body weight of 75 kg, which corresponds to a body weight-based dose of 15 mg / kg).

[0033] In some embodiments, methods for treating ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, comprising administering a PARP inhibitor to the subject in a fixed dose of 100 mg to 300 mg.

[0034] In some embodiments, methods for treating ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, comprising administering a fixed dose of 300 mg of a PARP inhibitor to the subjects.

[0035] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab. Durvalumab (MEDI4736, Imfinzi®) is a human monoclonal antibody against human PD-L1 that is capable of blocking the binding of PD-L1 to both PD1 and CD80 receptors. Disclosures relating to durvalumab can be found in U.S. Patents 8,779,108 and 9,493,565, which are incorporated herein by reference in their entirety.

[0036] The 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, the durvalumab or its antigen-binding fragments for use in the methods, compositions, and combinations provided herein comprise a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the 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, the heavy chain variable region comprising the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and the light chain variable region comprising the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8. Those skilled in the art can readily identify the Chothia definition, the Abm definition, or other CDR definitions known to those skilled in the art. In some embodiments, durvalumab or its antigen-binding fragments for use in the methods, compositions, and combinations provided herein include variable heavy chain and variable light chain CDR sequences of the 2.14H9OPT antibody disclosed in U.S. Patent No. 8,779,108 and No. 9,493,565.

[0037] Durvalumab light chain (LC) variable region: EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK(Sequence ID 1)

[0038] Durvalumab heavy chain (HC) variable region: EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS(Sequence ID 2)

[0039] Durvalumab heavy chain CDR: HC-CDR1:GFTFSRYWMS (Sequence ID 3) HC-CDR2:NIKQDGSEKYYVDSVKG (Sequence ID 4) HC-CDR3:EGGWFGELAFDY (Sequence ID 5)

[0040] Durvalumab, light chain CDR: LC-CDR1:RASQRVSSSYLA (Sequence ID 6) LC-CDR2:DASSRAT (Sequence ID 7) LC-CDR3:QQYGSLPWT (Sequence ID 8)

[0041] As used herein, the terms “vascular endothelial growth factor (VEGF) inhibitor” or “anti-VEGF antibody or its antigen-binding fragment” mean a drug that inhibits the activity of VEGF and VEGFR. VEGF and VEGFR (tyrosine kinase receptor) signaling regulates angiogenesis, which involves the formation of new blood vessels from existing blood vessels. Abnormal angiogenesis is known to occur in cancer, degenerative ophthalmic conditions, and other inflammatory conditions. Certain monoclonal antibodies can be used as VEGF inhibitors or anti-VEGF antibodies, and certain tyrosine kinase inhibitors are used as VEGFR inhibitors. Vascular endothelial growth factor (VEGF) / vascular endothelial growth factor receptor (VEGFR) inhibitors are used to treat various types of cancer.

[0042] VEGFR tyrosine kinase inhibitors (TKIs), including but not limited to ziv-aflibercept, bevacizumab, pazopanib, sunitinib, sorafenib, lenvatinib, cabozantinib, regorafenib, ponatinib, ramucirumab, and vandetanib. In certain embodiments, combination therapy further comprises administration of an anti-TIGIT antibody, monalizumab, oleanolic acid, and / or oleculumab. In some embodiments, the anti-VEGF antibody or its antigen-binding fragment is bevacizumab. Disclosures relating to bevacizumab can be found in U.S. Patents 6,407,213 and 7,365,166, which are incorporated herein by reference in whole.

[0043] As used herein, the term “PARP inhibitor” means any agent that inhibits the activity of the poly(ADP-ribose) polymerase (PARP) enzyme in cells. PARP helps repair DNA when it is damaged. DNA damage can be caused by a number of things, including exposure to UV light, radiation, certain anticancer drugs, or other substances in the environment. In cancer treatment, blocking PARP can help prevent cancer cells from repairing damaged DNA and thus kill them. In some embodiments, the PARP inhibitor is olaparib. Disclosures relating to olaparib can be found in European Patent Nos. 1330442 and 1633724, which are incorporated herein by reference in their entirety.

[0044] As used herein, “chemotherapy” or “chemotherapeutic agent” may include any chemotherapeutic agent. In some embodiments, the chemotherapeutic agent may include one or more platinum-based chemotherapeutic agents. In some embodiments, one or more platinum-based chemotherapeutic agents include carboplatin, cisplatin, oxaliplatin, or a combination thereof. In some embodiments, the chemotherapeutic agent may include one or more taxane-based chemotherapeutic agents. In some embodiments, one or more taxane-based chemotherapeutic agents include nab-paclitaxel, paclitaxel, docetaxel, cabazitaxel, abraxane, anthracycline (pegylated liposomal doxorubicin), or a combination thereof. In some embodiments, the chemotherapeutic agent may include one or more platinum-based chemotherapeutic agents in combination with one or more taxane-based chemotherapeutic agents. In various embodiments, the disclosure allows for the substitution of any other chemotherapeutic agent with one or more chemotherapeutic agents at any point during administration. Substitution of chemotherapeutic agents may be carried out for any reason, including, but not limited to, a reaction to one or more chemotherapeutic agents in a subject, or the development of hypersensitivity to them. In some embodiments, the chemotherapeutic agent includes cisplatin and paclitaxel. In some embodiments, the patient is administered one or more doses of cisplatin, the dose being approximately 25 mg / m². 2In some embodiments, the patient is administered one or more doses of cisplatin at a dose that produces an area under the curve (AUC) of AUC5 or AUC6. In some embodiments, the patient is administered 25 mg / m². 2 ~100mg / m 2 Administer a dose of cisplatin. In some embodiments, the patient is administered one or more doses of paclitaxel, the dose being approximately 175 mg / m². 2 In various embodiments, the dose of the chemotherapeutic agent can be reduced.

[0045] In some embodiments, the number of doses of one or more chemotherapeutic agents is measured in cycles. The number of therapeutic doses planned within each cycle depends on the chemotherapeutic agent. In some embodiments, each cycle may contain only one dose. In one non-limiting embodiment, a cycle may contain one dose administered on day 1 of the cycle. In other embodiments, a cycle may contain more than one dose. In one non-limiting embodiment, a cycle may contain more than one dose administered daily or weekly.

[0046] In some embodiments, the number of doses of anti-VEGF antibody or its antigen-binding fragment, anti-PD-L1 antibody or its antigen-binding fragment, and / or PARP inhibitor is measured per cycle. The number of therapeutic doses planned within each cycle depends on the antibody or inhibitor. In some embodiments, each cycle may contain only one dose. In one non-limiting embodiment, a cycle may contain one dose administered on day 1 of the cycle. In other embodiments, a cycle may contain more than one dose. In one non-limiting embodiment, a cycle may contain more than one dose administered daily or weekly.

[0047] As used herein, the term "subject" refers to a human patient.

[0048] In some embodiments, the methods, compositions, and combinations disclosed herein are used to treat subjects having ovarian cancer or ovarian tumor disorders. In some embodiments, the tumor is a solid tumor. As used herein, the term “solid tumor” refers to an abnormal mass of tissue that does not typically contain cysts or fluid areas.

[0049] As used herein, the terms “treatment” or “to treat” refer to both therapeutic procedures and preventive or protective measures. Subjects requiring treatment include subjects with cancer, subjects prone to developing cancer, or subjects for whom cancer should be prevented. In some embodiments, the methods, compositions, and combinations disclosed herein may be used for the treatment of ovarian cancer. In other embodiments, subjects requiring treatment include subjects with tumors, subjects prone to developing tumors, or subjects for whom tumors should be prevented. In certain embodiments, the methods, compositions, and combinations disclosed herein may be used for the treatment of tumors. In other embodiments, the treatment of a tumor includes inhibiting tumor growth, promoting tumor reduction, or both inhibiting tumor growth and promoting tumor reduction.

[0050] In some embodiments, the methods, compositions, and combinations disclosed herein result in an increase in progression-free survival (PFS) compared to placebo. In some embodiments, the methods, compositions, and combinations disclosed herein result in an increase in overall survival (OS) compared to placebo.

[0051] Overall survival (OS) refers to the time from the start of treatment to death from any cause. OS may refer to overall survival within a period such as 2 months, 3 months, 4 months, 6 months, 8 months, 12 months, 18 months, or 24 months. Such a period may be specified, for example, as "OS24," which refers to the number (%) of patients who are alive at 24 months after the start of treatment, per Kaplan-Meier estimate of overall survival at 24 months. In some embodiments, overall survival is measured against patients who received bevacizumab and chemotherapy only or chemotherapy only. In other embodiments, overall survival is measured against patients who received no treatment.

[0052] Progression-free survival (PFS) is defined as the time from the date of treatment to the date of objective disease progression (RECIST 1.1) or death (by any cause if there is no progression). In some embodiments, the methods, compositions, and combinations of the Disclosure result in a statistically significant and / or clinically meaningful increase in PFS. In some embodiments, the methods, compositions, and combinations of the Disclosure result in a PFS of at least 9 months to at least about 24 months (e.g., at least 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or more than 24 months, and up to about 5 years). In some embodiments, progression-free survival is measured in comparison to patients who received bevacizumab and chemotherapy alone or to patients who received chemotherapy alone. In other embodiments, overall survival is measured in comparison to patients who have not received treatment.

[0053] As used herein, the terms “administer” or “to administer” mean providing, contacting, and / or delivering one or more compounds by any suitable route to achieve a desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intra-articular, intra-arterial, intra-bursal, intrasternal, intrathecal, intrafocal, or intracranial injection), percutaneous, topical, buccal, rectal, vaginal, nasal, ocular, inhalation, and implantation.

[0054] In some embodiments, an anti-VEGF antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents are administered intravenously. In some embodiments, a PARP inhibitor is administered orally.

[0055] This specification provides methods, compositions, and combinations for treating ovarian cancer or ovarian tumors in subjects requiring treatment for ovarian cancer or ovarian tumors. Subjects may be inexperienced with PARP inhibitors and immuno-mediated therapies. As used herein, “ovarian cancer” refers to any cancer or tumor originating from the ovaries, or related areas of the fallopian tubes and peritoneum. These include, but are not limited to, epithelial ovarian cancer, germ cell ovarian tumors, sex cord-stromal tumors, and borderline ovarian tumors. The severity of ovarian cancer is measured by stage and malignancy grade.

[0056] As used herein, “stage” refers to the international system used to assess the extent to which cancer has spread. In Stage I, the cancer is confined to one or both ovaries and can be further subdivided into Stage IA: growth confined to one ovary with no tumor on the external surface; Stage IB: growth confined to both ovaries with no tumor on the external surface; and Stage IC: tumor is either Stage IA or IB, but tumor is present on the surface of one or both ovaries. In Stage II, the cancer has spread to the uterus or other surrounding organs and can be further subdivided into Stage IIA: cancer spread to the uterus and / or fallopian tubes and / or metastasis; Stage IIB: cancer spread to other pelvic tissues; and Stage IIC: tumor is either Stage IIA or IIB, but tumor is present on the surface of one or both ovaries. In Stage III, the cancer has spread to the lymph nodes or the inner lining of the abdomen, and can be further subdivided into Stage IIIA: tumors limited to the true pelvis; Stage IIIB: metastases to the abdominal peritoneal surface with a diameter of 2 cm or less; and Stage IIIC: peritoneal metastases beyond the pelvis with a diameter greater than 2 cm. In Stage IV, the cancer has spread to distal organs such as the lungs or liver.

[0057] Where used herein, “grade” or “grade assessment” refers to the degree to which cancer cells resemble normal cells and can help predict how cancer will behave. Ovarian tumors that rarely spread are called borderline or atypical proliferative neoplasms. In most ovarian cancers, tumors are divided into low-grade and high-grade, and no grade assessment number is assigned. The most common type of ovarian cancer is high-grade serous carcinoma. There is also low-grade serous carcinoma, which is less common. High-grade tumors are also more likely to respond to chemotherapy than low-grade tumors. All other ovarian cancers are graded 1, 2, and 3. Grade 1 tumors are well-differentiated cancers with cells that closely resemble normal cells and are less likely to spread or recur. Grade 2 tumors are moderately differentiated cancers, and grade 3 tumors are poorly differentiated cancers. Grades 2 and 3 show an increased difference in appearance compared to normal cells. They are also likely to spread and recur. In some embodiments, the methods, compositions, and combinations of the Disclosure are used to treat subjects with high-grade epithelial ovarian cancer. The methods, compositions, and combinations of the Disclosure are used to treat subjects with stage III-IV high-grade epithelial ovarian cancer. As used herein, “advanced ovarian cancer” means ovarian cancer that has spread beyond the ovary.

[0058] The ovarian cancer patient is considered to be at high risk of ovarian cancer due to hereditary breast and ovarian cancer syndrome (HBOC). HBOC is a hereditary genetic condition. There are two major genes, BRCA1 and BRCA2, that are associated with most families with HBOC. Mutations in either BRCA1 or BRCA2 increase the lifetime risk of breast and ovarian cancer in women. Men with these gene mutations also have a higher risk of breast and prostate cancer. Patients with BRCA1 or BRCA2 mutations have a slightly increased risk of other cancers, including pancreatic cancer and melanoma. Mutations in the BRCA gene BRCAm can include either germline BRCA mutations (gBRCAm) or somatic / tumor BRCA mutations (tBRCAm).

[0059] BRCA mutations can cause homologous recombination deficiency (HRD). As used herein, “homogenetic recombination deficiency (HRD)” refers to a phenotype characterized by the inability of cells to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. The majority of homologous recombination deficiency (HRD) tumors occur in patients with germline BRCA1 and BRCA2 mutations. However, there are also patients with germline mutations in other HR pathway genes, and patients who do not carry hereditary germline mutations but have tumors with sporadic HRD mutations.

[0060] As used herein, “homologous recombination (HR)” refers to the process for repairing DNA double-strand breaks. Germline variants in the HR pathway, including at least 10 genes such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1 (NBN), PALB2, RAD51C, and RAD51D, result in genetic susceptibility to certain types of cancer, including those of the breast, ovaries, prostate, and pancreas. In some embodiments, HRD status can be predictively assessed using the Myriad MyChoice CDx assay, and a cutoff of 42 or greater against the genomic instability score can be used to determine whether a tumor is HRD-positive.

[0061] In some embodiments, the methods, compositions, and combinations of the Disclosure are used to treat subjects having ovarian cancer in which the ovarian tumor does not contain BRCA1 / BRCA2 mutations (non-tBRCAm). The term "non-tBRCAm" may be defined as the absence or undetectability of harmful mutations in BRCA1 or BRCA2. In other embodiments, the methods, compositions, and combinations of the Disclosure are used to treat subjects having ovarian cancer in which the ovarian tumor contains BRCA1 / BRCA2 mutations (tBRCAm).

[0062] In some embodiments, the methods, compositions, and combinations of the Disclosure are used to treat subjects having ovarian cancer in which the ovarian tumor is homologous recombination deficiency (HRD) negative. In other embodiments, the methods, compositions, and combinations of the Disclosure are used to treat subjects having ovarian cancer in which the ovarian tumor is homologous recombination deficiency (HRD) positive.

[0063] This specification provides a method for treating ovarian cancer in a subject requiring treatment for ovarian cancer, comprising administering to the subject (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor. In some embodiments of this specification, step (b) may be omitted from the therapeutically effective amount of a PARP inhibitor. In these embodiments, step (b) comprises a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment.

[0064] In some embodiments, a method for treating ovarian cancer in a subject requiring treatment for ovarian cancer is provided herein, comprising administering to the subject an anti-VEGF antibody or its antigen-binding fragment in a dose of 10 mg / kg to 20 mg / kg, for example 15 mg / kg (or a uniform dose of 800 mg to 1500 mg), an anti-PD-L1 antibody or its antigen-binding fragment in a dose of 10 mg / kg to 20 mg / kg (or a uniform dose of 800 mg to 1500 mg, for example 1120 mg), and a PARP inhibitor in a dose of 100 mg to 300 mg.

[0065] Furthermore, this specification provides combinations for the treatment of ovarian cancer in subjects requiring treatment for ovarian cancer, the combinations comprising (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor. In some embodiments of this specification, the combination of (b) may omit the 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 its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment.

[0066] In some embodiments, the combinations provided herein include an anti-VEGF antibody or its antigen-binding fragment in a dose of 10 mg / kg to 20 mg / kg, for example 15 mg / kg (or a uniform dose of 800 mg to 1500 mg), an anti-PD-L1 antibody or its antigen-binding fragment in a dose of 10 mg / kg to 20 mg / kg (or a uniform dose of 800 mg to 1500 mg, for example 1120 mg), and a PARP inhibitor in a dose of 100 mg to 300 mg.

[0067] The doses of anti-VEGF antibodies or their antigen-binding fragments, anti-PD-L1 antibodies or their antigen-binding fragments, and PARP inhibitors administered to subjects may vary in part depending on the size (body weight, body surface area, or organ size) and condition (age and overall health status) of the subject.

[0068] In certain embodiments, a subject is administered one or more doses of anti-VEGF antibody or its antigen-binding fragment, where the dose is 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, 15 mg / kg, 20 mg / kg, or 25 mg / kg. In some embodiments, a subject is administered one or more doses of anti-VEGF antibody or its antigen-binding fragment, where the dose is 15 mg / kg.

[0069] In certain embodiments, one or more uniform doses of anti-VEGF antibody or its antigen-binding fragment are administered to the subject, where the doses are 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, 1 The doses are 120 mg, 1125 mg, 1150 mg, 1175 mg, 1180 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, or 1875 mg. In some embodiments, one or more uniform doses of anti-VEGF antibody or its antigen-binding fragment are administered to the subject, where the dose is 1120 mg.

[0070] In certain embodiments, the subject is administered one or more doses of anti-PD-L1 antibody or its antigen-binding fragment, where the dose is 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, or 15 mg / kg, 20 mg / kg, or 25 mg / kg. In some embodiments, the subject is administered one or more doses of anti-PD-L1 antibody or its antigen-binding fragment, where the dose is 15 mg / kg.

[0071] In certain embodiments, one or more uniform doses of anti-PD-L1 antibody or its antigen-binding fragment are administered to the subject, where the doses are 500 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, and 1100 mg. The doses are mg, 1120 mg, 1125 mg, 1150 mg, 1175 mg, 1180 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, or 1875 mg. In some embodiments, one or more uniform doses of anti-PD-L1 antibody or its antigen-binding fragment are administered to the subject, where the dose is 1120 mg.

[0072] In certain embodiments, a subject is administered one or more uniform doses of a PARP inhibitor, where the doses are 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, a subject is administered one or more uniform doses of a PARP inhibitor, where the dose is 300 mg. In some embodiments, a PARP inhibitor in doses of 100 mg to 300 mg is administered twice daily, so the PARP inhibitor is administered in a daily dose of 200 mg to 600 mg. In other embodiments, the daily dose of the PARP inhibitor may be reduced.

[0073] In one particular non-limiting embodiment, step (a) comprises administering 15 mg / kg of an anti-VEGF antibody or its antigen-binding fragment, and 1120 mg of an anti-PD-L1 antibody or its antigen-binding fragment.

[0074] In one particular non-limiting embodiment, step (b) comprises administering 15 mg / kg of an anti-VEGF antibody or its antigen-binding fragment, 1120 mg of an anti-PD-L1 antibody or its antigen-binding fragment, and 300 mg of a PARP inhibitor.

[0075] As used herein, the terms “simultaneously administered,” “in combination,” or “combination therapy” refer to the simultaneous or sequential administration of multiple compounds or drugs. A first compound or drug may be administered before, simultaneously with, or after the administration of a second compound or drug; a third compound or drug may be administered before, simultaneously with, or after the administration of the first and / or second compound or drug; and a fourth compound or drug may be administered before, simultaneously with, or after the administration of the first, second, and / or third compound or drug. The first, second, third, and fourth compounds or drugs may be administered simultaneously or sequentially on the same day, or sequentially within one, two, three, four, five, six days, one week, two weeks, three weeks, or one month. In some embodiments, the compounds or drugs are administered simultaneously for the duration that each compound or drug exerts at least some physiological effect and / or remains effective. In some embodiments, the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents of step (a) are administered to the subject simultaneously, separately, and / or sequentially (for example, separately and sequentially). In some embodiments, the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the PARP inhibitor of step (b) are administered to the subject simultaneously, separately, and / or sequentially (for example, separately and sequentially). In some embodiments, the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment of step (b) are administered to the subject simultaneously, separately, and / or sequentially (for example, separately and sequentially).

[0076] In certain embodiments, the first step (step (a)) of the method disclosed herein or the first component of the combination disclosed herein comprises a therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment, administered over a treatment period of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 24 weeks, or more than 1 year. In certain embodiments, the first step (step (a)) of the method disclosed herein or the first component of the combination disclosed herein comprises a therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment, administered over a treatment period of 9 to 15 weeks.

[0077] In certain embodiments, a subsequent step of the method disclosed herein (step (b)) or a subsequent component of the combination disclosed herein comprises a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment, a therapeutically effective amount of anti-VEGF antibody or its antigen-binding fragment, and optionally a therapeutically effective amount of a PARP inhibitor, administered over a treatment period of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 24 weeks, 6 months, 8 months, 12 months, 14 months, 15 months, 16 months, 18 months, 20 months, or 24 months or longer. In certain embodiments, an anti-VEGF antibody or its antigen-binding fragment is administered over a treatment period of 1 to 16 months or more, and an anti-PD-L1 antibody or its antigen-binding fragment and any PARP inhibitor are administered over a treatment period of 1 to 24 months or more. In specific embodiments, an anti-VEGF antibody or its antigen-binding fragment is administered over a treatment period of 15 months, and an anti-PD-L1 antibody or its antigen-binding fragment and a PARP inhibitor are administered over a treatment period of 24 months.

[0078] In certain embodiments of the methods (a), compositions, and combinations of the present disclosure, a therapeutically effective dose of one or more chemotherapeutic agents is administered weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment is administered weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment is administered weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks.

[0079] In one particular embodiment of (a), a therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment are administered every three weeks.

[0080] In another specific embodiment of (a), a therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment are administered every three weeks for a minimum of three cycles and a maximum of five cycles. In another specific embodiment of (a), a therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment are administered every three weeks for nine to fifteen weeks.

[0081] In certain embodiments of method (b), composition, and combination of the present disclosure, a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment is administered weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; a therapeutically effective dose of anti-VEGF antibody or its antigen-binding fragment is administered weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; and a therapeutically effective dose of a PARP inhibitor is administered once daily, twice daily, or three times daily.

[0082] In one particular embodiment of (b), a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective dose of anti-VEGF antibody or its antigen-binding fragment are administered every three weeks.

[0083] In another specific embodiment of (b), a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective dose of anti-VEGF antibody or its antigen-binding fragment are administered every three weeks, and a therapeutically effective dose of a PARP inhibitor is administered twice daily.

[0084] In another specific embodiment of (b), a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment is administered every three weeks for 24 months, and a therapeutically effective dose of anti-VEGF antibody or its antigen-binding fragment is administered every three weeks for 15 months.

[0085] In another specific embodiment of (b), a therapeutically effective dose of anti-PD-L1 antibody or its antigen-binding fragment is administered every three weeks for 24 months, a therapeutically effective dose of a PARP inhibitor is administered twice daily for 24 months, and a therapeutically effective dose of anti-VEGF antibody or its antigen-binding fragment is administered every three weeks for 15 months.

[0086] In certain embodiments, a therapeutically effective dose of one or more chemotherapeutic agents is administered for a minimum of 4 cycles and a maximum of 6 cycles. In one embodiment, a first cycle of one or more chemotherapeutic agents is administered alone or in combination with an anti-VEGF antibody or its antigen-binding fragment before (a). Therefore, in certain embodiments, a therapeutically effective dose of one or more chemotherapeutic agents is administered for a minimum of 3 cycles and a maximum of 6 cycles. In certain embodiments, a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment (e.g., bevacizumab) is administered alone or in combination with one or more chemotherapeutic agents, starting in the first cycle or starting in the second cycle, for a maximum of 15 months and a total of up to 23 cycles. In certain embodiments, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment (e.g., durvalumab) is administered for a total of up to 24 months and a total of up to 35 cycles. In certain embodiments, a therapeutically effective dose of a PARP inhibitor (e.g., olaparib) is administered for a total of up to 24 months.

[0087] In certain embodiments, methods, compositions, and combinations for the treatment of ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, wherein (a) one or more chemotherapeutic doses are administered every three weeks for nine to fifteen weeks, an anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 1120 mg every three weeks for nine to fifteen weeks, an anti-VEGF antibody or its antigen-binding fragment is administered at a dose of 15 mg / kg every three weeks for nine to fifteen weeks, and (b) an anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 1120 mg every three weeks for 24 months, an anti-VEGF antibody or its antigen-binding fragment is administered at a dose of 15 mg / kg every three weeks for a total of 15 months, and any PARP inhibitor is administered at a dose of 300 mg twice daily for a total of 24 months.

[0088] In certain embodiments, methods, compositions, and combinations for the treatment of ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, wherein (a) 175 mg / m² 2 (b) Paclitaxel at a dose of 120 mg and carboplatin at a dose of AUC5 or AUC6 are administered intravenously every 3 weeks for 9 to 15 weeks, durvalumab at a dose of 1120 mg every 3 weeks for 9 to 15 weeks, bevacizumab at a dose of 15 mg / kg every 3 weeks for 9 to 15 weeks, followed by (b) durvalumab at a dose of 1120 mg every 3 weeks for 24 months, bevacizumab at a dose of 15 mg / kg every 3 weeks for a total of 15 months, and optionally olaparib at a dose of 300 mg twice daily for a total of 24 months.

[0089] In certain embodiments, methods, compositions, and combinations for the treatment of ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, wherein the first step of the method disclosed herein (step (a)) or the first component of the combination disclosed herein comprises the administration of 3 to 5 doses of an anti-VEGF antibody or its antigen-binding fragment, 3 to 5 doses of an anti-PD-L1 antibody or its antigen-binding fragment, and 3 to 5 cycles of one or more chemotherapeutic agents.

[0090] In certain embodiments, methods, compositions, and combinations for the treatment of ovarian cancer in subjects requiring treatment for ovarian cancer are provided herein, wherein a subsequent step of the method disclosed herein (step (b)) or a subsequent component of the combination disclosed herein comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment every three weeks for up to 15 months, a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks for up to 24 months, and an administration of a PARP inhibitor twice daily for any up to 24 months.

[0091] In certain embodiments of the disclosed methods, compositions and / or combinations, step / combination (a) is administered before step / combination (b). In other embodiments, step / combination (b) is not administered until after the completion of step / combination (a).

[0092] In certain embodiments, the subject has completed one or more cycles of chemotherapy prior to administration of the disclosed methods, compositions, and / or combinations. In some embodiments, the subject has completed one, two, three, four, or five cycles of chemotherapy prior to administration of the disclosed methods, compositions, and combinations. In another embodiment, one or more chemotherapeutic agents are administered prior to (a). In one non-limiting embodiment, one or more chemotherapeutic agents administered prior to (a) are administered in one cycle. In one non-limiting embodiment, one or more chemotherapeutic agents administered prior to (a), either alone or in combination with an anti-VEGF antibody or its antigen-binding fragment, are administered three weeks before the start of (a).

[0093] As used herein, the terms “pharmaceutical composition” or “therapeutic composition” refer to a compound or composition that, when appropriately administered to a subject, can induce a desired therapeutic effect. 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.

[0094] As used herein, the terms “pharmaceutically acceptable carrier” or “physiologically acceptable carrier” refer to one or more formulation materials suitable for achieving or enhancing the delivery of one or more antibodies of this disclosure.

[0095] When used for in vivo administration, the formulations of the present disclosure should be sterile. The formulations of the present disclosure may be sterilized by various sterilization methods, such as sterile filtration or irradiation. In one embodiment, the formulation is sterilized by filtration through a pre-sterilized 0.22 micron filter. Sterile compositions for injection may be formulated in accordance with conventional pharmaceutical practices, such as those described in "Remington: The Science & Practice of Pharmacy," 21st ed., Lippincott Williams & Wilkins, (2005).

[0096] In some embodiments, antibodies can be formulated for administration via specific routes of administration, such as oral, nasal, pulmonary, topical (including oral and sublingual), rectal, vaginal, and / or parenteral administration. As used herein, the terms “parenteral administration” and “administered parenterally” refer to modes of administration other than intestinal and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions. Formulations of the present disclosure suitable for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Antibodies and other active substances may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed (see, for example, U.S. Patents Nos. 7,378,110, 7,258,873, and 7,135,180, and U.S. Patent Applications Publications 2004 / 0042972 and 2004 / 0042971).

[0097] The formulations may be provided in unit dosage forms and may be prepared by any method known in the field of pharmacy. The actual dose levels of the active ingredient in the formulations of this disclosure may be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject (e.g., "therapeutic effective dose"). Dosage may also be administered via continuous infusion (e.g., by pump). Dosage may also be route-dependent. For example, subcutaneous administration may require a higher dose than intravenous administration.

[0098] Without limiting the scope of this disclosure, several embodiments of this disclosure are described herein for illustrative purposes. Embodiment 1. A method for treating ovarian cancer in a subject requiring treatment for ovarian cancer, comprising administering to the subject (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

[0099] Embodiment 2. A method for treating ovarian cancer in a subject requiring treatment for ovarian cancer, comprising administering to the subject (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment.

[0100] Embodiment 3. The method according to either Embodiment 1 or Embodiment 2, wherein step (b) is performed after the completion of step (a).

[0101] Embodiment 4. A method according to any one of Embodiments 1 to 3, further comprising administering to a subject, prior to step (a), (i) a therapeutically effective dose of one or more chemotherapeutic agents, or (ii) a therapeutically effective dose of one or more chemotherapeutic agents and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment.

[0102] Embodiment 5. A method of Embodiment 4, further comprising administering to a subject, prior to step (a), (i) at least one therapeutically effective dose of one or more chemotherapeutic agents, or (ii) at least one therapeutically effective dose of one or more chemotherapeutic agents and at least one therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment.

[0103] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the anti-VEGF antibody or its antigen-binding fragment is bevacizumab.

[0104] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

[0105] Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein the PARP inhibitor is olaparib.

[0106] Embodiment 9. The method according to any one of Embodiments 1 to 8, wherein an anti-VEGF antibody or its antigen-binding fragment is administered at a dose of 5 mg / kg to 20 mg / kg.

[0107] Embodiment 10. The method according to Embodiment 9, wherein an anti-VEGF antibody or its antigen-binding fragment is administered at a dose of 15 mg / kg.

[0108] Embodiment 11. The method according to any one of Embodiments 1 to 10, wherein an anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 800 mg to 1500 mg.

[0109] Embodiment 12. The method according to Embodiment 11, wherein an anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 1120 mg.

[0110] Embodiment 13. The method according to any one of Embodiments 1 to 10, wherein an anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 10 mg / kg to 20 mg / kg.

[0111] Embodiment 14. The method according to Embodiment 13, wherein an anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 15 mg / kg.

[0112] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein the PARP inhibitor is administered in a dose of 100 mg to 300 mg.

[0113] Embodiment 16. The method according to Embodiment 15, wherein the PARP inhibitor is administered at a dose of 300 mg.

[0114] Embodiment 17. The method according to any one of Embodiments 1 to 16, wherein one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

[0115] Embodiment 18. Paclitaxel is 175 mg / m² 2 The method according to any one of Embodiments 1 to 17, administered in the dose of [specify dose].

[0116] Embodiment 19. The method according to either Embodiment 16 or Embodiment 18, wherein carboplatin is administered in a dose that produces an area under the curve (AUC) of AUC5 or AUC6.

[0117] Embodiment 20. The method according to any one of Embodiments 1 to 19, wherein step (a) comprises administering an anti-VEGF antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents every 2 to 4 weeks.

[0118] Embodiment 21. The method according to Embodiment 20, wherein step (a) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment, a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents every 2 to 4 weeks over a period of 9 to 18 weeks.

[0119] Embodiment 22. The method according to any one of Embodiments 1 to 19, wherein step (a) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment, a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents in a certain cycle, every three weeks.

[0120] Embodiment 23. The method according to Embodiment 22, wherein step (a) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment, a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents every three weeks for 9 to 15 weeks.

[0121] Embodiment 24. The method according to any one of Embodiments 1 to 23, wherein step (a) comprises administering 3 to 5 doses of an anti-VEGF antibody or its antigen-binding fragment, 3 to 5 doses of an anti-PD-L1 antibody or its antigen-binding fragment, and 3 to 5 cycles of one or more chemotherapeutic agents.

[0122] Embodiment 25. The method according to any one of Embodiments 1 to 24, wherein step (a) comprises administering 15 mg / kg of anti-VEGF antibody or its antigen-binding fragment and 1120 mg of anti-PD-L1 antibody or its antigen-binding fragment.

[0123] Embodiment 26. The method according to Embodiment 25, wherein step (a) includes the administration of 15 mg / kg of bevacizumab and 1120 mg of durvalumab.

[0124] Embodiment 27. The method according to Embodiment 26, wherein step (a) includes administration of 15 mg / kg bevacizumab every three weeks and 1120 mg durvalumab every three weeks.

[0125] Embodiment 28. Step (a) is 175 mg / m² 2 Paclitaxel and / or 25 mg / m² 2 The method according to any one of embodiments 25 to 27, further comprising the administration of cisplatin.

[0126] Embodiment 29. The method according to any one of Embodiments 1 to 28, wherein step (b) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment and a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks.

[0127] Embodiment 30. The method according to any one of Embodiments 1 to 29, wherein step (b) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment and a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks.

[0128] Embodiment 31. The method according to any one of Embodiments 1 to 28, wherein step (b) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment and a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks, and a certain dose of a PARP inhibitor twice daily.

[0129] Embodiment 32. The method according to any one of Embodiments 1 to 29, wherein step (b) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment and a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks, and a certain dose of a PARP inhibitor twice daily.

[0130] Embodiment 33. The method of Embodiment 22, wherein step (b) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment every three weeks for up to 15 months, and a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks for up to 24 months.

[0131] Embodiment 34. The method according to Embodiment 22, wherein step (b) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment every three weeks for up to 15 months, a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks for up to 24 months, and a PARP inhibitor twice daily for up to 24 months.

[0132] Embodiment 35. The method according to any one of Embodiments 1 to 30 or 33, wherein step (b) comprises administering 15 mg / kg of anti-VEGF antibody or its antigen-binding fragment and 1120 mg of anti-PD-L1 antibody or its antigen-binding fragment.

[0133] Embodiment 36. The method according to Embodiment 35, wherein step (b) includes administration of 15 mg / kg bevacizumab every three weeks and 1120 mg durvalumab every three weeks.

[0134] Embodiment 37. The method according to any one of Embodiments 1 to 28, 31, 32, or 34, wherein step (b) comprises administering 15 mg / kg of an anti-VEGF antibody or its antigen-binding fragment, 1120 mg of an anti-PD-L1 antibody or its antigen-binding fragment, and 300 mg of a PARP inhibitor.

[0135] Embodiment 38. The method according to Embodiment 37, wherein step (b) includes the administration of 15 mg / kg of bevacizumab, 1120 mg of durvalumab, and 300 mg of olaparib.

[0136] Embodiment 39. The method according to Embodiment 38, wherein step (b) comprises administering 15 mg / kg of bevacizumab every three weeks, 1120 mg of durvalumab every three weeks, and 300 mg of olaparib twice daily.

[0137] Embodiment 40. The method according to any one of Embodiments 1 to 39, wherein an anti-VEGF antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents are administered intravenously.

[0138] Embodiment 41. The method according to any one of Embodiments 1 to 40, wherein the PARP inhibitor is administered orally.

[0139] Embodiment 42. The method according to any one of Embodiments 1 to 41, wherein the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents in step (a) are administered to the subject simultaneously, separately, and / or sequentially.

[0140] Embodiment 43. The method according to any one of Embodiments 1 to 42, wherein the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment in step (b) are administered to the subject simultaneously, separately, and / or sequentially.

[0141] Embodiment 44. The method according to any one of Embodiments 1 to 42, wherein the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the PARP inhibitor of step (b) are administered to the subject simultaneously, separately, and / or sequentially.

[0142] Embodiment 45. The method according to any one of Embodiments 1 to 44, wherein the ovarian cancer is advanced ovarian cancer.

[0143] Embodiment 46. The method according to any one of Embodiments 1 to 45, wherein the ovarian cancer is high-grade epithelial ovarian cancer.

[0144] Embodiment 47. The method according to any one of Embodiments 1 to 46, wherein the ovarian cancer is a non-tBRCAm ovarian cancer tumor without BRCA1 / BRCA2 mutations.

[0145] Embodiment 48. The method according to any one of Embodiments 1 to 47, wherein the ovarian cancer is an ovarian cancer tumor that is homologous recombination deficiency (HRD) positive.

[0146] Embodiment 49. The method according to any one of Embodiments 1 to 47, wherein the ovarian cancer is an ovarian cancer tumor that is homologous recombination deficiency (HRD) negative.

[0147] Embodiment 50. The method according to any one of Embodiments 1 to 49, wherein the treatment results in an increased progression-free survival in the subject compared to a patient who received bevacizumab and chemotherapy alone.

[0148] Embodiment 51. The method according to Embodiment 50, wherein the treatment results in an increase in progression-free survival of at least four months.

[0149] Embodiment 52. The method according to any one of Embodiments 1 to 50, wherein the treatment results in an increase in overall survival in the subject compared to a patient who received bevacizumab and chemotherapy alone.

[0150] Embodiment 53. The method according to Embodiment 52, wherein the treatment results in an increase in overall survival of at least four months.

[0151] Embodiment 54. A combination for use in the treatment of ovarian cancer in a subject requiring treatment for ovarian cancer, comprising: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

[0152] Embodiment 55. A combination for use in the treatment of ovarian cancer in a subject requiring treatment for ovarian cancer, comprising: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment.

[0153] Embodiment 56. The combination for use according to either Embodiment 54 or Embodiment 55, wherein the anti-VEGF antibody or its antigen-binding fragment is bevacizumab.

[0154] Embodiment 57. A combination for use according to any one of Embodiments 54 to 56, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

[0155] Embodiment 58. The combination for use according to any one of Embodiments 54, 56, or 57, wherein the PARP inhibitor is olaparib.

[0156] Embodiment 59. A combination for use according to any one of Embodiments 54 to 58, comprising a therapeutically effective amount of anti-VEGF antibody or its antigen-binding fragment in doses of 5 mg / kg to 20 mg / kg.

[0157] Embodiment 60. The combination for use according to Embodiment 59, wherein the dose of the anti-VEGF antibody or its antigen-binding fragment is 15 mg / kg.

[0158] Embodiment 61. A combination for use according to any one of Embodiments 54 to 60, comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment in a dose of 800 mg to 1500 mg.

[0159] Embodiment 62. The combination for use according to Embodiment 61, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 1120 mg.

[0160] Embodiment 63. A combination for use according to any one of Embodiments 54 to 62, comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment in a dose of 10 mg / kg to 20 mg / kg.

[0161] Embodiment 64. The combination for use according to Embodiment 63, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg.

[0162] Embodiment 65. A combination for use according to any one of Embodiments 54 to 64, wherein the therapeutically effective dose of the PARP inhibitor is in a dose of 100 mg to 300 mg.

[0163] Embodiment 66. The combination for use according to Embodiment 65, wherein the dose of the PARP inhibitor is 300 mg.

[0164] Embodiment 67. A combination for use according to any one of Embodiments 54 to 66, wherein one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

[0165] Embodiment 68. A therapeutically effective dose of paclitaxel is 175 mg / m². 2 A combination for use according to Embodiment 67, including the dosage of the above.

[0166] Embodiment 69. A combination for use according to either Embodiment 67 or Embodiment 68, comprising a dose of therapeutically effective carboplatin that yields an area under the curve (AUC) of AUC5 or AUC6.

[0167] Embodiment 70. A combination for use according to any one of Embodiments 54 to 69, wherein the administration of an anti-VEGF antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents is performed every 2 to 4 weeks.

[0168] Embodiment 71. The combination for use described in Embodiment 70, wherein the administration is every 2 to 4 weeks over a period of 9 to 18 weeks.

[0169] Embodiment 72. A combination for use according to either Embodiment 70 or Embodiment 71, wherein the administration is every three weeks.

[0170] Embodiment 73. The combination for use described in Embodiment 72, wherein the administration is every three weeks over a period of 9 to 15 weeks.

[0171] Embodiment 74. A combination for use according to any one of Embodiments 54 to 73, wherein the administration of anti-VEGF antibody or its antigen-binding fragment is 4 to 6 doses, the administration of anti-PD-L1 antibody or its antigen-binding fragment is 3 to 5 doses, and the administration of one or more chemotherapeutic agents is 4 to 6 doses.

[0172] Embodiment 75. A combination for use according to any one of Embodiments 54 to 74, wherein the subject is administered (i) one or more chemotherapeutic agents, or (ii) one or more chemotherapeutic agents and an anti-VEGF antibody or its antigen-binding fragment, before the administration of an anti-VEGF antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents.

[0173] Embodiment 76. The combination for use according to Embodiment 75, wherein the subject is administered (i) at least one dose of one or more chemotherapeutic agents, or (ii) at least one dose of one or more chemotherapeutic agents and at least one dose of anti-VEGF antibody or its antigen-binding fragment, before the administration of an anti-VEGF antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents.

[0174] Embodiment 77(a) is a combination for use according to any one of Embodiments 54 to 76, comprising the administration of an anti-VEGF antibody or its antigen-binding fragment at a dose of 15 mg / kg and an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg.

[0175] Embodiment 78. The combination for use according to Embodiment 77, wherein the anti-VEGF antibody or its antigen-binding fragment is bevacizumab and the dose of bevacizumab is 15 mg / kg, and the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab and the dose of durvalumab is 1120 mg.

[0176] Embodiment 79. The combination for use according to either Embodiment 77 or Embodiment 78, wherein the anti-VEGF antibody or its antigen-binding fragment is bevacizumab and the dose of bevacizumab is 15 mg / kg every three weeks, and the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab and the dose of durvalumab is 1120 mg every three weeks.

[0177] Embodiment 80(a) is 175 mg / m² 2 Paclitaxel and 25 mg / m² 2 A combination for use according to any one of embodiments 77 to 79, further comprising cisplatin.

[0178] Embodiment 81(b) is a combination for use according to any one of Embodiments 54 to 80, comprising administration of an anti-VEGF antibody or its antigen-binding fragment and an anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks.

[0179] Embodiment 82(b) is a combination for use according to any one of Embodiments 54 to 80, comprising administration of an anti-VEGF antibody or its antigen-binding fragment and an anti-PD-L1 antibody or its antigen-binding fragment every three weeks.

[0180] Embodiment 83(b) is a combination for use according to any one of Embodiments 54 to 80, comprising administration of an anti-VEGF antibody or its antigen-binding fragment and an anti-PD-L1 antibody or its antigen-binding fragment every 2 to 4 weeks, and a PARP inhibitor twice daily.

[0181] Embodiment 84(b) is a combination for use according to any one of Embodiments 54 to 83, comprising administration of an anti-VEGF antibody or its antigen-binding fragment and an anti-PD-L1 antibody or its antigen-binding fragment every three weeks, and a PARP inhibitor twice daily.

[0182] Embodiment 85(b) is a combination for use according to any one of Embodiments 54 to 82, comprising the administration of an anti-VEGF antibody or its antigen-binding fragment at a dose of 15 mg / kg and an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg.

[0183] Embodiment 86(b) is the method of Embodiment 85, wherein Embodiment 86(b) comprises administering a certain dose of an anti-VEGF antibody or its antigen-binding fragment every three weeks for up to 15 months, and a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks for up to 24 months.

[0184] The combination for use according to Embodiment 85, wherein the anti-VEGF antibody or antigen-binding fragment of Embodiment 87(b) is bevacizumab and the dose of bevacizumab is 15 mg / kg, and the anti-PD-L1 antibody or antigen-binding fragment of (b) is durvalumab and the dose of durvalumab is 1120 mg.

[0185] The combination for use according to either Embodiment 85 or Embodiment 86, wherein the anti-VEGF antibody or antigen-binding fragment of Embodiment 88(b) is bevacizumab and the dose of bevacizumab is 15 mg / kg every three weeks, and the anti-PD-L1 antibody or antigen-binding fragment of (b) is durvalumab and the dose of durvalumab is 1120 mg every three weeks.

[0186] Embodiment 89. A combination for use according to any one of Embodiments 54-80, 83, or 84, comprising an anti-VEGF antibody or its antigen-binding fragment at a dose of 15 mg / kg, an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg, and a PARP inhibitor at a dose of 300 mg.

[0187] Embodiment 90(b) is the combination according to Embodiment 89, comprising administration of a certain dose of an anti-VEGF antibody or its antigen-binding fragment every three weeks for up to 15 months, a certain dose of an anti-PD-L1 antibody or its antigen-binding fragment every three weeks for up to 24 months, and a twice-daily dose of a PARP inhibitor for up to 24 months.

[0188] The combination for use according to Embodiment 89, wherein the anti-VEGF antibody or antigen-binding fragment of Embodiment 91(b) is bevacizumab and the dose of bevacizumab is 15 mg / kg, the anti-PD-L1 antibody or antigen-binding fragment of (b) is durvalumab and the dose of durvalumab is 1120 mg, and the PARP inhibitor of (b) is olaparib and the dose of olaparib is 300 mg.

[0189] A combination for use according to either Embodiment 89 or Embodiment 90, wherein the anti-VEGF antibody or antigen-binding fragment of Embodiment 92(b) is bevacizumab and the dose of bevacizumab is 15 mg / kg every three weeks, the anti-PD-L1 antibody or antigen-binding fragment of (b) is durvalumab and the dose of durvalumab is 1120 mg every three weeks, and the PARP inhibitor of (b) is olaparib and the dose of olaparib is 300 mg twice daily.

[0190] Embodiment 93. A combination for use according to any one of Embodiments 54 to 92, wherein the administration of an anti-VEGF antibody or its antigen-binding fragment, an anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents is intravenous.

[0191] Embodiment 94. A combination of use according to any one of Embodiments 54 to 93, wherein the administration of the PARP inhibitor is orally.

[0192] A combination for use according to any one of Embodiments 54 to 94, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents is carried out simultaneously, separately, and / or sequentially.

[0193] A combination for use according to any one of embodiments 54 to 95, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment is carried out simultaneously, separately, and / or sequentially.

[0194] A combination of uses according to any one of embodiments 54 to 95, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the PARP inhibitor is carried out simultaneously, separately, and / or sequentially.

[0195] Embodiment 98. A combination of uses according to any one of Embodiments 54 to 97, wherein the ovarian cancer is advanced ovarian cancer.

[0196] Embodiment 99. A combination for use according to any one of Embodiments 54 to 98, wherein the ovarian cancer is high-grade epithelial ovarian cancer.

[0197] Embodiment 100. A combination of uses according to any one of Embodiments 54 to 99, wherein the ovarian cancer is a non-tBRCAm ovarian cancer tumor without BRCA1 / BRCA2 mutations.

[0198] Embodiment 101. A combination for use according to any one of Embodiments 54 to 100, wherein the ovarian cancer is an ovarian cancer tumor that is homologous recombination deficiency (HRD) positive.

[0199] Embodiment 102. A combination for use according to any one of Embodiments 54 to 100, wherein the ovarian cancer is an ovarian cancer tumor that is homologous recombination deficiency (HRD) negative.

[0200] Embodiment 103. A combination for use according to any one of Embodiments 54 to 102, wherein the combination therapy results in an increased progression-free survival in the subject compared to patients who received bevacizumab and chemotherapy alone.

[0201] Embodiment 104. A combination of the treatments described in Embodiment 103 for use, wherein the treatment results in an increase in progression-free survival of at least four months.

[0202] Embodiment 105. A combination for use according to any one of Embodiments 54 to 102, wherein the combination therapy results in an increase in overall survival in the subject compared to patients who received bevacizumab and chemotherapy alone.

[0203] Embodiment 106. A combination of the treatments described in Embodiment 105 for use, wherein the treatment results in an increase in overall survival of at least four months.

[0204] Embodiment 107. Use of a combination in the manufacture of a pharmaceutical for the treatment of ovarian cancer in a subject requiring treatment for ovarian cancer, wherein the combination comprises (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

[0205] Embodiment 108. Use of a combination in the manufacture of a pharmaceutical for the treatment of ovarian cancer in a subject requiring treatment for ovarian cancer, wherein the combination comprises (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment. [Examples]

[0206] The following embodiments illustrate specific embodiments of the Disclosure and various uses thereof. They are provided for illustrative purposes only and should not be construed as limiting the scope of the Disclosure.

[0207] Example 1: Interim Analysis 1 (DCO-5 Dec 2022) - Durvalumab, paclitaxel / carboplatin, and bevacizumab, followed by maintenance therapy with durvalumab, bevacizumab, and olaparib in newly diagnosed patients with advanced ovarian cancer without tumor BRCA1 / BRCA2 mutations. The Phase III DUO-O trial evaluates paclitaxel / carboplatin + bevacizumab + durvalumab followed by bevacizumab + durvalumab + olaparib maintenance therapy in newly diagnosed patients with non-tBRCAm advanced occlusive disease, including a progression-free survival analysis from the DUO-O trial.

[0208] DUO-O enrolled patients who had not previously received systemic therapy and had not received PARP inhibitors or immune-mediated therapy. Furthermore, patients without tumor BRCA mutations could be enrolled if their disease was stable.

[0209] 1. Method As shown in Figure 1, after completing one cycle of chemotherapy, patients were randomly assigned in a 1:1:1 ratio to arms 1, 2, or 3. Randomization was stratified by the timing and outcome of cytoreductive surgery, as well as geographical location. Homologous recombination deficiency or HRD status was not a stratification factor in DUO-O randomization. Arm 1, the control arm, consisted of paclitaxel / carboplatin + bevacizumab followed by maintenance bevacizumab. Arm 2 consisted of paclitaxel / carboplatin + bevacizumab + durvalumab followed by maintenance bevacizumab + durvalumab. Arm 3 consisted of paclitaxel / carboplatin + bevacizumab + durvalumab followed by maintenance bevacizumab + durvalumab + olaparib.

[0210] All patients who completed the chemotherapy phase were able to proceed to the maintenance phase and continued treatment until disease progression, completion of the study treatment, or other discontinuation criteria were met as assessed by the principal investigator.

[0211] As shown in Figure 2, the primary endpoint in DUO-O was PFS in Arm 3, which included olaparib, versus Arm 1, which was a chemotherapy-plus-bevacizumab backbone arm, as assessed by the investigator first in the non-tumor BRCA mutation HRD-positive population, and then in the intention-to-treat or ITT population. HRD status was predictively assessed using the Myriad MyChoice CDx assay, and if the tumor was HRD-positive, HRD was determined using a cutoff of 42 or higher for the genomic instability score.

[0212] Key secondary endpoints included PFS, overall survival or OS, and safety in the ITT population, for arm 2 (durvalumab arm) versus arm 1 (chemotherapy + bevacizumab backbone).

[0213] As shown in Figure 3, the planned sample size was approximately 1,104, and a superiority intermediate PFS analysis was planned for when approximately 86% of the targeted PFS events occurred in arm 3 versus arm 1 in both the non-tumor BRCA mutation HRD-positive population and the ITT population.

[0214] Non-tBRCAm cohort Approximately 1104 patients without BRCA1 and BRCA2 mutations that are harmful or suspected to be harmful were randomized in a 1:1:1 ratio to receive berncizumab, followed by bevacizumab maintenance, and an additional 5 cycles of platinum-based chemotherapy for a maximum total of 15 months of treatment. The China cohort requires approximately 120 non-tBRCAm patients randomly assigned (1:1:1) from Chinese centers. If necessary, recruitment for the China cohort will continue after the global population has reached approximately 1104 patients. The investigational treatment will be conducted as described below. (i) Arm 1 (SoC): Patients in Arm 1 will receive saline IV Q3W as a placebo for durvalumab for a total of up to 35 cycles (24 months), starting from day 1 of cycle 2. At the end of chemotherapy, patients will receive placebo tablets corresponding to olaparib for a total of up to 24 months. (ii) Arm 2: Patients in Arm 2 will receive durvalumab 1120 mg Q3W for a total of up to 35 cycles (24 months) of treatment, starting from day 1 of cycle 2. At the end of chemotherapy, patients will also receive placebo tablets corresponding to olaparib for a total of up to 24 months. (iii) Arm 3: Patients in Arm 3 will be administered durvalumab 1120 mg Q3W for a total of up to 35 cycles (24 months) of treatment, starting from day 1 of cycle 2. At the end of chemotherapy, patients will also be administered 300 mg mouse olaparib tablets daily (bd) for a total of up to 24 months.

[0215] Multiple testing was used in the DUO-O trial. In the non-tumor BRCA mutation HRD-positive population, 5% alpha was allocated to compare PFS between Arm 3 (olaparib arm) and Arm 1 (chemotherapy + bevacizumab backbone). In the ITT population, 5% alpha was allocated to compare PFS between Arm 3 and Arm 1 when statistical significance was reached. In the ITT population, PFS was assessed between Arm 2 (durvalumab arm) and Arm 1, but will be reassessed in the final PFS analysis. As shown in Figure 4, more than 90% of patients in DUO-O had a known HRD status. At baseline, patient characteristics were well balanced across treatment arms. Approximately 90% of patients across all arms completed all planned chemotherapy cycles. 88%, 86%, and 80% of patients in Arms 1, 2, and 3 initiated maintenance therapy (Figure 5).

[0216] In the HRD-positive population, the median follow-up period for censored patients was 25.6 months in Arm 3 versus 28.8 months in Arm 1, with data maturity rates of 35% and 60%, respectively.

[0217] 2.Results DUO-O met its primary endpoint in the planned progression-free survival interim analysis, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival with first-line chemotherapy + bevacizumab + durvalumab compared to the control group in patients with advanced OC, with subsequent maintenance bevacizumab + durvalumab + olaparib.

[0218] Non-tBRCAm HRD positive: HR 0.49 (0.34~0.69); P<0.0001.

[0219] Non-tBRCAm ITT:HR 0.63(0.52-0.76); P<0.0001.

[0220] A consistent progression-free survival benefit was observed across subgroups, including patients with HRD-negative disease (HR 0.68 [0.54~0.86]).

[0221] At the time of the interim PFS analysis, in the non-tBRCAm ITT population, chemotherapy + bevacizumab + durvalumab and subsequent maintenance bevacizumab + durvalumab showed a numerical, not statistical, improvement in PFS compared to the control group.

[0222] The safety findings were generally consistent with the known profiles of each drug.

[0223] A statistically significant improvement in PFS was observed between Arm 3 and Arm 1. The median PFS was 37.3 months and 23.0 months, respectively, with a hazard ratio (HR) of 0.49. At 18 months, the PFS rate was 84% ​​in Arm 3 compared to 69% in Arm 1 (Figure 6). Similarly, in the ITT population, a statistically significant improvement in PFS was observed between Arm 3 and Arm 1. The median PFS was 24.2 months in Arm 3 compared to 19.3 months in Arm 1, with an HR of 0.63. The results for the ITT population were slightly more mature than those for the HRD-positive population, with data maturity rates of 51% and 69% in Arm 3 and Arm 1, respectively (Figure 7). A numerical improvement in PFS was observed in Arm 2 compared to Arm 1, but it did not reach statistical significance. At 18 months, the PFS rates were 71% in Arm 3, 56% in Arm 2, and 55% in Arm 1 (Figure 8).

[0224] Because these analyses used unstratified Cox proportional hazards models, there are numerical differences between the HR and 95% CI for the HRD-positive data presented here and those for the primary endpoint analysis presented previously. A benefit in PFS was observed in the HRD-negative population, with a median PFS of 17.4 months in arm 1 and 20.9 months in arm 3. For a comparison of PFS between arm 3 and arm 1, the HR was 0.68 in the HRD-negative subgroup (Figure 9). In arm 2, the median PFS in the HRD-negative population was 15.4 months (Figure 9).

[0225] The forest plot shows a consistent effect on PFS across subgroups for the ITT population in arm 3 versus arm 1 (Figure 10).

[0226] The incidence of serious adverse events was nearly consistent across the entire treatment arm during both the chemotherapy and maintenance phases (Figure 11). In particular, the incidence of myelodysplastic syndrome and acute myeloid leukemia, which are notable adverse events with olaparib, was low and consistent with previous Phase III trials in the first-line setting. The incidence of new primary malignancies and pneumonia was also low. Immune-mediated adverse events were reported throughout the trial, with a higher numerical proportion of patients experiencing such events in Arms 2 and 3 (Figure 11).

[0227] Overall, differences in discontinuation rates were observed between treatment arms, with a higher numerical percentage of patients discontinuing any treatment due to adverse events in Arm 3. 35% of patients in Arm 3, 26% in Arm 2, and 20% in Arm 1 discontinued any treatment due to adverse events (Figure 11).

[0228] Figure 12 shows adverse events of any grade with a frequency of 20% or more. In Arm 3, the most common adverse events during the maintenance period were nausea and anemia, reported by 52% and 41% of patients, respectively. In Arm 2, during the same period, nausea and anemia were reported by 17% and 10% of patients, respectively, and in Arm 1, nausea and anemia were reported by 15% and 5% of patients, respectively.

[0229] Similarly, among grade 3 or higher adverse events with an overall incidence of 5% or more, neutropenia and anemia were the most common events in arm 3 (Figure 13). During the maintenance period, grade 3 or higher anemia was reported in 21% of patients, compared to less than 1% in both arms 2 and 1. Other grade 3 or higher adverse events included leukopenia, hypertension, and thrombocytopenia. These adverse events were consistent with those predicted for the DUO-O treatment regimen (Figure 13).

[0230] DUO-O demonstrated a statistically significant and clinically meaningful improvement in PFS in patients with non-tumor BRCA-mutated advanced ovarian cancer, comparing arm 3 (first-line chemotherapy + bevacizumab + durvalumab followed by maintenance bevacizumab + durvalumab + olaparib) versus arm 1 (chemotherapy + bevacizumab followed by maintenance bevacizumab). The HR for PFS in arm 3 versus arm 1 was 0.49 in the non-tumor BRCA-mutated HRD-positive population, and 0.63 in the ITT population. A consistent PFS benefit for arm 3 versus arm 1 was reported across subgroup analyses including patients with HRD-negative disease. The HR for PFS in arm 3 versus arm 1 was 0.68 in the HRD-negative subgroup.

[0231] In the ITT population, arm 2 (chemotherapy + bevacizumab + durvalumab followed by maintenance bevacizumab + durvalumab) versus arm 1 (chemotherapy + bevacizumab followed by maintenance bevacizumab) showed a numerical but not statistically significant improvement in PFS.

[0232] The safety and tolerability of these combinations were generally consistent with those observed in previous clinical trials and in the known profiles of the individual drugs.

[0233] The DUO-O trial provides promising evidence for the combination of chemotherapy + bevacizumab + durvalumab followed by maintenance therapy with bevacizumab + durvalumab + olaparib in patients with non-tumor BRCA-mutated advanced ovarian cancer.

[0234] Example 2: Updated analysis: In patients with newly diagnosed advanced ovarian cancer without tumor BRCA1 / BRCA2 mutations, durvalumab and paclitaxel / carboplatin and bevacizumab, followed by maintenance with durvalumab, bevacizumab, and olaparib DUO-O met its primary endpoint, and carboplatin / paclitaxel, bevacizumab + durvalumab, and subsequent maintenance bevacizumab, durvalumab + olaparib were statistically significant and provided clinically meaningful progression-free survival benefits over carboplatin / paclitaxel + bevacizumab and subsequent maintenance bevacizumab in both the non-tBRCAm homologous recombination deficiency positive population and the intention-to-treat population. The safety profile observed in the experimental arms was generally consistent with the individual agents.

[0235] 1. Methods The materials and methods are as outlined in Example 1. Randomization and treatment All patients received Cycle 1 of chemotherapy and were determined for tBRCAm status (Figure 15). During Cycle 1 of chemotherapy, patients were intravenously administered carboplatin with an area under the serum concentration-time curve (AUC) of 5 or 6 and intravenous paclitaxel at 175 mg / m 2 was administered. Cycle 1 may have included 15 mg / kg of intravenous bevacizumab according to local practice.

[0236] After the BRCAm status was determined, before Cycle 2 of chemotherapy, non-tBRCA patients were randomly assigned (1:1:1) to receive paclitaxel at 175 mg / m every 3 weeks 2, Carboplatin every 3 weeks for 3 cycles (total of 6 cycles) with AUC5 or AUC6, and bevacizumab 15 mg / kg every 3 weeks + durvalumab placebo followed by bevacizumab 15 mg / kg every 3 weeks (total of 15 months), durvalumab placebo + olaparib placebo (control arm); Carboplatin / paclitaxel, bevacizumab every 3 weeks + intravenous durvalumab 1120 mg followed by maintenance bevacizumab every 3 weeks, durvalumab 1120 mg (total of 24 months) + olaparib placebo (durvalumab arm); or Carboplatin / paclitaxel + bevacizumab + durvalumab followed by maintenance bevacizumab + durvalumab + olaparib tablets 300 mg, twice daily (total of 24 months) (durvalumab + olaparib arm) were administered. Randomization was stratified according to the timing and outcome of debulking surgery (no macroscopic residual disease after upfront surgery vs. macroscopic residual disease after upfront surgery or planned interval debulking surgery) and geographical region (North America vs. Europe vs. the rest of the world).

[0237] Treatment was continued until the patient experienced objective radiographic disease progression (modified RECIST v1.1), met other stopping criteria, or completed the described period(s) of investigational treatment(s). Patients who did not have objective disease progression during the chemotherapy phase and met other predefined requirements could initiate maintenance therapy. Patients who discontinued one or more investigational treatments due to an adverse event (AE) considered to be due to one of the investigational treatments but not to the others could continue with the remaining investigational treatment(s).

[0238] Patients who could not initiate olaparib / placebo maintenance within 9 weeks from the last day of chemotherapy infusion continued with durvalumab / placebo and bevacizumab as maintenance therapy. Also, durvalumab / placebo was continued during the period of 3 to 9 weeks after the last day of chemotherapy infusion if the olaparib / placebo initiation criteria were not yet met.

[0239] Patients whose disease was stable at the end of maintenance therapy could continue to receive investigational treatment.

[0240] Outcome and evaluation During the trial period, homologous recombination deficiency (HRD) status was established as a clinically relevant biomarker in newly diagnosed ovarian cancer, along with other studies. 6、10、14、15 Following the release of results, the durvalumab + olaparib arm was prioritized, and on June 11, 2021, the primary endpoint was modified to progression-free survival (PFS; time from randomization to investigator-assessed progression [modified RECIST v1.1] or death) in the durvalumab + olaparib arm versus the control arm. PFS was formally statistically tested in a fixed hierarchical order in the non-tBRCAm HRD-positive population (defined as GIS ≥ 42), followed by the intention-to-treat population. PFS in the intention-to-treat population compared to the durvalumab arm versus the control arm was an important secondary endpoint included in the hierarchical testing. Pre-specified sensitivity and subgroup analyses of PFS were performed.

[0241] Secondary endpoints included progression-free survival (PFS) in the intend-to-treat population between the durvalumab arm and the control arm, as assessed by the investigator; overall survival (OS; time from randomization to death) in the non-tBRCAm HRD-positive population and the intend-to-treat population between the durvalumab + olaparib arm and the control arm, and in the intend-to-treat population between the durvalumab arm and the control arm; and time from randomization to progression 2 (assessment by the investigator as radiological, clinical, or CA-125 progression) or death (PFS2).

[0242] Tumor evaluation Patient tumors were evaluated by CT or magnetic resonance imaging (MRI) according to the modified RECIST v1.1. Baseline scans were performed within 28 days prior to the start of cycle 1 of chemotherapy (for patients who underwent primary debulking surgery, baseline scans were performed post-surgery), and for patients who underwent interval debulking surgery, additional scans were performed pre-surgery. Subsequent scans were performed within 3 weeks (±1 week) after the last dose of chemotherapy and before the start of maintenance therapy, then every 12 weeks (±2 weeks) for up to 3 years until objective radiological disease progression relative to the date of completion of the chemotherapy evaluation scan, and then every 24 weeks (±2 weeks). All treatment decisions were based on site evaluation by scan. Subsequent assessments of disease progression followed local clinical practice.

[0243] 2.Results Between January 30, 2019, and June 17, 2021, 1,130 non-tBRCAm patients were randomized. Of 378 patients, 376 were assigned to the control arm, of 374 patients, 373 were assigned to the durvalumab arm, and of 378 patients, 378 were assigned to the durvalumab + olaparib arm. All patients received at least one dose of the investigational treatment, and 331, 323, and 336 patients, respectively, initiated the maintenance phase (Figure 14).

[0244] DCOs for interim and final PFS analyses were conducted for each protocol on December 5, 2022, and September 18, 2023, respectively. The number of patients still receiving investigational treatment at the time of the DCO is shown in Figures 14A and 14B.

[0245] Regarding baseline characteristics, there was a good balance between the treatment arms in the treatment-intention group (Table 1) and the non-tBRCAm HRD-positive group (Table 1).

[0246] In the treatment intention population, the median (range) follow-up periods for PFS in censored patients were 25.5 (0.0–44.8) months, 23.1 (0.0–42.6) months, and 23.3 (0.0–41.7) months in the control arm, durvalumab arm, and durvalumab + olaparib arm, respectively, in the intermediate PFS analysis, and 34.5 (0.0–51.6) months, 33.1 (0.0–50.8) months, and 32.0 (0.0–51.3) months in the final PFS analysis.

[0247] In the pre-specified interim PFS analysis in the non-tBRCAm HRD-positive population, PFS events were observed in 135 out of 283 patients (data maturity, 47.7%), representing 135 out of 149 targeted PFS events (90.6%). The median PFS was 37.3 months in the durvalumab + olaparib arm and 23.0 months in the control arm (HR, 0.49 [95% CI, 0.34~0.69]; P<.0001) (Figure 16A). In the treatment intention population, PFS events were observed in 452 out of 756 patients (data maturity, 59.8%), representing 452 out of 453 targeted PFS events (99.8%). The median PFS was 24.2 months in the durvalumab + olaparib arm and 19.3 months in the control arm (HR, 0.63 [95% CI, 0.52~0.76]; P<.0001) (Figure 16B).

[0248] Because the primary endpoint was met, this interim PFS analysis (Example 1) (DCO: December 5, 2022) was designated as the primary analysis, and the final PFS analysis (DCO: September 18, 2023) for these treatment arms was descriptive. The improvement in PFS persisted in the final descriptive PFS analysis, with the HR for PFS in the durvalumab + olaparib arm versus the control arm being 0.46 (95% CI, 0.33–0.65) in the non-tBRCAm HRD-positive population (Figure 16C) and 0.61 (95% CI, 0.51–0.73) in the treatment intention population (Figure 16D).

[0249] Figure 16B shows the PFS of the durvalumab arm in the treatment intention population in the interim / primary PFS analysis. This treatment arm was re-evaluated in the final PFS analysis, at which point the median PFS was 20.6 months and 19.3 months in the durvalumab arm versus the control arm, respectively (HR, 0.87 [95% CI, 0.74~1.03]; P=.11) (Figure 16D).

[0250] The interim and final PFS analyses were supported by the results of pre-specified sensitivity analyses. In the pre-specified subgroup analyses, PFS was more favorable with the durvalumab + olaparib arm than with the control arm in all subgroups except the subgroup with unknown tumor area positivity (TAP5; PD-L1 expression) (Figures 18 and 19A). In both the interim PFS analysis (HR, 0.68 [95% CI, 0.58~0.86]) and the final PFS analysis (HR, 0.68 [95% CI, 0.54~0.85]), a PFS benefit was observed in the subgroup of patients with HRD-negative tumors between the durvalumab + olaparib arm and the control arm (Figures 21A and 21B). The results of the pre-specified subgroup analyses comparing the durvalumab arm and the control arm are shown in Figures 19B and 19C.

[0251] The hazard ratio (HR) for PFS2 was 0.82 (0.67–1.01) for the durvalumab + olaparib arm versus control and 0.91 (0.75–1.12) for the durvalumab arm versus control in the intention-to-treat population (Figure 20A), and 0.66 (0.43–1.00) for the durvalumab + olaparib arm versus control in the non-tBRCAm HRD-positive population (Figure 20B) (DCO: September 18, 2023). PFS2 in the HRD-negative subgroup is shown in Figure 21C. Intermediate OS data were immature (DCO: September 18, 2023). In the intention-to-treat population, 432 out of 1,130 patients died (data maturity, 38.2%). The median OS was 72.9 months and 72.5 months in the durvalumab + olaparib arm versus the control arm (HR, 0.95 [95% CI, 0.76~1.20]; P=.68), and 71.6 months and 72.5 months in the durvalumab arm versus the control arm (HR, 0.92 [95% CI, 0.73~1.16]) (Figure 20C). In the non-tBRCAm HRD-positive population, 65 out of 283 patients died (data maturity, 23.0%). Median OS was not reached in either the durvalumab + olaparib arm or the control arm (HR, 0.84 [95% CI, 0.51~1.37]) (Figure 20D). In the HRD-negative subgroup, the median OS was 41.1 months and 39.6 months in the durvalumab + olaparib arm versus the control arm, respectively (HR, 0.99 [95% CI, 0.76–1.31]) (Figure 21D).

[0252] Overall, grade 3 or higher adverse events were reported in 62.0% of patients in the control arm, 66.0% in the durvalumab arm, and 72.0% in the durvalumab + olaparib arm, respectively.

[0253] In the control arm, durvalumab arm, and durvalumab + olaparib arm, serious adverse events (AEs) were reported in 35.1%, 44.2%, and 39.7% of patients, respectively, and AEs with fatal outcomes, regardless of causal relationship, were reported in 1.1%, 2.4%, and 2.1% of patients, respectively.

[0254] In the control arm, durvalumab arm, and durvalumab + olaparib arm, MDS / AML was reported in 1 case (0.3%), 0 cases, and 3 cases (0.8%) of patients, respectively; new primary malignancies were reported in 3 cases (0.8%), 1 case (0.3%), and 5 cases (1.3%) of patients, respectively; and pneumonia was reported in 3 cases (0.8%), 5 cases (1.3%), and 7 cases (1.9%) of patients, respectively. In the durvalumab + olaparib arm, erythroid myelodysplasia and autoimmune hemolytic anemia were reported in 2 cases (0.5%) of patients, respectively, and no cases were reported in the durvalumab arm and the control arm.

[0255] Immune-mediated AEs were reported in 35.1%, 56.6%, and 54.0% of patients in the control arm, durvalumab arm, and durvalumab + olaparib arm, respectively.

[0256] AEs were usually managed by dose modification rather than discontinuation. Overall, trial treatment was discontinued due to AEs in 21.5%, 26.3%, and 34.7% of patients in the control arm, durvalumab arm, and durvalumab + olaparib arm, respectively.

[0257] PC + bev + durva followed by bev + durva + ola mtx continued to show improvement in PFS, with the longest mPFS of 4 months being observed in the non-tBRCAm HRD-positive population, and a related favorable trend in OS was observed. Safety was generally consistent with the known profiles of each drug.

[0258] [Table 2-1]

[0259] [Table 2-2] Abbreviations: ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IQR, interquartile range; TAP, tumor area positive PD-L1 expression. a Stratified data using randomization codes (geographical region, timing of weight loss surgery, and outcomes). b This includes patients whose prior surgery was partial or unsuccessful and who are also scheduled to undergo interval surgery. c The HRD status was assessed using the MyChoice® CDx assay (Myriad Genetic Laboratories, Salt Lake City, Utah). HRD positivity was defined as a genomic instability score of 42 or higher, HRD negativity as a genomic instability score of less than 42, and HRD unknown as the test was discontinued or failed. d The tumor HRRm status was evaluated using the Myriad tumor tissue gene panel. A positive HRRm status was defined as a specimen with a pathogenic mutation in one of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm status (non-HRRm) was defined as a specimen without pathogenic mutations in any of the pre-specified genes. An unknown HRRm status was defined as discontinuation or failure of the test. e PD-L1 expression was primarily evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics, Rothkreuz, Switzerland). High TAP5 was defined as ≥5%; low TAP5 was defined as <5%; and unknown TAP5 was defined as a sample for which PD-L1 expression was unavailable. 17

[0260] [Table 3-1]

[0261] [Table 3-2] Abbreviations: BRCA, BRCA1 and / or BRCA2; ECOG, East Coast Cancer Clinical Trials Group; FIGO, International Federation of Gynecology and Obstetrics; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IQR, interquartile range; non-tBRCAm, non-tumor BRCAm; PD-L1, programmed death ligand 1; TAP, tumor-positive PD-L1 expression. a Stratified data using randomization codes (geographical region, timing of weight loss surgery, and outcomes). b This includes patients whose prior surgery was partial or unsuccessful and who are also scheduled to undergo interval surgery. c The tumor HRRm status was evaluated using the Myriad tumor tissue gene panel. A positive HRRm status was defined as a specimen 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, or RAD54L. A negative HRRm status (non-HRRm) was defined as a specimen without pathogenic mutations in any of the pre-specified genes. An unknown HRRm status was defined as discontinuation or failure of the tumor HRRm test. d PD-L1 expression was primarily evaluated using the Ventana SP263 immunohistochemical assay (Roche Diagnostics, Rothkreuz, Switzerland). High TAP5 was defined as ≥5%; low TAP5 was defined as <5%; and unknown TAP5 was defined as a sample for which PD-L1 expression was unavailable.

[0262] [Table 4] Abbreviation: DCO, Data Cutoff. a The total period from the first dose to the last non-zero dose + 20 days, death, or DCO, whichever comes first. b The total time from the first dose of olaparib / placebo to the earliest of the last non-zero dose, death, or DCO. c Carboplatin or cisplatin substitutes. d Paclitaxel or nab-paclitaxel, docetaxel, or pegylated liposomal doxorubicin substitutes.

[0263] [Table 5] Abbreviation: DCO, Data Cutoff. a The total period from the first dose to the last non-zero dose + 20 days, death, or DCO, whichever comes first. b The total time from the first dose of olaparib / placebo to the earliest of the last non-zero dose, death, or DCO. c Carboplatin or cisplatin substitutes. d Paclitaxel or nab-paclitaxel, docetaxel, or pegylated liposomal doxorubicin substitutes.

[0264] [Table 6] * GIS was defined as 42 or higher (Myriad MyChoice® CDx assay). † Against Arm 1. ‡ HR and CI were estimated from stratified Cox proportional hazards models (stratified by timing and outcome of cytoreductive surgery [non-tBRCAm HRD-positive population], or by timing and outcome of cytoreductive surgery and geographical area [non-tBRCAm ITT population]). § Test boundary value: Two-tailed P<0.0248. [Table 7] HR and CI were estimated from an unstratified Cox proportional hazards model. ¶ Test boundary value: Two-tailed P<0.0104. * GIS was defined as less than 42 (Myriad MyChoice® CDx assay). CI (Confidence Interval); GIS (Genomic Instability Score); HR (Hazard Ratio); ITT (Intention to Treat); NR (Not Reached); tBRCAm (Tumor BRCA1 / BRCA Mutation).

[0265] Example 3: Interim Analysis 2 (DCO2-18 Sep 2023) PFS analysis of durvalumab (D) + paclitaxel / carboplatin (PC) + bevacizumab (B) followed by D, B + olaparib (O) maintenance (mtx) in newly diagnosed advanced ovarian cancer (AOC) without tumor BRCA1 / BRCA2 mutations (tBRCAm). The placebo-controlled DUO-O trial demonstrated a statistically significant clinically meaningful PFS benefit in the non-tBRCAm HRD+ and non-tBRCAm ITT populations with D+PC+B followed by D+B+O mtx versus PC+B followed by B.

[0266] 1. Method Patients (pts) had newly diagnosed high-grade epithelial AOCs and underwent primary interval debulking surgery or planned interval debulking surgery. After one cycle of PC±B, pts with non-tBRCAm AOCs were stratified by the timing and outcome of cytoreductive surgery (no macroscopic residual disease after prior primary surgery and all others), as well as geographical region (North America, Europe, and other regions), and randomized in a 1:1:1 ratio to arm 1 (control): PC+B and subsequent B; arm 2: PC+B+D and subsequent B+D; or arm 3: PC+B+D and subsequent B+D+O mtx. The inventors present the final descriptive PFS analysis and subgroup analysis (arm 3 vs arm 1); secondary endpoints of PFS (arm 2 vs arm 1; non-tBRCAm ITT) and intermediate OS (both formally tested according to the prescribed multiple testing method); and PFS2.

[0267] 2.Results In DCO2 (18 Sep 2023), the PFS benefit of arm 3 vs. arm 1 persisted in both the non-tBRCAm HRD+ and non-tBRCAm ITT populations (Table 6) and was consistent across pre-planned subgroups, including those related to stratification factors. The interim OS analysis for arm 3 vs. arm 1 (non-tBRCAm ITT) was not statistically significant. In the non-tBRCAm HRD+ population, a favorable OS trend was observed with arm 3 vs. arm 1. In both populations, PFS2 improved with arm 3 vs. arm 1 and arm 2 vs. arm 1 (Table 6). Safety findings in DCO2 were nearly identical to those in DCO1 (Figure 25). Safety findings were consistent with the primary analysis. Overall, the most common grade 3 or higher AEs in arm 3 were neutropenia (31% vs. 28% in arm 2 and 26% in arm 1) and anemia (25% vs. 8% in arm 2 and 8% in arm 1). In three patients in Arm 3 of the maintenance phase, grade 3 or higher PRCA and / or AIHA events were reported, and all events resolved.

[0268] D+PC+B and subsequent D+B+O mtx continued to improve PFS compared to controls, including subgroup-specific data. In the non-tBRCAm HRD+ population, the median PFS was 45.1 months, the longest ever seen for these pts in a first-line setting, and there was a corresponding favorable trend in OS. PFS2 improved in both the non-tBRCAm HRD+ and non-tBRCAm ITT populations (Figures 22-24). DUO-O continued to demonstrate a clinically meaningful PFS benefit in comparison to first-line chemotherapy + bevacizumab + durvalumab and subsequent bevacizumab + durvalumab + olaparib maintenance (arm 3) versus controls (arm 1). The 45.1-month mPFS in arm 3 is the longest ever seen in non-tBRCAm HRD-positive patients in a first-line setting. The final PFS results for arm 2 versus arm 1 were consistent with previous findings, showing a numerical improvement with a hazard ratio of 0.89. The DUO-O time-to-event data includes the duration of the chemotherapy phase, which is approximately 4.5 months.

[0269] In this interim OS analysis, the arm 3 vs. arm 1 ratio was not statistically significant in the non-tBRCAm population. However, a favorable trend was observed in the non-tBRCAm HRD-positive population within the ITT population. Safety remains largely consistent with previous analyses and known profiles of each drug.

[0270] [Table 8] * Myriad MyChoice® CDx assay, genome instability score of 42 or higher. † For Arm 1, estimations were obtained from stratified Cox models (stratified by timing and outcome of cytoreductive surgery [HRD+:PFS, OS, PFS2], or by timing and outcome of cytoreductive surgery and geographical region [ITT:PFS]) or unstratified Cox models (ITT:OS,PFS2).

[0271] Example 4: Updated Analysis: Durvalumab in combination with carboplatin / paclitaxel and bevacizumab, followed by maintenance therapy with durvalumab, bevacizumab, and olaparib in newly diagnosed non-BRCA mutation advanced ovarian cancer. Updated PFS and OS analyses in DUO-O: First-line durvalumab plus carboplatin / paclitaxel and bevacizumab, followed by maintenance with durvalumab or bevacizumab plus olaparib, demonstrated statistically significant and clinically meaningful improvements in PFS, with the greatest benefit observed in the non-tBRCAm HRD-positive population.

[0272] 1. Method The materials and methods are as outlined in Examples 1 to 3 above.

[0273] Determination of homologous recombination repair mutation (HRRm) status Tumor tissue samples were used for homologous recombination repair mutation (HRRm) testing. Tumor HRRm status was predictively assessed using the MyChoice® CDx assay. A sample was considered positive if harmful or suspected harmful HRRm was detected in any one of the following pre-specified genes associated with HRR: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. Although the inclusion criteria for the non-tBRCAm cohort required that patients not have harmful or suspected harmful mutations in BRCA1 and BRCA2, this pre-specified list of genes included BRCA1 and BRCA2, and therefore any patients who were mistakenly randomized were captured as having a positive HRRm. A negative HRRm status (non-HRRm) was defined as a specimen without harmful or suspected harmful mutations in any of the pre-specified genes. Unknown HRRm status included discontinuation or failure of testing, and one patient was recruited in China where HRR testing was not performed.

[0274] 2.Results Non-tBRCAm HRD-positive population In the pre-specified interim PFS analysis, PFS events were observed in 135 out of 283 patients in the non-tBRCAm HRD-positive population in the durvalumab + olaparib arm and the control arm (data maturity, 47.7%). The durvalumab + olaparib arm demonstrated a statistically significant 51% lower risk of disease progression or death compared to the control (HR, 0.49 [95% CI, 0.34~0.69]; P<.0001; median PFS [mPFS] 37.3 months vs. 23.0 months) (Figure 6 and Table 7).

[0275] In the final PFS analysis, the durvalumab + olaparib arm showed sustained improvement over the control arm (HR, 0.46; 95% CI, 0.33–0.65; mPFS 45.1 months vs. 23.3 months; 24-month PFS rate 72.9% vs. 46.5%; descriptive analysis) (Figure 27 and Table 7). The HR for PFS in the durvalumab arm versus control was 0.89 (95% CI, 0.67–1.19; mPFS 25.1 months vs. 23.3 months; 24-month PFS rate 50.9% vs. 46.5%) (Figure 27 and Table 7).

[0276] Pre-specified sensitivity analyses, including PFS assessed by blinded independent central review (BICR), showed consistent results. A generally consistent treatment effect was observed across pre-specified subgroups for the durvalumab + olaparib arm versus control (Figures 28 and 30).

[0277] Non-tBRCAm ITT group In the pre-specified interim PFS analysis of the non-tBRCAm ITT population, PFS events were observed in 452 out of 756 patients in the durvalumab + olaparib arm and the control arm (data maturity, 59.8%). The durvalumab + olaparib arm demonstrated a statistically significant 37% lower risk of disease progression or death compared to the control (HR, 0.63 [95% CI, 0.52~0.76]; P<.0001; mPFS 24.2 months vs. 19.3 months) (Figure 16B and Table 7). Since both primary endpoints were met in the interim PFS analysis, this is described below as the primary analysis. In the final PFS analysis, the durvalumab + olaparib arm showed sustained improvement over the control arm (HR, 0.61 [95% CI, 0.51-0.73]; mPFS 25.1 months vs. 19.3 months; 24-month PFS rate 53.0% vs. 33.2%; descriptive analysis) (Figure 16D and Table 7).

[0278] In the primary PFS analysis, no statistically significant PFS benefit was observed between the durvalumab arm and the control (Figure 16B and Table 7). Therefore, PFS in the durvalumab arm was retested in the final PFS analysis according to the MTP, and no statistically significant PFS benefit was observed (HR, 0.87 [95% CI, 0.74~1.03]; P=.11; mPFS 20.6 months vs. 19.3 months; 24-month PFS rate 38.7% vs. 33.2%) (Figure 16B and Table 7).

[0279] Consistent results were observed in pre-specified sensitivity analyses, including PFS assessed by BICR. Generally consistent treatment effects were observed across pre-specified subgroups (Figures 18 and 19A-19C).

[0280] HRD-negative subgroup In the subgroup with HRD-negative tumors, a PFS benefit was observed in both the primary PFS analysis (HR, 0.68 [95% CI, 0.54-0.86]; mPFS 20.9 months vs. 17.4 months; 18-month PFS rate 64.0% vs. 47.6%) and the final PFS analysis (HR, 0.68 [95% CI, 0.54-0.85]; mPFS 21.1 months vs. 17.5 months; 24-month PFS rate 41.1% vs. 26.1%) in the durvalumab + olaparib arm versus control (Table 7 and Figures 21A-21B).

[0281] PFS2 analysis (DCO September 18, 2023) Table 2 reports the PFS2 in the non-tBRCAm HRD-positive, non-tBRCAm ITT, and HRD-negative populations (see also Figures 20A-20B).

[0282] Interim OS analysis (DCO September 18, 2023) Non-tBRCAm ITT population: In the non-tBRCAm ITT population, the interim OS analysis showed that 432 out of 1,130 patients in the durvalumab + olaparib arm, durvalumab arm, and control arm died (data maturity, 38.2%). The HR for OS in the durvalumab + olaparib arm versus control was 0.95 (95% CI, 0.76–1.20; P=.68; median OS [mOS] 48.5 months vs. 48.0 months; 24-month OS rate 83.3% vs. 79.8%), and in the durvalumab arm versus control it was 0.92 (95% CI, 0.73–1.16; mOS not reached (NR) vs. 48.0 months; 24-month OS rate 81.2% vs. 79.8%) (Figure 20C and Table 7). In the durvalumab + olaparib arm versus the control arm, no statistically significant improvement in overall survival (OS) was observed, and therefore, in accordance with the MTP (Method-to-Principle) guidelines, no further testing was performed. 18.5%, 17.6%, and 7.1% of patients in the control arm, durvalumab arm, and durvalumab + olaparib arm, respectively, received subsequent PARP inhibitor therapy, while 6.1%, 1.3%, and 0.8% received subsequent immunotherapy (Table 7).

[0283] HRD-negative subgroup In the HRD-negative subgroup, the hazard ratio for OS in the durvalumab + olaparib arm versus control was 0.99 (95% CI, 0.76–1.31; mOS 41.1 months vs. 39.6 months; 24-month OS rate 76.4% vs. 76.9%) (Table 7 and Figure 21D).

[0284] 3. Conclusion DUO-O met its primary endpoint in the planned interim PFS analysis, demonstrating a statistically significant and clinically meaningful improvement in PFS in women with newly diagnosed advanced ovarian cancer, in both the non-tBRCAm HRD-positive and non-tBRCAm ITT populations. This improvement was achieved by adding durvalumab to a chemotherapy-plus-bevacizumab backbone, followed by maintenance with bevacizumab, durvalumab, and olaparib, compared to bevacizumab alone after chemotherapy-plus-bevacizumab. The PFS benefit persisted in the final PFS analysis and was consistent across pre-specified subgroups in both the non-tBRCAm HRD-positive and non-tBRCAm ITT populations, including patients with HRD-negative tumors (55.4% of the DUO-O population) and the PD-L1 biomarker subgroup.

[0285] The 45.1-month mPFS achieved in the durvalumab + olaparib arm of the non-tBRCAm HRD-positive population in DUO-O is the longest ever seen in any trial in the setting of newly diagnosed advanced ovarian cancer.

[0286] In the DUO-O study, at the time of the interim OS analysis, OS maturity was 38% in the non-tBRCAm ITT population and 21% in the HRD-positive population, respectively, with a favorable OS trend observed in the non-tBRCAm HRD-positive population. Notably, at the time OS was assessed, the use of subsequent therapies such as PARP inhibitors and immunotherapy was low and was not explained in the interim OS analysis. The DUO-O study is ongoing, and updated OS analyses with longer-term follow-up are planned.

[0287] In the durvalumab + olaparib arm or the durvalumab arm versus control, no significant differences in QLQ-C30 GHS scores were observed between the treatment arms, suggesting no adverse effects on HRQoL.

[0288] [Table 9-1]

[0289] [Table 9-2] Abbreviations: BRCA, BRCA1 and / or BRCA2; CI, confidence interval; DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; NR, not reached; OS, overall survival; PFS, progression-free survival; PFS2, second disease progression; tBRCAm, tumor BRCAm. a The median was calculated using the Kaplan-Meier method. The 95% confidence intervals (CIs) for median PFS, median PFS2, and median OS were derived based on the Brookmeyer-Crowley method. b HR and CI estimated from a stratified Cox proportional hazards model (stratified by timing and outcome of cell reduction surgery). c Primary endpoint. d P-values ​​obtained from stratified log-rank text. e HR and CI estimated from a stratified Cox proportional hazards model (stratified by timing and outcome of cytoreductive surgery, as well as geographical region). f HR and CI estimated from an unstratified Cox proportional hazards model. g P-values ​​obtained from unstratified log-rank text.

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(in press). 13.AstraZeneca:Global policy:bioethics(2019)https: / / www.astrazeneca.com / content / dam / az / PDF / 2019 / Bioethics%20Policy%20final.pdf 14.Moore et al.,「Atezolizumab,bevacizumab,and chemotherapy for newly diagnosed Stage III or IV ovarian cancer:placebo-controlled randomized Phase III trial(IMagyn050 / GOG 3015 / ENGOT-OV39),」J.Clin.Oncol.39(17):1842-55(2021)。 15.Monk et al.,「Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer(JAVELIN Ovarian 100):an open-label,randomised,phase 3 trial,」Lancet Oncol.22(9):1275-89(2021)。 16.Osoba et al.,「Interpreting the significance of changes in health-related quality-of-life scores,」J.Clin.Oncol.16(1):139-44(1998)。 17.Liu et al.,「Tumor Area Positivity(TAP)score of programmed death-ligand 1(PD-L1):a novel visual estimation method for combined tumor cell and immune cell scoring,」Diagn.Pathol.18:48(2023)。 18.Matulonis et al.,「Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer:results from the phase II KEYNOTE-100 study,」Ann.Oncol.30(7):1080-87(2019)。 19.Gonzalez-Martin et al.,「Progression-free survival and safety at 3.5years of follow-up:results from the randomised phase 3 PRIMA / ENGOT-OV26 / GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer,」Eur.J.Cancer 189:112908(2023)。 20.Moore et al.,「Atezolizumab,bevacizumab,and chemotherapy for newly diagnosed Stage III or IV ovarian cancer:placebo-controlled randomized Phase III trial(IMagyn050 / GOG 3015 / ENGOT-OV39),」J.Clin.Oncol.39(17):1842-55(2021)。 21.Monk et al.,「Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer(JAVELIN Ovarian 100):an open-label,randomised,phase 3 trial,」Lancet Oncol.22(9):1275-89(2021)。 22.Ray-Coquard et al.,「Olaparib plus bevacizumab as first-line maintenance in ovarian cancer,」N.Engl.J.Med.381(25):2416-28(2019)。 23.Gonzalez-Martin et al.,「Niraparib in patients with newly diagnosed advanced ovarian cancer,」N.Engl.J.Med.381(25):2391-402(2019)。 24.Liu et al.,「Tumor Area Positivity(TAP)score of programmed death-ligand 1(PD-L1):a novel visual estimation method for combined tumor cell and immune cell scoring,」Diagn.Pathol.18:48(2023)。 25.Aaronson et al.,「The European Organization for Research and Treatment of Cancer QLQ-C30:a quality-of-life instrument for use in international clinical trials in oncology,」J.Natl.Cancer Inst.85(5):365-76(1993)。 26.Osoba et al.,「Interpreting the significance of changes in health-related quality-of-life scores,」J.Clin.Oncol.16(1):139-44(1998)。 27.Greimel et al.,「An international field study of the reliability and validity of a disease-specific questionnaire module(the QLQ-OV28)in assessing the quality of life of patients with ovarian cancer,」Eur.J.Cancer 39(10):1402-08(2003)。 28.Stone,「The application of bespoke spending functions in group-sequential designs and the effect of delayed treatment switching in survival trials,」Pharm.Stat.9(2):151-61(2010)。

Claims

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

2. A combination for use in the treatment of ovarian cancer in a subject requiring treatment for ovarian cancer, wherein the combination is (a) A therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment, (b) A combination for use comprising a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of anti-VEGF antibody or its antigen-binding fragment.

3. The combination for use according to claim 1 or claim 2, wherein the anti-VEGF antibody or its antigen-binding fragment is bevacizumab.

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

5. The combination for use according to any one of claims 1, 3, or 4, wherein the PARP inhibitor is olaparib.

6. The combination for use according to any one of claims 1 to 5, wherein the therapeutically effective amount of anti-VEGF antibody or its antigen-binding fragment comprises a dose of 5 mg / kg to 20 mg / kg.

7. The combination for use according to claim 6, wherein the dose of the anti-VEGF antibody or its antigen-binding fragment is 15 mg / kg.

8. The combination for use according to any one of claims 1 to 7, wherein the therapeutically effective amount of the anti-PD-L1 antibody or its antigen-binding fragment comprises a dose of 800 mg to 1500 mg.

9. The combination for use according to claim 8, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 1120 mg.

10. The combination for use according to any one of claims 1 to 9, wherein the therapeutically effective amount of the anti-PD-L1 antibody or its antigen-binding fragment comprises a dose of 10 mg / kg to 20 mg / kg.

11. The combination for use according to claim 10, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg.

12. The combination for use according to any one of claims 1 to 11, wherein the therapeutically effective amount of the PARP inhibitor comprises a dose of 100 mg to 300 mg.

13. The combination for use according to claim 12, wherein the dose of the PARP inhibitor is 300 mg.

14. The combination for use according to any one of claims 1 to 13, wherein one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

15. The aforementioned therapeutically effective dose of paclitaxel is 175 mg / m². ２ A combination for use according to claim 14, comprising the dose of the above.

16. The combination for use according to either claim 14 or claim 15, wherein the therapeutically effective amount of carboplatin comprises a dose that results in an area under the curve (AUC) of AUC5 or AUC6.

17. The combination for use according to any one of claims 1 to 16, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the one or more chemotherapeutic agents is every two to four weeks.

18. The combination for use according to claim 17, wherein the administration is every 2 to 4 weeks over a period of 9 to 18 weeks.

19. The combination for use according to either claim 17 or claim 18, wherein the administration is every three weeks.

20. The combination for use according to claim 19, wherein the administration is every three weeks over a period of nine to fifteen weeks.

21. The combination for use according to any one of claims 1 to 20, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment is 4 to 6 doses, the administration of the anti-PD-L1 antibody or its antigen-binding fragment is 3 to 5 doses, and the administration of one or more chemotherapeutic agents is 4 to 6 doses.

22. The subject, before administration of the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents, (i) one or more chemotherapeutic agents, (ii) The combination for use according to any one of claims 1 to 21, wherein one or more chemotherapeutic agents and the anti-VEGF antibody or its antigen-binding fragment are administered.

23. The subject, before administration of the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents, (i) at least one dose of one or more of the chemotherapeutic agents, (ii) The combination for use according to claim 22, wherein at least one dose of the one or more chemotherapeutic agents and at least one dose of the anti-VEGF antibody or its antigen-binding fragment are administered.

24. (a) is, The anti-VEGF antibody or its antigen-binding fragment in a dose of 15 mg / kg, and A combination for use according to any one of claims 1 to 23, comprising administering a dose of 1120 mg of the anti-PD-L1 antibody or its antigen-binding fragment.

25. The anti-VEGF antibody or its antigen-binding fragment is bevacizumab, and the dose of bevacizumab is 15 mg / kg, and The combination for use according to claim 24, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab, and the dose of durvalumab is 1120 mg.

26. The anti-VEGF antibody or its antigen-binding fragment is bevacizumab, and the dose of bevacizumab is 15 mg / kg every three weeks, The combination for use according to either claim 24 or claim 25, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab, and the dose of durvalumab is 1120 mg every three weeks.

27. (a) is, 175 mg / m² ２ Paclitaxel, and 25 mg / m² ２ A combination for use according to any one of claims 24 to 26, further comprising cisplatin.

28. (b) a combination for use according to any one of claims 1 to 27, wherein (b) is an administration of the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment every two to four weeks.

29. (b) a combination for use according to any one of claims 1 to 27, wherein (b) comprises administering the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment every three weeks.

30. (b) is, Every 2 to 4 weeks, the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment, A combination for use according to any one of claims 1 to 27, comprising administering the PARP inhibitor twice daily.

31. (b) is, Every three weeks, the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment, and A combination for use according to any one of claims 1 to 30, comprising administering the PARP inhibitor twice daily.

32. (b) is, The anti-VEGF antibody or its antigen-binding fragment in a dose of 15 mg / kg, and A combination for use according to any one of claims 1 to 29, comprising a dose of 1120 mg of the anti-PD-L1 antibody or its antigen-binding fragment.

33. (b) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment every three weeks for a maximum of 15 months, and The method according to claim 32, comprising administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks for a maximum of 24 months.

34. (b) The anti-VEGF antibody or its antigen-binding fragment is bevacizumab, and the dose of bevacizumab is 15 mg / kg, and The combination for use according to claim 32, wherein the anti-PD-L1 antibody or antigen-binding fragment of the same in (b) is durvalumab, and the dose of durvalumab is 1120 mg.

35. (b) The anti-VEGF antibody or its antigen-binding fragment is bevacizumab, and the dose of bevacizumab is 15 mg / kg every three weeks, The combination for use according to claim 32 or claim 33, wherein the anti-PD-L1 antibody or antigen-binding fragment of the same in (b) is durvalumab, and the dose of durvalumab is 1120 mg every three weeks.

36. (b) is, The anti-VEGF antibody or its antigen-binding fragment in a dose of 15 mg / kg, A dose of 1120 mg of the anti-PD-L1 antibody or its antigen-binding fragment, and A combination for use according to any one of claims 1 to 27, 30, or 31, comprising administering a dose of 300 mg of the PARP inhibitor.

37. (b) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment every three weeks for a maximum of 15 months, A certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks for up to 24 months, and The method according to claim 36, comprising administering the PARP inhibitor in a twice-daily dose for up to 24 months.

38. (b) The anti-VEGF antibody or antigen-binding fragment is bevacizumab, and the dose of bevacizumab is 15 mg / kg, (b) The anti-PD-L1 antibody or its antigen-binding fragment is durvalumab, and the dose of durvalumab is 1120 mg, and The combination for use according to claim 36, wherein the PARP inhibitor in (b) is olaparib and the dose of olaparib is 300 mg.

39. (b) The anti-VEGF antibody or antigen-binding fragment is bevacizumab, and the dose of bevacizumab is 15 mg / kg every three weeks. (b) The anti-PD-L1 antibody or its antigen-binding fragment is durvalumab, and the dose of durvalumab is 1120 mg every three weeks, The combination for use according to claim 36 or claim 37, wherein the PARP inhibitor in (b) is olaparib, and the administration of olaparib is 300 mg twice daily.

40. The combination for use according to any one of claims 1 to 39, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the one or more chemotherapeutic agents is intravenous.

41. The combination for use according to any one of claims 1 to 40, wherein the administration of the PARP inhibitor is orally.

42. The combination for use according to any one of claims 1 to 41, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the one or more chemotherapeutic agents is carried out simultaneously, separately, and / or sequentially.

43. The combination for use according to any one of claims 1 to 42, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment in (b) is carried out simultaneously, separately, and / or sequentially.

44. The combination for use according to any one of claims 1 to 42, wherein the administration of the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the PARP inhibitor in (b) is carried out simultaneously, separately, and / or sequentially.

45. The combination for use according to any one of claims 1 to 44, wherein the ovarian cancer is advanced ovarian cancer.

46. The combination for use according to any one of claims 1 to 45, wherein the ovarian cancer is high-grade epithelial ovarian cancer.

47. The combination for use according to any one of claims 1 to 46, wherein the ovarian cancer is an ovarian cancer tumor without a BRCA1 / BRCA2 mutation (non-tBRCAm).

48. The combination for use according to any one of claims 1 to 47, wherein the ovarian cancer is an ovarian cancer tumor that is homologous recombination deficiency (HRD) positive.

49. The combination for use according to any one of claims 1 to 47, wherein the ovarian cancer is an ovarian cancer tumor that is homologous recombination deficiency (HRD) negative.

50. The combination for use according to any one of claims 1 to 49, wherein the treatment by combination results in an increase in progression-free survival in the subject compared to patients who received bevacizumab and chemotherapy alone.

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

52. The combination for use according to any one of claims 1 to 49, wherein the treatment by combination results in an increase in overall survival in the subject compared to patients who received bevacizumab and chemotherapy alone.

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

54. A method for treating ovarian cancer in a person requiring treatment for ovarian cancer, wherein the person requires treatment for ovarian cancer (a) A therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment, (b) A method comprising administering a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment, a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment, and a therapeutically effective amount of a PARP inhibitor.

55. A method for treating ovarian cancer in a person requiring treatment for ovarian cancer, wherein the person requires treatment for ovarian cancer (a) A therapeutically effective dose of one or more chemotherapeutic agents, a therapeutically effective dose of an anti-PD-L1 antibody or its antigen-binding fragment, and a therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment, (b) A method comprising administering a therapeutically effective amount of anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of anti-VEGF antibody or its antigen-binding fragment.

56. The method according to claim 54 or claim 55, wherein step (b) is performed after the completion of step (a).

57. Before step (a), the subject, (i) one or more chemotherapeutic doses, (ii) The method according to any one of claims 54 to 56, further comprising administering a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-VEGF antibody or its antigen-binding fragment.

58. Before step (a), the subject, (i) one or more chemotherapeutic doses of at least one effective dose, (ii) The method according to claim 57, further comprising administering at least one therapeutically effective dose of one or more chemotherapeutic agents and at least one therapeutically effective dose of an anti-VEGF antibody or its antigen-binding fragment.

59. The method according to any one of claims 54 to 58, wherein the anti-VEGF antibody or its antigen-binding fragment is bevacizumab.

60. The method according to any one of claims 54 to 59, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab.

61. The method according to any one of claims 54 to 60, wherein the PARP inhibitor is olaparib.

62. The method according to any one of claims 54 to 61, wherein the anti-VEGF antibody or its antigen-binding fragment is administered in a dose of 5 mg / kg to 20 mg / kg.

63. The method according to claim 62, wherein the anti-VEGF antibody or its antigen-binding fragment is administered at a dose of 15 mg / kg.

64. The method according to any one of claims 54 to 63, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 800 mg to 1500 mg.

65. The method according to claim 64, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 1120 mg.

66. The method according to any one of claims 54 to 63, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered in a dose of 10 mg / kg to 20 mg / kg.

67. The method according to claim 66, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 15 mg / kg.

68. The method according to any one of claims 54 to 67, wherein the PARP inhibitor is administered in a dose of 100 mg to 300 mg.

69. The method according to claim 68, wherein the PARP inhibitor is administered in a dose of 300 mg.

70. The method according to any one of claims 54 to 69, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin.

71. Paclitaxel, 175 mg / m² ２ The method according to any one of claims 54 to 70, administered in the dose of [specified dose].

72. The method according to claim 69 or claim 71, wherein carboplatin is administered in a dose that produces an area under the curve (AUC) of AUC5 or AUC6.

73. The method according to any one of claims 54 to 72, wherein step (a) comprises administering the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and one or more chemotherapeutic agents every two to four weeks.

74. Step (a) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment administered every 2 to 4 weeks over a period of 9 to 18 weeks, A certain dose of the anti-PD-L1 antibody or its antigen-binding fragment, and The method according to claim 73, comprising administering one or more chemotherapeutic agents in a cycle.

75. Step (a) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment, administered every three weeks. A certain dose of the anti-PD-L1 antibody or its antigen-binding fragment, and The method according to any one of claims 54 to 72, comprising administering one or more of the chemotherapeutic agents in a cycle.

76. Step (a) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment, administered every three weeks for 9 to 15 weeks. A certain dose of the anti-PD-L1 antibody or its antigen-binding fragment, and The method according to claim 75, comprising administering one or more of the chemotherapeutic agents in a cycle.

77. Step (a) is, 3 to 5 doses of the anti-VEGF antibody or its antigen-binding fragment, The method according to any one of claims 54 to 76, comprising administering 3 to 5 doses of the anti-PD-L1 antibody or its antigen-binding fragment, and 3 to 5 cycles of the one or more chemotherapeutic agents.

78. Step (a) is, 15 mg / kg of the anti-VEGF antibody or its antigen-binding fragment, and The method according to any one of claims 54 to 77, comprising administering 1120 mg of the anti-PD-L1 antibody or its antigen-binding fragment.

79. Step (a) is, 15 mg / kg of bevacizumab, and The method according to claim 78, comprising administration of 1120 mg of durvalumab.

80. Step (a) is, Bevacizumab at a dose of 15 mg / kg every three weeks, and The method according to claim 79, comprising administering 1120 mg of durvalumab every three weeks.

81. Step (a) is, 175 mg / m² ２ Paclitaxel, and / or 25 mg / m² ２ The method according to any one of claims 78 to 80, further comprising the administration of cisplatin.

82. Step (b) is, The method according to any one of claims 54 to 81, comprising administering a certain dose of the anti-VEGF antibody or its antigen-binding fragment and a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every two to four weeks.

83. Step (b) is, The method according to any one of claims 54 to 82, comprising administering a certain dose of the anti-VEGF antibody or its antigen-binding fragment and a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks.

84. Step (b) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment and a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment, administered every 2 to 4 weeks, The method according to any one of claims 54 to 81, comprising administering a certain dose of the PARP inhibitor twice a day.

85. Step (b) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment and a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment, administered every three weeks, The method according to any one of claims 54 to 82, comprising administering a certain dose of the PARP inhibitor twice a day.

86. Step (b) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment every three weeks for a maximum of 15 months, and The method according to claim 75, comprising administering a certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks for a maximum of 24 months.

87. Step (b) is, A certain dose of the anti-VEGF antibody or its antigen-binding fragment every three weeks for a maximum of 15 months, A certain dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks for up to 24 months, and The method according to claim 75, comprising administering the PARP inhibitor in a twice-daily dose for up to 24 months.

88. Step (b) is, 15 mg / kg of the anti-VEGF antibody or its antigen-binding fragment, and The method according to any one of claims 54 to 83 or 86, comprising administering 1120 mg of the anti-PD-L1 antibody or its antigen-binding fragment.

89. Step (b) is, Bevacizumab at a dose of 15 mg / kg every three weeks, and The method according to claim 88, comprising administering 1120 mg of durvalumab every three weeks.

90. Step (b) is, 15 mg / kg of the anti-VEGF antibody or its antigen-binding fragment, 1120 mg of the anti-PD-L1 antibody or its antigen-binding fragment, and The method according to any one of claims 54 to 81, 84, 85, or 87, comprising administering 300 mg of the PARP inhibitor.

91. Step (b) is, 15 mg / kg of bevacizumab, 1120 mg of durvalumab, and The method according to claim 90, comprising administration of 300 mg of olaparib.

92. Step (b) is, Bevacizumab 15 mg / kg every three weeks, 1120 mg of durvalumab every three weeks, and The method according to claim 91, comprising administering 300 mg of olaparib twice daily.

93. The method according to any one of claims 54 to 92, wherein the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the one or more chemotherapeutic agents are administered intravenously.

94. The method according to any one of claims 54 to 93, wherein the PARP inhibitor is administered orally.

95. The method according to any one of claims 54 to 94, wherein the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the one or more chemotherapeutic agents of step (a) are administered to the subject simultaneously, separately, and / or sequentially.

96. The method according to any one of claims 54 to 95, wherein the anti-VEGF antibody or its antigen-binding fragment and the anti-PD-L1 antibody or its antigen-binding fragment of step (b) are administered to the subject simultaneously, separately, and / or sequentially.

97. The method according to any one of claims 54 to 95, wherein the anti-VEGF antibody or its antigen-binding fragment, the anti-PD-L1 antibody or its antigen-binding fragment, and the PARP inhibitor of step (b) are administered to the subject simultaneously, separately, and / or sequentially.

98. The method according to any one of claims 54 to 97, wherein the ovarian cancer is advanced ovarian cancer.

99. The method according to any one of claims 54 to 98, wherein the ovarian cancer is a high-grade epithelial ovarian cancer.

100. The method according to any one of claims 54 to 99, wherein the ovarian cancer is an ovarian cancer tumor without a BRCA1 / BRCA2 mutation (non-tBRCAm).

101. The method according to any one of claims 54 to 100, wherein the ovarian cancer is an ovarian cancer tumor that is homologous recombination deficiency (HRD) positive.

102. The method according to any one of claims 54 to 100, wherein the ovarian cancer is an ovarian cancer tumor that is homologous recombination deficiency (HRD) negative.

103. The method according to any one of claims 54 to 102, wherein the treatment results in an increased progression-free survival in the subject compared to patients who received bevacizumab and chemotherapy alone.

104. The method according to claim 103, wherein the treatment results in an increase in the progression-free survival period of at least four months.

105. The method according to any one of claims 54 to 103, wherein the treatment results in an increase in overall survival in the subject compared to a patient who received bevacizumab and chemotherapy alone.

106. The method according to claim 105, wherein the treatment results in an increase in overall survival for at least four months.

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

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

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