Anti-pd-l1 antibodies in combinations with one or more chemotherapy agents for treating endometrial cancer

Abstract

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

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480054116.5 (22) Application Date 2024.08.16 (30) Priority Data 63 / 520,115 2023.08.17 US 63 / 590,525 2023.10.16 US 63 / 649,524 2024.05.20 US (85) PCT International Application Entering National Phase Date 2026.02.14 (86) PCT International Application Application Data PCT / IB2024 / 057958 2024.08.16 (87) PCT International Application Publication Data WO2025 / 037273 EN 2025.02.20 (71) Applicant AstraZeneca (Sweden) Ltd. Address Südtelje, Sweden (72) Inventors E. Leo G. Rossi T. P. Milenkova-Ileva (74) Patent Agency China Patent Agency (Hong Kong) Ltd. 72001 Patent Attorney Li Tang Peng Chang (51) Int.Cl. A61K 31 / 337 (2006.01) A61K 31 / 502 (2006.01) A61K 33 / 243 (2006.01) A61K 39 / 395 (2006.01) A61P 35 / 00 (2006.01) A61P 35 / 02 (2006.01) (54) Invention Title Anti-PD-L1 Antibody for the Treatment of Endometrial Cancer in Combination with One or More Chemotherapy Agents (57) Abstract This disclosure relates to methods, compositions and combinations for the treatment of endometrial cancer. Specifically, this disclosure relates to methods for treating endometrial cancer in a subject of need, methods comprising administering to the subject one or more chemotherapeutic agents, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. This disclosure also relates to combinations for use in the treatment of endometrial cancer, combinations comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. Claims 9 pages, Description 48 pages, Drawings 46 pages, CN 122094673 A 2026.05.26 CN 1 22 09 46 73 A 1. A method for treating endometrial cancer in a subject of need, the method comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. 2. A method for treating endometrial cancer in a subject of need, the method comprising administering to the subject:(a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment. 3. The method of claim 1 or 2, wherein step (b) occurs after step (a) is completed. 4. The method of any one of claims 1 to 3, wherein the anti-PD-L1 antibody or its antigen-binding fragment is durvalumab. 5. The method of any one of claims 1 to 4, wherein the PARP inhibitor is olaparib. 6. The method of any one of claims 1 to 5, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 800 mg to 1500 mg. 7. The method of claim 6, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 1120 mg and / or 1500 mg. 8. The method of any one of claims 1 to 7, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 10 mg / kg to 20 mg / kg. 9. The method of claim 8, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 15 mg / kg and / or 20 mg / kg. 10. The method of any one of claims 1 to 9, wherein the PARP inhibitor is administered at a dose of 100 mg to 300 mg. 11. The method of claim 10, wherein the PARP inhibitor is administered at a dose of 300 mg. 12. The method of any one of claims 1 to 11, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin. 13. The method of any one of claims 1 to 12, wherein the paclitaxel is administered at a dose of 175 mg / m². 14. The method of claim 12 or claim 13, wherein the carboplatin is administered at a dose that produces an area under the curve (AUC) of AUC5 or AUC6. 15. The method of any one of claims 1 to 14, wherein step (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents every two to four weeks. 16. The method of claim 15, wherein step (a) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every two to four weeks and one cycle of the one or more chemotherapeutic agents for nine to eighteen weeks. 17. The method of any one of claims 1 to 15, wherein step (a) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks and one cycle of the one or more chemotherapeutic agents. 18. The method of claim 17, wherein step (a) comprises administering one dose of the anti-PD-L1 antibody every three weeks.19. The method of claim 17, wherein step (a) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every three weeks and one cycle of the one or more chemotherapeutic agents for eighteen weeks. 20. The method of any one of claims 1 to 19, wherein step (a) comprises administering four to six doses of the anti-PD-L1 antibody or its antigen-binding fragment and four to six cycles of the one or more chemotherapeutic agents. 21. The method of any one of claims 1 to 20, wherein step (a) comprises administering 1120 mg of the anti-PD-L1 antibody or its antigen-binding fragment. 22. The method of claim 21, wherein step (a) comprises administering 1120 mg of durvalumab. 23. The method of claim 22, wherein step (a) comprises administering 1120 mg of durvalumab every three weeks. 24. The method of any one of claims 21 to 23, wherein step (a) further comprises administering: 175 mg / m² paclitaxel; carboplatin with an AUC 5 or AUC 6; and / or 25 mg / m² cisplatin. 25. The method of any one of claims 1 to 24, wherein step (b) comprises: administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every two to four weeks; and administering one dose of the PARP inhibitor twice daily. 26. The method of any one of claims 1 to 25, wherein step (b) comprises: administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks; and administering one dose of the PARP inhibitor twice daily. 27. The method of any one of claims 1 to 26, wherein step (b) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and administering one dose of the PARP inhibitor twice daily for at least 12 weeks. 28. The method of claim 27, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and administering a dose of the PARP inhibitor twice daily for up to 24 months. 29. The method of any one of claims 1 to 28, wherein step (b) comprises administering: 1500 mg of the anti-PD-L1 antibody or its antigen-binding fragment; and 300 mg of the PARP inhibitor. 30. The method of claim 29, wherein step (b) comprises: 1500 mg of durvalumab; and 300 mg of olaparib. 31. The method of claim 30, wherein step (b) comprises:32. The method of any one of claims 2 to 24, wherein step (b) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every two to four weeks. 33. The method of any one of claims 2 to 24 or 32, wherein step (b) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks. 34. The method of any one of claims 2 to 24 or 32 to 33, wherein step (b) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks. 35. The method of claim 34, wherein step (b) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months. 36. The method of any one of claims 2 to 24 or 32 to 35, wherein step (b) comprises administering 1500 mg of the anti-PD-L1 antibody or its antigen-binding fragment thereof. 37. The method of claim 36, wherein step (b) comprises administering 1500 mg of durvalumab. 38. The method of claim 37, wherein step (b) comprises administering 1500 mg of durvalumab every 4 weeks. 39. The method of any one of claims 1 to 38, wherein the anti-PD-L1 antibody or its antigen-binding fragment thereof and the one or more chemotherapeutic agents are administered intravenously. 40. The method of any one of claims 1 to 39, wherein the PARP inhibitor is administered orally. 41. The method of any one of claims 1 to 40, wherein the antigen-binding fragment thereof, the anti-PD-L1 antibody or its antigen-binding fragment thereof, and the one or more chemotherapeutic agents in step (a) are administered to the subject simultaneously, separately, and / or sequentially. 42. The method of any one of claims 1 to 42, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the PARP inhibitor in step (b) are administered to the subject simultaneously, separately, and / or sequentially. 43. The method of any one of claims 1 to 42, wherein the endometrial cancer is advanced endometrial cancer. 44. The method of any one of claims 1 to 43, wherein the endometrial cancer is an endometrial cancer tumor lacking mismatch repair (mMR-deficient (dMMR)). 45. The method of claim 44, comprising administering to the subject suffering from dMMR endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment; and(b) A therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment. 46. The method of any one of claims 1 to 43, wherein the endometrial cancer is a pMMR (mature mismatch repair) endometrial cancer tumor. 47. The method of claim 46, comprising administering to the subject suffering from pMMR endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor. 48. The method of any one of claims 1 to 47, wherein the endometrial cancer is a PD-L1-positive endometrial cancer tumor. 49. The method of any one of claims 1 to 47, wherein the endometrial cancer is a PD-L1-negative endometrial cancer tumor. 50. The method of any one of claims 1 to 49, wherein the treatment increases the progression-free survival of the subject compared to a patient receiving only devalumab and chemotherapy. 51. The method of claim 50, wherein the treatment increases progression-free survival by at least 4 months. 52. The method of any one of claims 1 to 51, wherein the treatment increases the overall survival of the subject compared to a patient receiving only durvalumab and chemotherapy. 53. The method of claim 52, wherein the treatment increases overall survival by at least 4 months. 54. A combination for use in treating endometrial cancer in a subject in need of treatment, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. 55. A combination for use in treating endometrial cancer in a subject in need of treatment, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof. 56. The combination for use according to claim 54 or claim 55, wherein the anti-PD-L1 antibody or its antigen-binding fragment is divorumab. 57. The combination for use according to any one of claims 54 to 56, wherein the PARP inhibitor is olaparib. 58. The combination for use according to any one of claims 54 to 57, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 800 mg to 1500 mg.59. The combination for use according to claim 58, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 1120 mg and / or 1500 mg. 60. The combination for use according to any one of claims 54 to 59, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 10 mg / kg to 20 mg / kg. 61. The combination for use according to claim 60, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg and / or 20 mg / kg. 62. The combination for use according to any one of claims 54 to 61, wherein the dose of the PARP inhibitor is 100 mg to 300 mg. 63. The combination for use according to claim 62, wherein the dose of the PARP inhibitor is 300 mg. 64. The combination for use according to any one of claims 54 to 63, wherein one or more chemotherapeutic agents are paclitaxel and / or carboplatin. 65. The combination for use according to claim 64, wherein the dose of paclitaxel is 175 mg / m². 66. The combination for use according to claim 64 or claim 65, wherein the dose of said carboplatin produces an area under the curve (AUC) of AUC5 or AUC6. 67. The combination for use according to any one of claims 54 to 66, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment therefrom and said one or more chemotherapeutic agents every two to four weeks. 68. The combination for use according to claim 67, wherein administration is performed every two to four weeks for nine to twenty-four weeks. 69. The combination for use according to claim 67 or claim 68, wherein administration is performed every three weeks or every four weeks. 70. The combination for use according to claim 69, wherein administration is performed every three weeks for twelve to eighteen weeks. 71. The combination for use according to claim 70, wherein administration is performed every three weeks for eighteen weeks. 72. The combination for use according to any one of claims 54 to 71, wherein (a) comprises administering three to six doses of said anti-PD-L1 antibody or its antigen-binding fragment therefrom, and four to six doses of said one or more chemotherapeutic agents. 73. The combination for use according to any one of claims 54 to 72, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg. 74. The combination for use according to claim 73, wherein the durvalumab is administered at a dose of 1120 mg. 75. The combination for use according to claim 73 or claim 74, wherein the durvalumab is administered at a dose of 1120 mg every 3 weeks.76. The combination for use according to any one of claims 73 to 75, wherein (a) further comprises: 175 mg / m² paclitaxel; carboplatin with an AUC 5 or AUC 6; and / or 25 mg / m² cisplatin. 77. The combination for use according to any one of claims 54 to 76, wherein (b) comprises: the anti-PD-L1 antibody or its antigen-binding fragment administered every two to four weeks; and the PARP inhibitor administered twice daily. 78. The combination for use according to any one of claims 54 to 77, wherein (b) comprises: the anti-PD-L1 antibody or its antigen-binding fragment administered every four weeks; and the PARP inhibitor administered twice daily. 79. The combination for use according to any one of claims 54 to 78, wherein (b) comprises: administration of the anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1500 mg; and the PARP inhibitor at a dose of 300 mg. 80. The combination for use according to claim 77, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and administering a dose of the PARP inhibitor twice daily for at least 12 weeks. 81. The combination for use according to claim 79, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and administering a dose of the PARP inhibitor twice daily for up to 24 months. 82. The combination for use according to claim 79, wherein (b) comprises: administering durvalumab at a dose of 1500 mg; and administering olaparib at a dose of 300 mg. 83. The combination for use according to any one of claims 79 to 81, wherein (b) comprises: administering durvalumab at a dose of 1500 mg every 3 weeks; and administering olaparib at a dose of 300 mg twice daily. 84. The combination for use according to any one of claims 55 to 76, wherein (b) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment every two to four weeks. 85. The combination for use according to any one of claims 55 to 76 or 84, wherein (b) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment every four weeks. 86. The combination for use according to any one of claims 55 to 76 or 84 to 85, wherein (b) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1500 mg. 87. The combination for use according to claim 85, wherein step (b) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks. 88. The combination for use according to claim 87, wherein step (b) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks.The anti-PD-L1 antibody or its antigen-binding fragment thereof lasts for up to 24 months. Claims 5 / 9, page 6, CN 122094673 A 89. The combination for use according to claim 86, wherein (b) comprises administration of durvalumab at a dose of 1500 mg. 90. The combination for use according to any one of claims 84 to 89, wherein (b) comprises administration of durvalumab at a dose of 1500 mg every 3 weeks. 91. The combination for use according to any one of claims 54 to 90, wherein the anti-PD-L1 antibody or its antigen-binding fragment thereof and the one or more chemotherapeutic agents are administered intravenously. 92. The combination for use according to any one of claims 54 to 91, wherein the PARP inhibitor is administered orally. 93. The combination for use according to any one of claims 54 to 92, wherein the anti-PD-L1 antibody or its antigen-binding fragment thereof in (a) and the one or more chemotherapeutic agents are administered to the subject simultaneously, separately, and / or sequentially. 94. The combination for use according to any one of claims 54 to 93, wherein the anti-PD-L1 antibody or its antigen-binding fragment in (b) and the PARP inhibitor are administered to the subject simultaneously, separately, and / or sequentially. 95. The combination for use according to any one of claims 54 to 94, wherein the endometrial cancer is advanced endometrial cancer. 96. The combination for use according to any one of claims 54 to 95, wherein the endometrial cancer is a mismatch repair-deficient (dMMR) endometrial cancer tumor. 97. The combination for use in treating a subject with defective mismatch repair (dMMR) endometrial cancer according to claim 96, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment. 98. The combination for use according to any one of claims 54 to 95, wherein the endometrial cancer is a pMMR endometrial cancer tumor. 99. The combination of claim 98 for use in treating intact mismatch repair (pMMR) endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. 100. The combination of any one of claims 54 to 99 for use, wherein the endometrial cancer is a PD-L1-positive endometrial cancer tumor.101. The combination for use according to any one of claims 54 to 99, wherein the endometrial cancer is a PD-L1 negative endometrial cancer tumor. 102. The combination for use according to any one of claims 54 to 101, wherein treatment with the combination increases the progression-free survival of the subject compared to a patient receiving only durvalumab and chemotherapy. 103. The combination for use according to claim 102, wherein the treatment increases progression-free survival by at least 4 months. 104. The combination for use according to any one of claims 54 to 101, wherein treatment with the combination increases the overall survival of the subject compared to a patient receiving only durvalumab and chemotherapy. 105. The combination for use according to claim 104, wherein the treatment increases overall survival by at least 4 months. 106. Use in the manufacture of a medicament for treating endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. 107. Use in the manufacture of a medicament for treating endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof. 108. The use according to claim 106 or claim 107, wherein the antiPD-L1 antibody or antigen-binding fragment thereof is divorumab. 109. The use according to any one of claims 106 to 108, wherein the PARP inhibitor is olaparib. 110. The use according to any one of claims 106 to 109, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 800 mg to 1500 mg. 111. The use according to claim 110, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 1120 mg and / or 1500 mg. 112. The use according to any one of claims 106 to 111, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 10 mg / kg to 20 mg / kg. 113. The use according to claim 112, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg and / or 20 mg / kg. 114. The use according to any one of claims 106 to 113, wherein the dose of the PARP inhibitor is 100 mg to 300 mg.115. The use according to claim 114, wherein the dose of the PARP inhibitor is 300 mg. 116. The use according to any one of claims 114 to 115, wherein the one or more chemotherapeutic agents are paclitaxel and / or carboplatin. 117. The use according to claim 116, wherein the dose of the paclitaxel is 175 mg / m². 118. The use according to claim 116 or claim 117, wherein the dose of the carboplatin produces an area under the curve (AUC) of AUC5 or AUC6. 119. The use according to any one of claims 106 to 118, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents every two to four weeks. 120. The use according to claim 119, wherein administration is performed every two to four weeks for nine to twenty-four weeks. 121. The use according to claim 119 or claim 120, wherein administration is performed every three weeks or every four weeks. 122. The use according to claim 121, wherein administration is performed every three weeks for twelve to eighteen weeks. 123. The use according to claim 122, wherein administration is performed every three weeks for a period of eighteen weeks. 124. The use according to any one of claims 106 to 123, wherein (a) comprises administering three to six doses of the anti-PD-L1 antibody or its antigen-binding fragment, and four to six doses of the one or more chemotherapeutic agents. Claims 7 / 9 Page 8 CN 122094673 A 125. The use according to any one of claims 106 to 124, wherein (a) comprises administering the anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg. 126. The use according to claim 125, wherein the durvalumab is administered at a dose of 1120 mg. 127. The use according to claim 125 or claim 126, wherein the durvalumab is administered at a dose of 1120 mg every three weeks. 128. The use according to any one of claims 125 to 127, wherein (a) further comprises: 175 mg / m² paclitaxel; carboplatin with an AUC 5 or AUC 6; and / or 25 mg / m² cisplatin. 129. The use according to any one of claims 106 to 128, wherein (b) comprises: the anti-PD-L1 antibody or its antigen-binding fragment administered every two to four weeks; and the PARP inhibitor administered twice daily. 130. The use according to any one of claims 106 to 129, wherein (b) comprises: the anti-PD-L1 antibody or its antigen-binding fragment administered every four weeks; and the PARP inhibitor administered twice daily. 131. The use according to any one of claims 106 to 130, wherein (b) comprises:132. The use according to claim 131, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and administering a dose of the PARP inhibitor twice daily for at least 12 weeks. 133. The use according to claim 131, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months, and administering a dose of the PARP inhibitor twice daily for up to 24 months. 134. The use according to claim 131, wherein step (b) comprises: administering durvalumab at a dose of 1500 mg; and administering olaparib at a dose of 300 mg. 135. The use according to any one of claims 131 to 134, wherein (b) comprises: administration of durvalumab at a dose of 1500 mg every 3 weeks; and administration of olaparib at a dose of 300 mg twice daily. 136. The use according to any one of claims 107 to 128, wherein (b) comprises administration of the anti-PD-L1 antibody or its antigen-binding fragment every two to four weeks. 137. The use according to any one of claims 107 to 128 or 136, wherein (b) comprises administration of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks. 138. The use according to any one of claims 106 to 128 or 136 to 137, wherein (b) comprises administration of the anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1500 mg. 139. The use according to claim 137, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and administering a dose of the PARP inhibitor twice daily for at least 12 weeks. Claims 8 / 9, page 9, CN 122094673 A 140. The use according to claim 137, wherein step (b) comprises administering a dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for up to 24 months. 141. The use according to claim 137, wherein (b) comprises administering durvalumab at a dose of 1500 mg. 142. The use according to any one of claims 137 to 141, wherein (b) comprises administering durvalumab at a dose of 1500 mg every 3 weeks. 143. The use according to any one of claims 106 to 142, wherein the anti-PD-L1 antibody or its antigen-binding fragment and the one or more chemotherapeutic agents are administered intravenously.144. The use according to any one of claims 106 to 143, wherein the PARP inhibitor is administered orally. 145. The use according to any one of claims 106 to 144, wherein the anti-PD-L1 antibody or its antigen-binding fragment thereof in (a) and the one or more chemotherapeutic agents are administered to the subject simultaneously, separately, and / or sequentially. 146. The use according to any one of claims 106 to 145, wherein the anti-PD-L1 antibody or its antigen-binding fragment thereof in (b) and the PARP inhibitor are administered to the subject simultaneously, separately, and / or sequentially. 147. The use according to any one of claims 106 to 146, wherein the endometrial cancer is advanced endometrial cancer. 148. The use according to any one of claims 106 to 147, wherein the endometrial cancer is an endometrial cancer tumor lacking mismatch repair (dMMR). 149. Use of the invention according to claim 148 in the manufacture of a medicament for treating defective mismatch repair (dMMR) endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof. 150. Use according to any one of claims 106 to 147, wherein the endometrial cancer is a pMMR endometrial cancer tumor. 151. Use of the invention according to claim 150 in the manufacture of a medicament for treating pMMR endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. 152. The use according to any one of claims 106 to 151, wherein the endometrial cancer is a PD-L1 positive endometrial cancer tumor. 153. The use according to any one of claims 106 to 151, wherein the endometrial cancer is a PD-L1 negative endometrial cancer tumor. 154. The use according to any one of claims 106 to 153, wherein the combination therapy increases the progression-free survival of the subject compared to a patient receiving only durvalumab and chemotherapy. 155. The use according to claim 154, wherein the treatment increases progression-free survival by at least 4 months. 156. The use according to any one of claims 106 to 153, wherein the combination therapy increases the overall survival of the subject compared to a patient receiving only durvalumab and chemotherapy.157. The use according to claim 156, wherein the treatment increases overall survival by at least 4 months. Claims 9 / 9 pages 10 CN 122094673 A Anti-PD-L1 antibody in combination with one or more chemotherapeutic agents for the treatment of endometrial cancer Technical Field

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

[0002] Treatment of cancer typically requires surgical resection followed by chemotherapy and radiotherapy. Long-term success rates of standard treatment regimens vary considerably because tumor cells can largely evade treatment by regenerating the primary tumor and, more often importantly, they can spread to form distant metastases. Recent advances in the treatment of cancer and cancer-related diseases, conditions, and symptoms include the use of combination therapies that combine immunotherapy with more traditional chemotherapy and radiation therapy. In most cases, immunotherapy is less toxic than traditional chemotherapy because it utilizes the patient’s own immune system to recognize and eliminate tumor cells.

[0003] Endometrial cancer is a disease in which malignant cancer cells form in the tissue of the endometrium (the inner lining of the uterus). Endometrial cancer is sometimes referred to as uterine cancer. Endometrial cancer is one of the most common malignant tumors of the female reproductive tract, with more than 380,000 new cases worldwide in 2018 and an estimated 61,880 new cases diagnosed in the United States (US) in 2019. The incidence is increasing in developed countries, and the highest incidence has been observed in the United States, Canada, and Northern and Western Europe. From 2006 to 2015, the incidence increased by about 1% per year and from 2007 to 2016, the mortality increased by about 2% per year (American Cancer Society 2019). The main risk factors considered to be associated with the development of endometrial cancer are exposure to excessive estrogen levels associated with obesity, diabetes, tamoxifen use, and reproductive factors (early menarche, late menopause, nulliparity). The aging population may also play a role in the increased incidence. Alternative treatment options for recurrent endometrial cancer are limited, and there is a significant unmet need for new treatments. Summary of the Invention

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

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

[0006] In another aspect, this disclosure provides a combination for use in the treatment of endometrial cancer in a subject of need, 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 (page 1 / 48, CN 122094673 A) or its antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment thereof and optionally a therapeutically effective amount of a PARP inhibitor.

[0007] In another aspect, this disclosure provides the use of a combination in the manufacture of a medicament for treating endometrial cancer in a subject of need, the combination comprising: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0008] In another aspect, this disclosure provides the use of a combination in the manufacture of a medicament for treating ovarian cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and optionally a therapeutically effective amount of a PARP inhibitor.

[0009] These and other features and advantages of this disclosure will be more fully understood from the following detailed description in conjunction with the appended claims. It should be noted that the scope of the claims is defined by the statements therein and not by the specific discussion of the features and advantages listed in this specification. Brief Description of the Drawings

[0010] Figure 1 illustrates the screening process. Abbreviations: ICF = Informed Consent; MMR = Mismatch Repair. Freshly collected tumor samples are permitted, provided they are part of routine clinical practice. Patients with unknown MMR status prior to randomization will be considered screening failures and will be ineligible. If, due to technical malfunction, the original MMR test cannot be completed by the end of the 28-day screening period, patients must be rescreened to ensure sufficient time for MMR retesting.Samples must be shipped before the primary informed consent form is signed, and MMR results must be available before randomization. New samples may only be submitted and tested if the original test fails due to technical malfunction. Further details regarding the retesting procedure can be found in the laboratory manual.

[0011] Figure 2 illustrates the study design. During chemotherapy, IV study treatments were administered on the same day in the following order: 1. durvalumab / placebo (1120 mg, over 1 hour, or up to 8 hours if infusion was interrupted), 2. IV infusion of paclitaxel 175 mg / m², over 3 hours), 3. carboplatin (or, according to local practice, IV infusion of AUC 5 or AUC 6, over 1 hour). Maintenance therapy was initiated 3 to 9 weeks after the last chemotherapy infusion. Disease measurable according to RECIST v1.1 after surgery or diagnostic biopsy (FIGO stage III) or disease with / without disease after surgery or diagnostic biopsy (FIGO stage IV) with or without RECIST v1.1 measurable or non-measurable disease, where the likelihood of cure by surgery alone or in combination is low. Prior adjuvant systemic anticancer therapy is permitted for recurrent disease ≥12 months from the last dose to subsequent recurrence. bid, twice daily; EC, endometrial cancer; IV, intravenous; MMR, mismatch repair; PARP, poly(ADP-ribose) polymerase; q3w, every 3 weeks; q4w, every 4 weeks; R, randomization.

[0012] Figure 3 illustrates the multivariate control strategy. The α levels presented are bilateral. The overall 2.5% was assigned using the Lan-DeMets consumption function approximating the O'Brien-Fleming method. H, hypothesis; PFS, progression-free survival; OS, overall survival.

[0013] Figures 4A-4B show progression-free survival (A) and overall survival (B) in the intention-to-treat population as assessed by investigators according to RECIST version 1.1. For the PFS analysis, HR and CI were estimated using a Cox proportional hazards model stratified by MMR and disease status. For the OS analysis, HR and CI were estimated using an unstratified Cox proportional hazards model. P-values ​​were calculated using a stratified log-rank test. Checkmarks indicate censored observations. Censorship was performed on patients who did not experience events at the latest evaluable RECIST assessment. CI, confidence interval; HR, hazard ratio; MMR, mismatch repair; NR, not reached; OS, overall survival; PFS, progression-free survival; RECIST, criteria for response to solid tumors.

[0014] Figures 5A-5B show subgroup analyses of progression-free survival in (A) the twin group and (B) the triple group. CI tableConfidence intervals are indicated; ECOG Eastern Oncology Cooperative Group; FIGO International Federation of Gynecologic and Obstetric Societies; G grade; HRRm, homologous recombination repair mutation; MMR mismatch repair; PD-L1 programmed cell death ligand-1; and other regions of the RoW world. Stratification factors (MMR status [intact vs. defective], disease status [new diagnosis vs. recurrence], and geographic region [Asia vs. other regions of the world]) were performed according to randomization codes.

[0015] Figure 6 illustrates recruitment, randomization, and intervention.

[0016] Figure 7 illustrates a sensitivity analysis of progression-free survival assessed by blinded independent central review.

[0017] Figures 8A-8B illustrate progression-free survival assessed by investigators according to RECIST version 1.1 in the (A) dMMR and (B) pMMR subgroups. CI indicates confidence intervals; dMMR mismatch repair defective type; pMMR mismatch repair intact type; and RECIST solid tumor response evaluation criteria.

[0018] Figure 9 illustrates overall survival in the intention-to-treat population.

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

[0020] Figure 11 shows a summary of the DUO-E study design including patients and endpoints.

[0021] Figures 12A-12B show patient characteristic data. Gynecologic Consortium; HRR(m), homologous recombination repair (mutation); MMR, mismatch repair; NGS, next-generation sequencing; PD-L1; programmed death-ligand-1; TAP, tumor region proportion.

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

[0023] Figures 14A-14C show the evaluation of secondary endpoints in the ITT population for (A) time to first follow-up therapy or death (TFST), (B) second progression-free survival (PFS2), and (C) time to first follow-up therapy or death (TFST) and time to second follow-up therapy or death (TSST).

[0024] Figures 15A-15B show a post-hoc exploratory analysis of the MMR subsets in terms of overall survival (OS) for (A) dMMR and (B) pMMR.

[0025] Figures 16A-16F show post-hoc exploratory analyses of the dMMR subgroups: (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR.

[0026] Figures 17A-17F show post-hoc exploratory analyses of the pMMR subgroups: (A) TFST, (B) PFS2, (C) TSST, (D) PFS by subgroup, (E) ORR, and (F) DoR.

[0027] Figures 18A-18B show the PFS of the MMR subgroups, and pre-specified exploratory analyses of (A) dMMR and (B) pMMR.

[0028] Figures 19A-19B show additional results for the ITT population in terms of (A) PFS and (B) OS.

[0029] Figures 20A-20D show additional results from exploratory PFS analyses for (A) the dMMR subgroup, (B) the pMMR subgroup, (C) the PD-L1 positive subgroup, and (D) the PD-L1 negative subgroup. Detailed Description

[0030] This disclosure relates to methods, compositions, and combinations for treating endometrial cancer. Specifically, this disclosure relates to methods for treating endometrial cancer in a subject of need, comprising administering one or more chemotherapeutic agents, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. This disclosure also relates to combinations for use in the treatment of endometrial cancer, comprising one or more chemotherapeutic agents, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor.

[0031] As stated in this disclosure, unless otherwise stated or defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following references provide those skilled in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (edited by Walker, 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (edited), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise stated, the following terms have the meanings assigned to them below.

[0032] In this disclosure, the terms “comprising,” “including,” “containing,” and “having” may have the meanings assigned to them under U.S. patent law and may mean “comprising,” “including,” etc. “Constitutes substantially of” has the meaning assigned to it under U.S. patent law and is open-ended, allowing for more than those listed, provided that the essential or novel features of the listed are not altered by the presence of more than those listed, excluding prior art aspects.

[0033] Unless specifically stated or obvious from the context, the term “or” as used herein shall be understood as inclusive. Unless specifically stated or obvious from the context, the terms “an,” “a,” and “the” as used herein shall be understood as singular or plural. Unless the context otherwise requires, singular terms shall include plural forms and plural terms shall include singular forms.

[0034] Unless specifically stated or obvious from the context, the term “about” as used herein shall be understood as meaning within normal tolerances in the art, such as within two standard deviations of the mean. “About” can be understood as referring to values ​​within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%. Unless the context clearly indicates otherwise, all numerical values ​​provided herein are modified by the term “about”.

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

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

[0037] As used herein, the term “antibody” refers to a protein capable of specifically binding to an antigen. Common or conventional mammalian antibodies comprise tetramers, which typically consist of two pairs of identical polypeptide chains, each pair consisting of a "light" chain (typically with a molecular weight of about 25 kDa) and a "heavy" chain (typically with a molecular weight of about 50 kDa–70 kDa). As used herein, the terms "heavy chain" and "light chain" refer to any immunoglobulin polypeptide having a sufficient sequence of variable domains to confer specificity against a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids, which is generally responsible for antigen recognition. The carboxyl-terminal portion of each chain typically defines a constant domain responsible for effector function.Domains. Therefore, in naturally occurring antibodies, full-length heavy chain immunoglobulin polypeptides include a variable domain (VH) and three constant domains (CH1, CH2, and CH3) and a hinge region between CH1 and CH2, wherein the VH domain is at the amino terminus of the polypeptide and the CH3 domain is at the carboxyl terminus, and full-length light chain immunoglobulin polypeptides include a variable domain (VL) and a constant domain (CL), wherein the VL domain is at the amino terminus of the polypeptide and the CL domain is at the carboxyl terminus.

[0038] Within the full-length light and heavy chains, the variable and constant domains are typically linked by a “J” region of about 12 or more amino acids, wherein the heavy chain also includes a “D” region of about 10 or more amino acids. The variable region of each light / heavy chain pair typically forms an antigen-binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure as a relatively conserved backbone region (FR) linked by three hypervariable regions (also known as complementarity-determining regions or CDRs). The CDRs from the two chains of each pair are typically aligned through the backbone region, which allows binding to specific epitopes. From the amino terminus to the carboxyl terminus, the variable domains of both the light and heavy chains typically include the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0039] The term “antigen-binding fragment” refers to a portion of a complete antibody and / or the antigen-determining variable domain of a complete 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, Fab', F(ab')2, and Fv fragments, linear antibodies, single-chain antibodies, biantibodies, and multispecific antibodies formed from antibody fragments.

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

[0041] In one embodiment, the method, composition, and combination comprise administering to the subject: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

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

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

[0044] The number of planned treatment doses per cycle depends on the chemotherapy agent. In some embodiments, each cycle may contain only one dose. In other embodiments, a cycle may contain more than one dose.

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

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

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

[0048] In a non-limiting embodiment, the antiPD-L1 antibody is administered at a fixed dose of 1120 mg or 1500 mg (based on an average body weight of 75 kg, which is equivalent to a weight-based dose of 15 mg / kg or 20 mg / kg).

[0049] In some embodiments, this document provides a method of treating endometrial cancer in a subject of need, the method comprising administering to the subject a fixed dose of a PARP inhibitor from about 100 mg to 300 mg.

[0050] In some embodiments, this document provides a method of treating endometrial cancer in a subject of need, the method comprising administering to the subject a fixed dose of a PARP inhibitor of 300 mg.

[0051] In some embodiments, the antiPD-L1 antibody or an antigen-binding fragment thereof is divalbumin. Dvorumab (MEDI4736, Imfinzi®) is a human monoclonal antibody against human PD-L1 that blocks the binding of PD-L1 to both PD1 and CD80 receptors. Publications regarding Dvorumab can be found in U.S. Patent Nos. 8,779,108 and 9,493,565, page 5 / 48, CN 122094673 A. The full text of both patents is incorporated herein by reference.

[0052] Dvorumab and its antigen-binding fragments used 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 Dvorumab or its antigen-binding fragment used in the methods, compositions, and combinations provided herein comprises a fragment having SEQ ID NO:The amino acid sequence of SEQ ID NO: 1 comprises a light chain variable region 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 fragment used in the methods, compositions, and combinations provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2, and CDR3 sequences defined by Kabat in SEQ ID NO: 3-5, and wherein the light chain variable region comprises the CDR1, CDR2, and CDR3 sequences defined by Kabat in SEQ ID NO: 6-8. Those skilled in the art can readily identify CDR definitions defined by Chothia, Abm, or other CDR definitions known to those skilled in the art. In some embodiments, the durvalumab or its antigen-binding fragment used in the methods, compositions, and combinations provided herein comprises variable heavy chain and variable light chain CDR sequences of the 2.14H9OPT antibody, as disclosed in U.S. Patent Nos. 8,779,108 and 9,493,565.

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

[0054] EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGS GTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK (SEQ ID NO: 1)

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

[0056] EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRF TISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS (SEQ ID NO: 2)

[0057] Dvalumab heavy chain CDR:

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

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

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

[0061] Dvalumab, light chain CDR:

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

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

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

[0065] As used herein, the term “PARP inhibitor” means any agent that inhibits the activity of poly(ADP-ribose) polymerase (PARP) in cells. PARP helps repair DNA when it is damaged. DNA damage can be caused by many factors, including exposure to UV light, radiation, certain anticancer drugs, or other substances in the environment. In cancer treatment, blocking PARP helps prevent cancer cells from repairing their damaged DNA, leading to their death. In some embodiments, the PARP inhibitor is olaparib (Lynparza®). Publications regarding olaparib can be found in European Patent Nos. 1330442 and 1633724, the full text of which is incorporated herein by reference.

[0066] As used herein, “chemotherapy” or “chemotherapeutic agent” can include any chemotherapeutic agent. In some embodiments, the chemotherapeutic agent includes one or more platinum-based chemotherapeutic agents. In some embodiments, the one or more platinum-based chemotherapeutic agents include carboplatin, cisplatin, oxaliplatin, or combinations thereof. In some embodiments, the chemotherapeutic agent includes one or more taxane-based chemotherapeutic agents. In some embodiments, the one or more taxane-based chemotherapeutic agents include albumin-bound paclitaxel, paclitaxel, docetaxel, cabazitaxel, abraxane, anthracyclines (pegylated liposomal doxorubicin), or combinations thereof. In some embodiments, the chemotherapeutic agent comprises a combination of one or more platinum-based chemotherapeutic agents and one or more taxane-based chemotherapeutic agents. In various embodiments, this disclosure allows for the substitution of any other chemotherapeutic agent with one or more chemotherapeutic agents at any time during administration. Substitution can occur for any reason, including but not limited to a subject's response to one or more chemotherapeutic agents or an allergic reaction. In some embodiments, the chemotherapeutic agent comprises cisplatin and paclitaxel. In some embodiments, one or more doses of cisplatin are administered to the patient, wherein the dose is about 25 mg / m². In some embodiments, one or more doses of cisplatin are administered to the patient at a dose that produces an area under the curve (AUC) of AUC5 or AUC6. In some embodiments, cisplatin is administered to the patient at a dose of about 25 mg / m² to 100 mg / m². In some embodiments, one or more doses of paclitaxel are administered to the patient, wherein the dose is about 175 mg / m². In various embodiments, the dose of the chemotherapeutic agents can be reduced.

[0067] In some embodiments, the number of doses of one or more chemotherapeutic agents is measured in cycles. The number of planned treatment doses in each cycle depends on the chemotherapeutic agent. In some embodiments, each cycle may contain only one dose. In a non-limiting embodiment, the 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, the cycle may contain more than one dose administered daily or weekly.

[0068] In some embodiments, the number of doses of the anti-PD-L1 antibody or its antigen-binding fragment and / or PARP inhibitor is measured in cycles. The number of planned treatment doses within each cycle depends on the antibody or inhibitor. In some embodiments, each cycle may contain only one dose. In one non-limiting embodiment, the 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, the cycle may contain more than one dose administered daily or weekly.

[0069] The term “subject” as used herein can refer to a human patient.

[0070] In some embodiments, the methods, compositions, and combinations disclosed herein are used to treat a subject suffering from endometrial cancer, endometrial neoplasia, or uterine cancer.

[0071] As used herein, the term “treatment” refers to therapeutic treatment and prophylactic or preventative measures. Subjects requiring treatment include subjects with cancer, subjects predisposed to cancer, or subjects who will receive cancer prevention treatment. In some embodiments, the methods, compositions, and combinations disclosed herein can be used to treat endometrial cancer. In other embodiments, subjects requiring treatment include subjects with tumors, subjects predisposed to cancer, or subjects who will receive cancer prevention treatment. In some embodiments, the methods, compositions, and combinations disclosed herein can be used to treat tumors. In other embodiments, tumor treatment includes inhibiting tumor growth, promoting tumor reduction, or both inhibiting tumor growth and promoting tumor reduction.

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

[0073] Overall survival (OS) refers to the period from the start of treatment until death from any cause. OS can refer to overall survival over a specific time period (e.g., 2 months, 3 months, 4 months, 6 months, 8 months, 12 months, 18 months, 24 months, etc.). Such a time period can be identified, for example, as "OS24," which refers to the percentage of patients surviving 24 months after treatment initiation, based on Kaplan-Meier estimates of overall survival at 24 months. In some implementations, overall survival is measured compared to patients receiving only durvalumab and chemotherapy or only chemotherapy. In other implementations, overall survival is measured compared to untreated patients.

[0074] Progression-free survival (PFS) refers to the period from the start of treatment until the date of objective disease progression (RECIST 1.1) or death (for any cause without progression). In some embodiments, the methods, compositions, and combinations disclosed herein provide an increase in PFS (statistically significant and / or clinically meaningful). In some embodiments, the methods, compositions, and combinations disclosed on page 7 / 48 of this specification, CN 122094673 A, provide 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 compared to patients receiving chemotherapy alone or chemotherapy alone (e.g., platinum-based doublet chemotherapy) and devalumab. In other embodiments, overall survival is measured compared to untreated patients. In various embodiments, the PFS benefit is independent of PD-L1 status (PD-L1 positive or PD-L1 negative).

[0075] As used herein, the term “administration” means the provision, contact, and / or delivery of one or more compounds to achieve the desired effect via any suitable route. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, percutaneous, local, oral, rectal, vaginal, nasal, ocular, inhalation, and implantation.

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

[0077] This document provides methods, compositions, and combinations for treating endometrial cancer, endometrial tumors, uterine cancer, or uterine tumors in subjects in need. The subject may not have received PARP inhibitors or immuno-mediated therapy. As used herein, “endometrial cancer” means any cancer or tumor originating from the endometrium or the inner lining of the uterus. Endometrial cancer may also be referred to as uterine cancer.

[0078] Endometrial cancer typically presents with symptoms of abnormal uterine bleeding. Most patients (approximately 75%) are diagnosed at an early stage (stage I or II), and these patients have a better prognosis, with a 5-year overall survival (OS) rate ranging from 74% to 91% (Creasman et al. 2006, Siegel et al. 2015). The standard of care for these patients is surgery with or without radiation therapy. Systemic therapy is not frequently administered to these early-stage patients. However, the prognosis is poor for patients diagnosed at a later stage or with advanced endometrial cancer.Many more. Although endometrial cancer shows strong initial sensitivity to platinum-based doublet chemotherapy compared to many other solid tumors, with a response rate of approximately 51%, most patients diagnosed at an advanced stage will show disease progression, with a median PFS of approximately 12 months (Miller et al. 2012, Aghajanian et al. 2018). For these patients with advanced disease, the five-year overall survival (OS) rate remains poor (57% to 66% for stage III and 20% to 26% for stage IV (Creasman et al. 2006, Siegel et al. 2015).

[0079] The severity of endometrial cancer is measured by staging. As used herein, “staging” refers to an international system used to assess the extent of cancer spread. In stage I, the cancer is confined to the uterus. In stage II, the cancer has spread to the cervix. In stage III, the cancer has spread to the vagina, ovaries, and / or lymph nodes. In stage IV, the cancer has spread to the bladder, rectum, or organs distant from the uterus, such as the lungs or bones. Stages III and IV are considered advanced endometrial cancer. Endometrial cancer referred to herein may be selected from stage II, III, IV, and recurrent cancer. In one embodiment, endometrial cancer referred to herein is stage III, IV, or recurrent cancer.

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

[0081] Defective mismatch repair (dMMR) and its characteristic genetic features, high level of microsatellite length throughout the genome. (Page 8 / 48, 18 CN 122094673 A) Stability (MSI-H) defines a unique biological subset of cancer characterized by a high tumor mutational burden and potential responsiveness to immunotherapy based on anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors. dMMR can occur, for example, due to mutations in one or more (e.g., all) of the following MMR proteins: MLH1, PMS2, MSH2, and MSH6; and optionally, the V600E-mutated BRAF protein. MMR can be determined using the VENTANA MMR IHC group. VENTANA MMRThe IHC group includes the following primary antibodies: VENTANA anti-MLH1 (M1), VENTANA anti-PMS2 (A16-4), VENTANA anti-MLH2 (G219-1129), VENTANA anti-MSH6 (SP93), and VENTANA anti-BRAF V600E (VE1).

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

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

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

[0085] In one embodiment, the endometrial cancer is untreated with first-line systemic anticancer therapy. In one embodiment, the endometrial cancer is untreated with PARP inhibitors and immune-mediated therapy.

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

[0087] This document provides a method for treating endometrial cancer in a subject of need, the method comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. In some embodiments herein, step (b) may not include 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 an antigen-binding fragment thereof.

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

[0089] This document also provides a combination for treating endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor. In some embodiments herein, the combination of (b) may not contain a therapeutically effective amount of a PARP inhibitor. In these embodiments, the combination of (b) comprises a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof.

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

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

[0092] In a particular embodiment, one or more doses of the anti-PD-L1 antibody or its antigen-binding fragment are administered to the subject, wherein the dose is about 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, or 15 mg / kg, 20 mg / kg, or 25 mg / kg. In some embodiments, one or more doses of the anti-PD-L1 antibody or its antigen-binding fragment are administered to the subject, wherein the dose is about 15 mg / kg or 20 mg / kg.

[0093] In a particular embodiment, a subject is administered one or more fixed doses of an anti-PD-L1 antibody or its antigen-binding fragment, wherein the dose is approximately 500 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 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 fixed doses of the anti-PD-L1 antibody or its antigen-binding fragment are administered to the subject, wherein the dose is about 1120 mg or 1500 mg.

[0094] In certain embodiments, a subject is administered one or more fixed doses of a PARP inhibitor, wherein the dose is about 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg. In some embodiments, a subject is administered one or more fixed doses of a PARP inhibitor, wherein the dose is 300 mg. In some embodiments, a dose of 100 mg to 300 mg of the PARP inhibitor is administered twice daily. Thus, the PARP inhibitor can be administered at a daily dose of 200 mg to 600 mg (2 × 100 mg to 300 mg). In other embodiments, the daily dose of the PARP inhibitor may be reduced.

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

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

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

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

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

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

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

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

[0103] In a specific embodiment of (b) of the methods, compositions and combinations of this disclosure, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment is administered about weekly, bi-weekly ...

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

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

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

[0107] In another specific embodiment of (b), a therapeutically effective amount of the anti-PD-L1 antibody or its antigen-binding fragment is administered every 11 / 48 pages of the specification, 21 CN.122094673 A Administered for four weeks, lasting at least 12 weeks or 3 months, and up to twenty-four months.

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

[0109] In a particular embodiment, methods, compositions, and combinations thereof are provided herein for treating endometrial cancer in a subject of need, wherein (a) a therapeutically effective amount of one or more chemotherapeutic agents is administered every three weeks for nine, ten, or twelve to eighteen weeks, and an anti-PD-L1 antibody or an antigen-binding fragment thereof is administered at a dose of 1120 mg every three weeks for nine, ten, or twelve to eighteen weeks; and (b) an anti-PD-L1 antibody or an antigen-binding fragment thereof is administered at a dose of 1500 mg every four weeks, preferably for a total of twenty-four months, and a PARP inhibitor is administered at a dose of 300 mg twice daily, preferably for a total of twenty-four months.

[0110] In a particular embodiment, methods, compositions, and combinations thereof are provided herein for treating endometrial cancer in a subject of need, wherein (a) a dose of paclitaxel at 175 mg / m² and a dose of carboplatin at AUC5 or AUC6 are administered intravenously every three weeks for nine, ten, or twelve to eighteen weeks, and durvalumab is administered intravenously at a dose of 1120 mg every three weeks for nine, ten, or twelve to eighteen weeks; and subsequently (b) durvalumab is administered intravenously at a dose of 1500 mg every four weeks, preferably for a total of twenty-four months, and olaparib is administered orally at a dose of 300 mg twice daily, preferably for a total of twenty-four months.

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

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

[0113] In some embodiments of the disclosed methods, compositions and / or combinations, step / combination (a) is administered prior to step / combination (b). In another embodiment, step / combination (b) is administered only after step / combination (a) is completed.

[0114] As used herein, the term “pharmaceutical composition” or “therapeutic composition” refers to a compound or composition that, when properly administered to a subject, can induce a desired therapeutic effect. In some embodiments, this disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one antibody of this disclosure.

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

[0116] When intended for in vivo administration, the formulations of this disclosure shall be sterile. The formulation disclosed herein can be sterilized by various sterilization methods, including, for example, sterile filtration or radiation. In one embodiment, the formulation is sterilized by filtration using a pre-sterilized 0.22-micron filter. The sterile composition for injection can be formulated according to conventional pharmaceutical practices as described in “Remington: The Science & Practice of Pharmacy,” 21st edition, Lippincott Williams & Wilkins, (2005).

[0117] In some embodiments, the antibody can be formulated for specific routes of administration, such as oral, nasal, pulmonary, topical (including oral and sublingual), rectal, vaginal, and / or parenteral administration. As used herein, the term "parenteral administration" refers to a mode of administration other than enteral and local administration (usually by injection), and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. Formulations of this disclosure suitable for local or percutaneous administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. Antibodies and other active substances may be mixed under sterile conditions with pharmaceutically acceptable carriers and with any preservatives, buffers, or propellants that may be required (see, for example, U.S. Patent Nos. 7,378,110; 7,258,873; and 7,135,180; U.S. Patent Application Publications Nos. 2004 / 0042972 and 2004 / 0042971).

[0118] The formulation may be present in a unit dosage form and may be prepared by any method known in the pharmaceutical field. The actual dose level of the active ingredient in the formulation of this disclosure may vary in order to obtain an amount of active ingredient (e.g., “therapeutic effective amount”) that is effective in achieving the desired therapeutic remission for a particular subject, composition and administration mode without toxicity to the subject. The dose may also be administered via continuous infusion (such as by a pump). The administration dose may also depend on the route of administration. For example, subcutaneous administration may require a higher dose than intravenous administration.

[0119] Without limiting the present disclosure, many embodiments of the present disclosure are described herein for illustrative purposes.

[0120] Embodiment 1. A method of treating a subject with endometrial cancer, the method comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0121] Embodiment 2. A method of treating endometrial cancer in a subject in need, the method comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof.

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

[0123] Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein the antiPD-L1 antibody or an antigen-binding fragment thereof is divalbumin.

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

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

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

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

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

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

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

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

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

[0133] Embodiment 14. The method according to Embodiment 12 or Embodiment 13, wherein the carboplatin is administered at a dose that produces an area under the curve (AUC) of AUC5 or AUC6.

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

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

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

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

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

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

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

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

[0142] Embodiment 23. The method according to Embodiment 22, wherein step (a) comprises administering 1120 mg of devalumab every 3 weeks.Varumarucumab.

[0143] Embodiment 24. The method according to any one of Embodiments 21 to 23, wherein step (a) further comprises administering: paclitaxel at 175 mg / m2; carboplatin at AUC 5 or AUC 6; and / or cisplatin at 25 mg / m2.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0164] Embodiment 45. The method according to Embodiment 44, the method comprising administering to the subject suffering from defective mismatch repair (dMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof.

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

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

[0167] Embodiment 48. The method of any one of Embodiments 1 to 47, wherein the endometrial cancer is a PD-L1 positive endometrial cancer tumor.

[0168] Embodiment 49. The method of any one of Embodiments 1 to 47, wherein the endometrial cancer is a PD-L1 negative endometrial cancer tumor.

[0169] Embodiment 50. The method of any one of Embodiments 1 to 49, wherein the treatment increases the progression-free survival of the subject compared to a patient receiving only devalumab and chemotherapy.

[0170] Embodiment 51. The method of Embodiment 50, wherein the treatment increases progression-free survival by at least 4 months.

[0171] Embodiment 52. The method according to any one of Embodiments 1 to 51, wherein the treatment increases the overall survival of the subject compared to a patient receiving only durvalumab and chemotherapy.

[0172] Embodiment 53. The method according to Embodiment 52, wherein the treatment increases overall survival by at least 4 months.

[0173] Embodiment 54. A combination for use in treating endometrial cancer in a subject in need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0174] Embodiment 55. A combination for use in treating endometrial cancer in a subject in need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof.

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

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

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

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

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

[0180] Embodiment 61. The combination for use according to Embodiment 60, wherein the dose of the anti-PD-L1 antibody or its antigen-binding fragment is 15 mg / kg and / or 20 mg / kg. Specification 16 / 48 pages 26 CN 122094673 A

[0181] Embodiment 62. The combination for use according to any one of Embodiments 54 to 61, wherein the dose of the PARP inhibitor is 100 mg to 300 mg.

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

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

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

[0185] Embodiment 66. The combination for use according to Embodiment 64 or Embodiment 65, wherein the dose of carboplatin produces an area under the curve (AUC) of AUC5 or AUC6.

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

[0187] Embodiment 68. The combination for use according to Embodiment 67, wherein administration is performed every two to four weeks for a period of nine to twenty-four weeks.

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

[0189] Embodiment 70. The combination for use according to Embodiment 69, wherein administration is performed every three weeks for a period of twelve to eighteen weeks.

[0190] Embodiment 71. The combination for use according to Embodiment 70, wherein administration is performed every three weeks for a period of eighteen weeks.

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

[0192] Implementation Scheme 73. The combination for use according to any one of Implementation Schemes 54 to 72, wherein (a) comprises administration of the anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1120 mg.

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

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

[0195] Implementation Scheme 76. The combination for use according to any one of Implementation Schemes 73 to 75, wherein (a) further comprises: paclitaxel at 175 mg / m²; carboplatin at AUC 5 or AUC 6; and / or cisplatin at 25 mg / m².

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

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

[0198] Embodiment 79. The combination for use according to any one of embodiments 54 to 78, wherein (b) comprises: administration of the anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1500 mg; and a dose of the PARP inhibitor of 300 mg. Instructions for Use, Pages 17 / 48, CN 122094673 A

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0216] Implementation Scheme 97. The combination for use in treating defective mismatch repair (dMMR) endometrial cancer in a subject in need, as described in Implementation Scheme 96, page 18 / 48, CN 122094673 A, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof.

[0217] Implementation Scheme 98. The combination for use according to any one of Implementation Schemes 54 to 95, wherein the endometrial cancer is an MMR intact (pMMR) endometrial cancer tumor.

[0218] Embodiment 99. The combination for use according to Embodiment 98 for treating intact mismatch repair (pMMR) endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

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

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

[0221] Embodiment 102. The combination for use according to any one of Embodiments 54 to 101, wherein treatment with the combination increases progression-free survival in the subject compared to patients receiving only devalumab and chemotherapy.

[0222] Embodiment 103. The combination for use according to Embodiment 102, wherein the treatment increases progression-free survival by at least 4 months.

[0223] Embodiment 104. The combination for use according to any one of Embodiments 54 to 101, wherein treatment with the combination increases the overall survival of the subject compared to a patient receiving only durvalumab and chemotherapy.

[0224] Embodiment 105. The combination for use according to Embodiment 104, wherein the treatment increases overall survival by at least 4 months.

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

[0226] Embodiment 107Use in the manufacture of a medicament for treating endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof.

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

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

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

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

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

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

[0233] Embodiment 114. The use according to any one of Embodiments 106 to 113, wherein the dose of the PARP inhibitor is 100 mg to 300 mg.

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

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

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

[0237] Embodiment 118. The use according to Embodiment 116 or Embodiment 117, wherein the dose of said carboplatin produces an area under the curve (AUC) of AUC5 or AUC6.

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

[0239] Implementation Scheme 120. The use according to Implementation Scheme 119, wherein the administration is performed every two to four weeks for a period of nine to twenty-four weeks.

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

[0241] Implementation Scheme 122. The use according to Implementation Scheme 121, wherein the administration is performed every three weeks for a period of twelve to eighteen weeks.

[0242] Implementation Scheme 123. The use according to Implementation Scheme 122, wherein the administration is performed every three weeks for a period of eighteen weeks.

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

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

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

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

[0247] Embodiment 128. The use according to any one of Embodiments 125 to 127, wherein (a) further comprises: paclitaxel at 175 mg / m2; carboplatin at AUC 5 or AUC 6; and / or cisplatin at 25 mg / m2.

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

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

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

[0251] Embodiment 132. The use according to embodiment 131, wherein step (b) comprises administering one dose of the anti-PD-L1 antibody or its antigen-binding fragment every four weeks for at least 12 weeks, and administering the PARP inhibitor at a dose twice daily for at least 12 weeks. Specification 20 / 48 pages 30 CN122094673 A

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0267] Implementation Scheme 148. The use according to any one of Implementation Schemes 106 to 147, wherein the endometrial cancer is an endometrial cancer tumor lacking mismatch repair (dMMR).

[0268] Embodiment 149. Use in the manufacture of a medicament for treating defective mismatch repair (dMMR) endometrial cancer in a subject of need, according to Embodiment 148, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof.

[0269] Embodiment 150. Use according to any one of Embodiments 106 to 147, wherein the endometrial cancer is a pMMR endometrial cancer tumor.

[0270] Embodiment 151. Use of the invention according to Embodiment 150 in the manufacture of a medicament for treating intact mismatch repair (pMMR) endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof; and (b) a therapeutically effective amount of an antiPD-L1 antibody or an antigen-binding fragment thereof and a therapeutically effective amount of a PARP inhibitor.

[0271] Embodiment 152. Use according to any one of Embodiments 106 to 151, wherein the endometrial cancer is a PD-L1 positive endometrial cancer tumor.

[0272] Embodiment 153. Use according to any one of Embodiments 106 to 151, wherein the endometrial cancer is a PD-L1 negative endometrial cancer tumor.

[0273] Embodiment 154. Use according to any one of Embodiments 106 to 153, wherein treatment with the combination increases progression-free survival in the subject compared to a patient receiving only devalumab and chemotherapy.

[0274] Embodiment 155. The use according to embodiment 154, wherein the treatment can increase progression-free survival by at least 4 months.

[0275] Embodiment 156. The use according to any one of embodiments 106 to 153, wherein the combination therapy with said subject increases overall survival compared to patients receiving only durvalumab and chemotherapy.

[0276] Embodiment 157. The use according to embodiment 156, wherein said treatment increases overall survival by at least 4 months.

[0277] Examples

[0278] The following examples are illustrations of specific embodiments of the present disclosure and their various uses. They are shown for illustrative purposes only and should not be construed as limiting the scope of the present disclosure in any way.

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

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

[0281] Overall Design

[0282] This is a randomized, double-blind, placebo-controlled, multicenter phase III study to evaluate the efficacy, safety, and patient-reported outcomes of durvalumab in combination with platinum-based chemotherapy (carboplatin and paclitaxel) followed by maintenance durvalumab versus platinum-based chemotherapy, with or without olaparib, in patients with advanced or recurrent endometrial cancer. AstraZeneca considers the endometrial cancer patient population involved in this study to fall within the category of advanced cancer with limited life expectancy outlined in the ICH S9 guidelines “Non-clinical evaluation of anticancer drugs” and to meet the requirements outlined in those guidelines. The primary endpoint of this study will be progression-free survival (using investigator assessment of scan results according to RECIST 1.1). Secondary endpoints will include OS, PFS2, ORR, DoR, TFST, TSST, and TDT. An overview of the study design is shown in Figure 2.

[0283] This study will include 3 arms: Instructions 22 / 48 pages 32 CN 122094673 A

[0284]

[0285] Abbreviations: IV = intravenous; Q3W = every 3 weeks; Q4W = every 4 weeks.

[0286] Patients will be stratified according to MMR expression status (intact vs. deficient), disease status (recurrence vs. new diagnosis), and geographic region (Asia vs. the rest of the world [RoW]). Patients will provide tumor samples at screening to determine the MMR status used for stratification.

[0287] As part of global recruitment, approximately 699 patients will be randomized in a 1:1:1 ratio to the following designated study treatments (N = 233 patients / arm). If necessary, global recruitment will be terminated at the end of the global recruitment (i.e., the last subject is from a non-Chinese country).Recruitment in China will continue after site-based randomization to allow for the inclusion of a Chinese cohort of approximately 129 patients randomized from Chinese sites at a 1:1:1 ratio. Any patients from China randomized before the end of global recruitment will be included in the global population.

[0288] Arm A (Control): Platinum-based chemotherapy (paclitaxel and carboplatin) plus durvalumab placebo (IV) during chemotherapy. Patients who achieve and maintain disease control (i.e., complete response [CR], partial response [PR], or stable disease [SD]) during chemotherapy will receive durvalumab placebo (IV) and olaparib placebo (tablets) during the maintenance period.

[0289] Arm C (Durvalumab + Olaparib): Platinum-based chemotherapy (paclitaxel and carboplatin) plus durvalumab (IV) during chemotherapy. Patients who achieve and maintain disease control (i.e., CR, PR, or SD) during chemotherapy will receive durvalumab (IV) plus olaparib (tablets) during the maintenance period.

[0290] Patients will be randomized and begin treatment on day 1. The randomization scheme will be based on the following stratifications:

[0291] Tumor mismatch repair (MMR) status: Patients with MMR-deficient tumors versus patients with intact tumors. Prior to randomization, tumor MMR status will be determined based on the MMR status of tumor cells from formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples evaluated using the Ventana immunohistochemistry (IHC) MMR panel.

[0292] Disease status: Patients with recurrent disease versus patients with newly diagnosed disease. This study will recruit patients with newly diagnosed stage III / IV and recurrent endometrial cancer. Generally, recurrent disease shows a lower response rate to treatment and a worse prognosis compared to newly diagnosed cancer. In addition, patients with recurrent cancer may have unresolved toxicities from previous anticancer therapies and more comorbidities, making them more vulnerable than newly diagnosed patients due to the longer duration of disease. Due to these differences, disease status will be included as a stratification factor in randomization.

[0293] Stratification is performed according to MMR status. Mismatch repair deficiencies, termed MMR loss / deficiency, have been observed across various tumor types. Approximately 15% of patients with advanced endometrial cancer have MMR deficiency. Several institutions in the United States have begun testing all patients with histologically confirmed endometrial cancer for MMR or MSI (Universal Oncology Test). MMR deficiency can be detected by IHC staining and is typically the loss of expression of any one of the four most common MMR proteins: MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), and PMS1 homolog 2 (PMS2).Loss of expression of any MMR protein indicates the likelihood of germline mutations in the corresponding MMR gene. Patients with such pathogenic germline MMR mutations have Lynch Syndrome. NCCN guidelines recommend screening for MMR deficiency in all patients with endometrial cancer to identify individuals at risk for Lynch Syndrome. As highlighted in previous sections, preliminary data suggest that agents targeting the PD-1 pathway elicit significant clinical responses in patients with endometrial cancer having MMR-deficient tumors and less pronounced clinical responses in patients with intact MMR tumors, thus providing a basis for stratification based on MMR status.

[0294] Treatment and Duration of Treatment

[0295] Patients should receive platinum-based chemotherapy and devalumab / placebo for the first 6 cycles (minimum 4 cycles). Patients without signs of PD (according to RECIST 1.1) will receive devalumab / placebo and olaparib / placebo during the maintenance period.

[0296] Arm A (Control): Patients will receive platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks (Q3W) for up to 6 cycles during chemotherapy, along with durvalumab placebo (intravenous [IV]) Q3W. After completion of chemotherapy, patients without objective disease progression will receive durvalumab placebo (IV) every 4 weeks (Q4W) and olaparib placebo (tablets) twice daily (bd) during the maintenance period until disease progression.

[0297] Arm B (Durvalumab + Placebo): Patients will receive platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks (Q3W) for up to 6 cycles during chemotherapy, along with 1120 mg durvalumab (IV) Q3W. After completion of chemotherapy, patients without objective disease progression will receive 1500 mg durvalumab (IV) Q4W and olaparib placebo (tablets) bd during the maintenance period until disease progression.

[0298] Arm C (Dvorumab + Olaparib): Patients will receive platinum-based chemotherapy (paclitaxel and carboplatin) for up to 6 cycles Q3W during chemotherapy. After completion of chemotherapy, patients without objective disease progression will receive 1500 mg divarumab (IV) orally Q4W and 300 mg olaparib (tablets) bd during maintenance until disease progression.

[0299] Unless there is unacceptable toxicity, withdrawal of consent or another confirmed discontinuation criterion is met, patients should continue study treatment until radiation-induced disease progression as assessed by the investigator according to RECIST 1.1 (see Appendix G). The overall study design is summarized in Figure 2.

[0300] Objectives and endpoints

[0301] Objectives and relevant endpoints are presented in Table 2. 24 / 48 pages of the instruction manual 34 CN 122094673 A

[0302] 25 / 48 pages of the instruction manual35 CN 122094673 A

[0303]

[0304] Efficacy Assessment and Analysis

[0305] Tumor Assessment by CT and MRI Scans (RECIST 1.1)

[0306] An efficacy assessment (performed by AstraZeneca) will be derived using RECIST 1.1 assessment based on investigator evaluation. Details of RECIST 1.1 (Eisenhauer et al. 2009) are provided in Appendix G. The assessment method is CT or MRI scans of the chest, abdomen, and pelvis. The use of positron emission tomography (PET) scans is described in Appendix G. The same tumor burden assessment method must be used at baseline and at each subsequent follow-up assessment. Additional imaging should be performed on any other areas affected by the disease based on the individual patient’s signs and symptoms.

[0307] Radiological examinations performed during the conduct of this study should be kept on-site as source data. Anonymous copies of the scans will be collected from all patients and sent to the CRO designated by AstraZeneca; the scans will undergo BICR assessment.

[0308] All treatment decisions will be based on on-site assessment of the scans. After the initial PFS analysis, no further central review of the scans will be required, and the investigator will be notified when it is no longer necessary to share a copy of the scan with the CRO that conducted the central review. However, on-site RECIST 1.1 tumor assessment should continue until radiological progression, and RECIST assessments should be recorded in the eCRF.

[0309] It is important to follow the assessment plan as closely as possible; the timing of the scans is related to the randomization date, not to any delay in dosing. If a scan is performed outside the planned visit window and the patient has not progressed, every effort should be made to perform a follow-up scan at its planned time point. Patients will be assessed according to RECIST 1.1 until objective radiological disease progression, followed by a second assessment of progression and survival, regardless of whether study treatment is discontinued or delayed and / or protocol violation occurs, unless the patient withdraws consent.

[0310] Tumor Assessment

[0311] RECIST 1.1 criteria will be used to assess the patient's response to treatment by determining PFS time and ORR. The RECIST 1.1 guidelines and objective tumor response criteria defining measurable and non-measurable target lesions (TLs) and non-target lesions (NTLs) are presented in Appendix G. Overall response classification will be based on assessment of TLs, NTLs, and new lesions.

[0312] For patients with TLs at baseline, progress will be calculated compared to when the tumor burden is at its minimum (i.e., the minimum sum of diameters previously recorded in the study, i.e., the lowest point). Tumor responses (CR, PR, SD) are calculated by comparing them to baseline tumor measurements obtained before randomization.

[0313] (Instructions 26 / 48 pages 36 CN 122094673 A)For patients with no signs of disease (NED) at baseline (i.e., TL and NTL are not applicable [NA]), the RECIST 1.1 result at follow-up after complete surgical resection is NED or PD. Progression is defined by the detection of new lesions during follow-up radiological evaluation (RECIST 1.1).

[0314] For patients with only non-measurable disease at baseline, the classification of objective tumor response assessment will be based on the RECIST 1.1 criteria for response: CR, PD, and non-CR / non-PD.

[0315] In the absence of clinical progression or if the investigator has doubts about the response to progression, particularly to the presence of NTL or new lesions, it is recommended to continue randomized treatment and treatment evaluation until the next scheduled scan, or sooner if clinically indicated, and to reassess the patient's status with a new scan. If a repeat scan confirms progression, the date of the initial scan should be declared the date of progression.

[0316] For a “clear progression” to be achieved on the basis of an NTL, there must be substantial overall deterioration in the NTL such that, even in the case of SD or PR in the TL, the overall tumor burden has increased sufficiently to indicate the need to discontinue treatment. A modest “increase” in the size of one or more NTLs is generally insufficient to qualify as a clear progression status.

[0317] Central Scan Reading

[0318] All scans used for tumor assessment will be independently reviewed in accordance with RECIST 1.1. All imaging assessments, including unplanned visit scans, will be collected on a continuous basis and sent to the CRO designated by AstraZeneca for central analysis. The results of this independent review will not be communicated to the investigator, and patient management will be based solely on the results of the RECIST 1.1 assessment performed by the investigator.

[0319] Subgroup Analysis

[0320] Subgroup analyses will be performed to compare PFS (using investigator assessment according to RECIST 1.1) in the durvalumab + placebo arm versus control and the durvalumab + olaparib arm versus control to assess the concordance of treatment effects across potential or expected prognostic factors, including (but not limited to) the following subgroups of FAS:

[0321] • MMR status (intact vs. deficient)

[0322] • Disease status (relapse vs. new diagnosis)

[0323] • Region (Asia vs. RoW).

[0324] Other baseline variables, including biomarkers, may also be assessed if there is clinical evidence or an imbalance is observed between treatment arms.

[0325] No adjustments will be made to the significance level and sensitivity analysis of the subgroup tests, as all of these analyses will be considered to support the PFS analysis.

[0326] Overall Survival

[0327] OS will be analyzed using a stratified log-rank test, using the same methodology described for the primary PFS endpoint.Different stratification factors will be used for preliminary PFS analysis. If the number of deaths is too small for a meaningful analysis (less than 5 deaths per stratum), a pre-specified strategy that takes such cases into account will be applied. Further details will be documented in SAP. The effect of durvalumab + placebo compared to control will be estimated by HR and its corresponding CI and p-value. This will be repeated to compare durvalumab + olaparib with control.

[0328] For each comparison (dvalvalumab + placebo compared to control, and durvalumab + olaparib compared to control), a KM plot of OS will be presented by treatment arm.

[0329] A summary of the number and percentage of patients who have died, patients still in survival follow-up, patients lost to follow-up, and patients who withdrew consent, as well as the median OS for each treatment, will be provided.

[0330] Dosage and Study Treatment Instructions 27 / 48 pages 37 CN 122094673 A

[0331] Study treatment is defined as any study product and non-study product (including commercially available product comparators and placebos) or medical device intended to be administered to study participants in accordance with the study protocol. In this study, study treatment refers to chemotherapy, durvalumab / placebo, and olaparib / placebo. Study treatments are summarized in Table 1.

[0332] Patients should receive platinum-based chemotherapy and durvalumab / placebo for the first 6 cycles (minimum 4 cycles). Patients without signs of PD (according to RECIST 1.1) will receive durvalumab / placebo and olaparib / placebo during the maintenance period.

[0333] During chemotherapy, ideally, the intravenous study treatment should be administered on the same day in the following order:

[0334] Devallumab / placebo: 1120 mg (Q3W) of devallumab should be administered over 1 hour; however, if there are interruptions during infusion, the total infusion time at room temperature should not exceed 8 hours.

[0335] Paclitaxel: 175 mg / m2, IV infusion over 3 hours.

[0336] Carboplatin: AUC5 or AUC6 via IV infusion over 1 hour (or according to local practice).

[0337] Devallumab

[0338] For ease of use and convenience for researchers and patients, devallumab will be administered Q3W during chemotherapy to be consistent with the treatment interval of platinum-based chemotherapy, and a fixed dose of 1120 mg will be used (based on an average body weight of 75 kg, which is equivalent to a body weight-based dose of 15 mg / kg Q3W).

[0339] Population pharmacokinetic analysis indicated that body weight had a small impact on the pharmacokinetic (PK) of durvalumab, and subsequent modeling demonstrated that body weight-based and fixed dosing regimens produced similar median steady-state PK concentrations. Based on a median body weight of 75 kg, numerous clinical studies across multiple tumor types have currently administered a fixed dose of 1500 mg durvalumab every 4 weeks (equivalent to 20 mg / kg every 4 weeks). Durvalumab 1500 mgQ4W dosing is convincingly supported by the National Cancer Institute (NCI) Study ESR 14-10366 (hereinafter referred to as the “NCI Study”; Lee et al. 2017). This dosing regimen is equivalent to a fixed dose of 1120 mg Q3W and was selected for the maintenance phase of this study to be consistent with other studies.

[0340] The two dosing regimens of durvalumab used in this study (1120 mg Q3W during chemotherapy and 1500 mg Q4W during maintenance) are equivalent to 10 mg / kg Q2W as recommended on the label.

[0341] Note that if a patient’s weight drops to 30 kg or less (≤30 kg) during the maintenance phase, the patient should receive a weight-based dose of 20 mg / kg durvalumab Q4W after consultation between the investigator and the investigational physician until the patient’s weight improves to above 30 kg (>30 kg), at which point the patient should begin receiving a fixed dose of 1500 mg Q4W durvalumab.

[0342] Olaparib

[0343] Olaparib will be administered at the dose approved for use in ovarian and breast cancer, i.e., 300 mg twice daily. The permissible dose will be reduced according to prescribing information.

[0344] Combination of Dvalumab and Olaparib

[0345] Dvalumab and olaparib have been used in combination for a range of indications, including ovarian cancer, breast cancer, SCLC, and gastric cancer (MEDIOLA; NCT02734004). NCI studies have convincingly supported the safety and tolerability of the combination of olaparib 300 mg twice daily with Dvalumab 1500 mg twice daily (Lee et al. 2017). Instructions for Use, Pages 28 / 48, 38, CN 122094673 A

[0346] Instructions for Use, Pages 29 / 48, 39, CN 122094673 A

[0347]

[0348] Abbreviations: bd = twice daily; GMP = Good Manufacturing Practice; HDPE = High-density polyethylene; IP = Investigational product; IV = intravenous; IWRS = Interactive Network Response System; Q3W = every 3 weeks; Q4W = every 4 weeks; w / v = weight / volume.

[0349] Chemotherapy Agents

[0350] Chemotherapy agents (paclitaxel and carboplatin) will be locally sourced or, in some cases, when local sourcing is not feasible, AstraZeneca will centrally supply the drugs, which will be labeled in the local language in accordance with regulatory guidelines. In the EU, carboplatin and paclitaxel are considered adjunctive pharmaceutical products according to the EU Clinical Trials Guidelines (EU Guidelines 2017).

[0351] Chemotherapy is a “non-investigational drug” because it is a SoC recommended in international guidelines. Chemotherapy will be administered according to the recommendations for this treatment combination in the international guidelines (NCCN Uterine Neoplasms 2019).

[0352] Platinum-based chemotherapy should be administered for a maximum of 6 cycles. If necessary due to toxicity, a minimum of 4 cycles of platinum-based chemotherapy may be given. Chemotherapy administration will be as follows:

[0353] • Carboplatin (AUC5 or AUC6) Q3W (Note: For patients who have received prior pelvic radiotherapy, a dose reduction to AUC5 may be considered)

[0354] • Paclitaxel 175 mg / m2 Q3W.

[0355] Each chemotherapy agent will be administered according to local guidelines and may be provided as a prophylactic dose.

[0356] For carboplatin administration recommendations, please refer to the NCCN guidelines https: / / www.nccn.org / professionals / OrderTemplates / PDF / appendix_B.pdf. According to the NCCN guidelines, to avoid overestimation of CrCL and subsequent carboplatin dosage, in patients with low serum creatinine, the lowest value of 0.7 mg / dL (equivalent to 62 µmol / L) should be used to estimate creatinine clearance. The carboplatin dosage should be calculated using the Calvert formula as follows:

[0357] Carboplatin dosage (mg) = Target AUC × (GFR + 25)

[0358] Note: It is recommended that the GFR used in the Calvert formula should not exceed 125 mL / min. For the purposes of this protocol, GFR is considered equivalent to the estimated creatinine clearance.

[0359] Maximum dose of carboplatin (mg) = target AUC (mg / mL × min) × 150 mL / min

[0360] The maximum recommended dose of carboplatin is:

[0361] • AUC6 = 900 mg

[0362] • AUC5 = 750 mg

[0363] If chemotherapy is prematurely and permanently discontinued (before completing 4 cycles) due to toxicity or disease progression, all study treatment will be discontinued and the patient will not enter the maintenance phase. A study treatment discontinuation visit will be conducted, and follow-up will continue unless the patient withdraws consent to continue the study.

[0364] Patients who develop hypersensitivity to carboplatin should be managed according to standard clinical practice. Patients may be retreated according to local clinical guidance including increased hypersensitivity prophylaxis or the use of desensitization protocols. If hypersensitivity prevents further administration of carboplatin, cisplatin may be considered for the patient, provided that this is consistent with standard clinical practice in the field and only if the chemotherapy is of local origin. Cisplatin substitution should be discussed with the AstraZeneca study physician before implementation.

[0365] Patients experiencing hypersensitivity to paclitaxel should be managed according to standard clinical practice. Depending on the severity of the reaction, patients may be retreated according to local clinical guidelines. In cases of recurrent hypersensitivity, despite appropriate prophylaxis...Dosing prevented further administration of paclitaxel, but investigators may consider omitting paclitaxel from the chemotherapy regimen or replacing it with another taxane (nab-paclitaxel or docetaxel), provided that this is consistent with standard clinical practice on site and only if the chemotherapy is of local origin.

[0366] Patients who develop chemotherapy-induced peripheral neuropathy should be managed according to standard clinical practice. The dose of chemotherapy may be reduced according to local clinical guidelines. If permanent discontinuation of paclitaxel is required due to persistent significant peripheral neuropathy, docetaxel may be considered for the patient, provided that this is consistent with standard clinical practice on site and only if the chemotherapy is of local origin.

[0367] Example 2: Devalumab plus olaparib for newly diagnosed advanced or recurrent endometrial cancer

[0368] Methods

[0369] Trial design and patients

[0370] DUO-E was a randomized, double-blind, placebo-controlled, multicenter phase III trial conducted in 22 countries. Eligible patients were ≥18 years of age, had newly diagnosed advanced (FIGO Stage III / IV) or recurrent epithelial histology endometrial cancer (excluding sarcoma), and were untreated with first-line systemic anticancer therapy. For patients with recurrent disease, prior chemotherapy was permitted if it was administered adjuvantally and ≥12 months had passed between the last chemotherapy dose and subsequent recurrence. DNA MMR status was determined prior to randomization (see Supplementary Appendix). Patients also had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Full inclusion and exclusion criteria are provided in the Supplementary Appendix. 41 CN 122094673 A

[0371] Randomization and Study Treatment

[0372] Patients were randomized 1:1:1 to the three treatment arms (Figure 2) using an interactive voice / web response system, stratified by MMR expression status (intact vs. deficient), disease status (newly diagnosed vs. recurrent), and geographic region (Asia vs. the rest of the world). Patients with unknown MMR status prior to randomization were ineligible.

[0373] Patients entered a chemotherapy period, followed by a maintenance period, which continued until radiographic disease progression (RECIST version 1.1, investigator-assessed), unacceptable toxicity, withdrawal consent, or other discontinuation criteria were met. Maintenance therapy was only permitted for patients who did not experience objective disease progression during chemotherapy and met other eligibility requirements (see full eligibility criteria below).

[0374] Patients received intravenous platinum-based chemotherapy (carboplatin with an area under the curve of 5 or 6 and paclitaxel at 175 mg / m²) plus placebo every 3 weeks for six cycles, followed by maintenance placebo plus twice daily intravenous administration every 4 weeks.The patient was given a placebo tablet once; or intravenous platinum-based chemotherapy plus 1120 mg of durvalumab every 3 weeks for six cycles, followed by intravenous 1500 mg of durvalumab plus a placebo tablet twice daily every 4 weeks; or intravenous platinum-based chemotherapy plus 1120 mg of durvalumab every 3 weeks for six cycles, followed by intravenous 1500 mg of durvalumab plus 300 mg of olaparib twice daily every 4 weeks.

[0375] Determination of DNA mismatch repair (MMR) status

[0376] Prior to randomization, DNA MMR status was determined using the Ventana MMR IHC group (Roche Diagnostics, Rotkreuz, Switzerland) via a central test of the MMR status of tumor cells from formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples.

[0377] In accordance with local regulations, FFPE tumor tissue samples from previously unirradiated tumor lesions were provided to each patient. FFPE tumor tissue samples can be from local areas or metastatic sites and can be any of the following:

[0378] • Tumor samples obtained from cytoreductive surgery (in patients who have undergone such surgery)

[0379] • Biopsy samples obtained at diagnosis (if samples from cytoreductive surgery are unavailable)

[0380] • Newly collected tumor samples (if the samples are used as part of routine clinical practice).

[0381] Determination of programmed death-ligand-1 (PD-L1) status

[0382] Pretreatment tumor tissue samples were centrally tested using the VENTANA PD-L1 (SP263) immunohistochemical assay (Roche Diagnostics) after randomization. PD-L1 expression was determined using a combined tumor cell and tumor-associated immune cell positivity scoring method. The tumor area positivity (TAP) score was calculated as the proportion of tumor area occupied by tumor cells and immune cells with PD-L1 staining of any intensity. If the TAP score is ≥1%, the sample is considered PD-L1 positive, and if the TAP score is <1%, the sample is considered PD-L1 negative.

[0383] Determination of Homologous Recombination Repair Mutation (HRRm) Status

[0384] Baseline tumor tissue samples before treatment were used for homologous recombination repair mutation (HRRm) testing after randomization. HRRm status was centrally assessed using the Foundation One CDx NGS assay (Foundation Medicine, Inc., Cambridge, MA). If a harmful or suspected HRRm mutation was detected in any of the following pre-specified genes associated with HRR, the HRRm status was determined.Samples with a suspected harmful HRRm are considered positive for: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. A negative HRRm status (non-HRRm) is defined as a sample that does not carry a pathogenic mutation in any pre-specified gene associated with HRR. Unknown HRRm status includes patients recruited in China who have not undergone HRR testing and patients who withdrew their consent or due to unavailable samples.

[0385] Eligibility for Maintenance Period

[0386] Patients receive up to 6 cycles of chemotherapy and must receive at least 4 cycles of platinum-based chemotherapy to continue into the maintenance period of the study.

[0387] After completion of chemotherapy, the dosing regimen of durvalumab / placebo is changed to 1500 mg every 4 weeks. After chemotherapy, patients also received maintenance olaparib / placebo (maintenance therapy was initiated at least 3 weeks and at most 9 weeks after the last day of chemotherapy infusion).

[0388] Subgroup analysis: Pre-specified subgroup analyses evaluated progression-free survival in the dual group versus control group, triple group versus control group, and triple group versus dual group based on the following factors: MMR status (intact versus defective), HRRm status (HRRm versus non-HRRm versus unknown), PD-L1 status (PD-L1 positive, PD-L1 negative, unknown), disease status (relapse versus new diagnosis), region (Asia versus other parts of the world), age (<65 years versus ≥65 years), race (white versus black / African American versus Asian versus other races), histology (endometrioid versus serous versus other), ECOG performance status (0 versus 1), and FIGO stage.

[0389] Efficacy data were summarized and analyzed in the intended treatment cohort (all randomized patients), and safety data were summarized in the safety analysis set (all randomized patients receiving at least one dose of investigational treatment, i.e., olaparib / placebo or olaparib / placebo); for the maintenance phase, safety data were summarized in patients from the safety analysis set who entered the maintenance phase and received at least one dose of olaparib / placebo.

[0390] Preliminary progression-free survival analyses for each comparison were performed individually using a stratified log-rank test to generate p-values, where hazard ratios and confidence intervals (CIs) were estimated using a stratified Cox proportional hazards model. Kaplan-Meier (KM) plots were presented by treatment arm and used every 6 months from randomization to estimate median survival and the proportion of surviving and progression-free patients. Secondary time-event endpoints were analyzed using a similar approach.

[0391] Results

[0392] Patients

[0393] From June 2, 2020 to April 20, 2022, 718 patients were randomized: 241, 238, and 239 patients were randomized to the control group, the dual therapy group, and the triple therapy group, respectively. Of those randomized patients, 236 patients (97.9%) in the control group, 235 patients (98.7%) in the dual therapy group, and 238 patients (99.6%) in the triple therapy group received any study treatment, and 169 patients (70.1%), 183 patients (76.9%), and 192 patients (80.3%), respectively, started maintenance therapy and received olaparib / placebo (Figure 6).

[0394] Patient baseline characteristics across the treatment arm were generally balanced (Table 4) and represent patients with newly diagnosed advanced or recurrent endometrial cancer (Table 5). Stratification factors across treatment arms are balanced: 80% of patients in each arm have intact MMR (pMMR) tumors, approximately 28% are from Asia, and approximately 47% have newly diagnosed disease.

[0395] Table 4. Patient baseline characteristics. Instructions 33 / 48 pages 43 CN 122094673 A

[0396] Instructions 34 / 48 pages 44 CN 122094673 A

[0397]

[0398] Abbreviations: ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; HRRm, Homologous Recombination Repair Mutation; MMR, Mismatch Repair; PD-L1, Programmed Death-Ligand-1; TAP, Tumor Region Positive Rate.

[0399] a Stratification factors (MMR status [intact vs. defective], disease status [newly diagnosed vs. recurrent], and geographic region [Asia vs. non-Asia]) are randomized according to codes.

[0400] b Includes China, India, Japan, South Korea, and Singapore. Two patients from India were incorrectly stratified to the Asian subgroup.

[0401] cFIGO staging was determined via electronic case report forms. Reported as a percentage of the total number of patients in each arm.

[0402] d. Pathologically relevant disease features were collected at the initial disease diagnosis in the study.

[0403] e. MMR status was assessed using the Ventana MMR RxDx panel (Roche Diagnostics, Rotkreuz, Switzerland).

[0404] f. HRRm status was assessed using the Foundation One CDx NGS assay (Foundation Medicine, Inc., Cambridge, MA). Positive HRRm status (HRRm) was defined as a sample carrying a pathogenic mutation in any of the following pre-specified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2,RAD51B, RAD51C, RAD51D, RAD54L. Negative HRRm status (non-HRRm) was defined as a sample that did not carry a pathogenic mutation in any pre-specified gene. Unknown HRRm status included patients recruited in China who did not undergo HRR testing and patients who withdrew consent or due to sample unavailability.

[0405] g PD-L1 expression was assessed using the Ventana SP263 immunohistochemical assay (Roche Diagnostics). PD-L1 positive was defined as TAP ≥ 1%. PD-L1 negative was defined as TAP < 1%. Unknown included patients who withdrew consent or due to sample unavailability.

[0406] h Only report "Yes".

[0407] Table 5. Representativeness of study participants. Instructions for Use, Pages 35 / 48, CN 122094673 A

[0408]

[0409] Efficacy

[0410] A preliminary analysis of investigator-assessed progression-free survival was performed in 438 of the 718 patients in the intention-to-treat population who had disease progression or death (data maturity, 61%) (data cutoff, April 12, 2023). The median duration of follow-up in censored patients was 12.6 months (range, 0.0 to 31.6) in the control group, 15.4 months (range, 0.0 to 29.1) in the doublet group, and 15.4 months (range, 0.0 to 31.7) in the triplet group.

[0411] In the intention-to-treat population, the durvalumab arm had a statistically significant 29% lower risk of disease progression or death compared to the control (HR, 0.71; 95% CI, 0.57 to 0.89; P = 0.003; median PFS 10.2 months vs. 9.6 months) (Figure 4A; Table 7). Compared to the control, the durvalumab + olaparib arm had a statistically significant 45% lower risk of disease progression or death (HR, 0.55; 95% CI, 0.43 to 0.69; P < 0.001; median PFS 15.1 months vs. 9.6 months) (Figure 4A; Table 7). The PFS Kaplan-Meier curves overlapped until approximately 6 months, after which a clear and sustained separation was observed, which favored both study arms compared to the control (Figure 4A). This delayed separation was expected due to the known delayed treatment effect of durvalumab and the fact that olaparib maintenance therapy only begins after chemotherapy is completed. The delay in curve separation indicates disproportion (P = 0.018 for durvalumab vs. control and P = 0.03 for durvalumab + olaparib vs. control). In the presence of disproportionate risk, the overall PFS HR should be interpreted as an average estimate of the observed benefit. The ratios and median PFS values ​​at specific time points are shown in Table 7.

[0412] In an exploratory analysis of investigator-assessed progression-free survival in the triplet and doublet groups, the hazard ratio for disease progression or death was 0.78 (95% CI, 0.61 to 0.99; P = 0.045).

[0413] Sensitivity analyses of progression-free survival assessed by blinded independent central review were consistent with investigator-assessed results in comparisons between doublet and control (hazard ratio 0.74; 95% CI 0.58 to 0.94) and triplet and control (hazard ratio 0.55; 95% CI 0.42 to 0.70) (Figure 6).

[0414] In the investigator-assessed exploratory analysis of advance-free survival (PFS) in the durvalumab + olaparib arm compared to durvalumab, the HR was 0.78 (95% CI, 0.61 to 0.99; median PFS 15.1 months vs. 10.2 months) (Table 7).

[0415] Exploratory analyses of progression-free survival in predefined subgroups demonstrated consistent treatment efficacy, with all observed hazard ratio estimates favoring the dual group compared to control and the triple group compared to control (Figures 5A–5B). Global interactive tests showed that treatment efficacy by MMR status and region may differ numerically for dual versus control (Table 6). Analyses by MMR status are reported in Tables 7 and Figures 8.

[0416] The first interim analysis of OS was performed during the preliminary PFS analysis, at which time 199 (28%) deaths occurred in the intention-to-treat population. The median (range) duration of follow-up in OS-censored patients was 18.6 months (0.5–32.9) in the control arm, 18.4 months (2.1–33.0) in the durvalumab arm, and 18.7 months (1.1–33.4) in the durvalumab + olaparib arm. The HRs for both comparisons were favorable to the study arm; however, neither comparison reached statistical significance at this first interim analysis of OS (dvalvalumab vs. control: HR, 0.77, 95% CI, 0.56 to 1.07; P = 0.120; durvalumab + olaparib vs. control: HR, 0.59, 95% CI, 0.42 to 0.83; P = 0.003, Figure 4B). In pre-specified exploratory subgroup analyses of PFS, all observed HR point estimates were favorable to both durvalumab and durvalumab + olaparib arms compared to control (Figures 5A–5B). In the dMMR subgroups, the HR for PFS was 0.42 for durvalumab compared to control (95% CI, 0.22 to 0.80, median PFS not reached [NR] at 7.0 months) and 0.41 for durvalumab + olaparib compared to control (95% CI, 0.21 to 0.75, median PFS 31 months).0.8 months vs. 7.0 months (Table 7 and Figure 8A). In the pMMR subgroup, the HR for PFS was 0.77 for durvalumab compared to control (95% CI, 0.60 to 0.97, median PFS 9.9 months vs. 9.7 months) and 0.57 for durvalumab + olaparib compared to control (95% CI, 0.44 to 0.73, 15.0 months vs. 9.7 months) (Table 7 and Figure 8B). Table 7 reports the comparison of durvalumab + olaparib versus durvalumab based on MMR status. In subgroup analyses based on PD-L1 status, in the PD-L1 positive subgroup (defined as tumor region positivity [TAP] ≥1%), the HR for PFS was 0.63 (95% CI, 0.48 to 0.83) for durvalumab compared to control, with median PFS of 11.3 months and 9.5 months, and 0.42 (95% CI, 0.31 to 0.57) for durvalumab + olaparib compared to control, with median PFS of 20.8 months and 9.5 months (Figure 10A). In the PD-L1 negative subgroup (TAP <1%), the HR for PFS was 0.89 (95% CI, 0.59 to 1.34) for durvalumab compared to control, with median PFS of 9.7 and 9.9, and 0.80 (95% CI, 0.55 to 1.16) for durvalumab + olaparib compared to control, with median PFS of 10.1 and 9.9 (Figure 10B). Details of the duration of treatment studied are provided in Table 8.

[0417] Table 6. Interaction test for progression-free survival based on investigator assessment (RECIST, version 1.1).

[0418]

[0419] MMR indicates mismatch repair; NA is not applicable; and RECIST criteria for response in solid tumors. Instructions for Use, pages 37 / 48, CN 122094673 A

[0420] Instructions for Use, pages 38 / 48, CN 122094673 A

[0421] Instructions for Use, pages 39 / 48, CN 122094673 A

[0422]

[0423] The Phase 3 DUO-E trial demonstrated that, in patients with newly diagnosed advanced or recurrent endometrial cancer, durvalumab in combination with first-line carboplatin and paclitaxel, followed by maintenance administration of durvalumab with or without olaparib, significantly reduced the risk of disease progression or death (45% reduction with olaparib, 29% reduction without olaparib). These data confirm the clinical benefit of incorporating immunotherapy, with or without PARP inhibitors, into first-line chemotherapy for patients with newly diagnosed advanced or recurrent endometrial cancer, and are evidence of this benefit in such cases.First data on the additional benefit from adding a PARP inhibitor.

[0424] In pre-specified exploratory subgroup analyses of PFS, all observed HR point estimates were favorable to the durvalumab and durvalumab + olaparib arms compared to controls. Analyses by MMR status showed similar clinically meaningful benefits in the dMMR subgroups in the durvalumab arm compared to controls (HR, 0.42; 95% CI, 0.22 to 0.80) and in the durvalumab + olaparib arm compared to controls (HR, 0.41; 95% CI, 0.21 to 0.75). In the pMMR subgroup, a clinically significant benefit was observed in the durvalumab arm compared to control (HR, 0.77; 95% CI, 0.60 to 0.97), and the addition of maintenance olaparib to durvalumab indicated a further benefit (HR, 0.57; 95% CI, 0.44 to 0.73 compared to control). Pre-specified exploratory analyses of durvalumab + olaparib compared to the durvalumab arm showed a contribution from olaparib in the pMMR subgroup (HR, 0.76, 95% CI, 0.59 to 0.99 in the pMMR subgroup; HR, 0.97, 95% CI, 0.49 to 1.98 in the dMMR subgroup). Analysis based on PD-L1 status indicated benefits for the PD-L1-positive subgroup demonstrating clinically meaningful improvement in PFS (HR 0.63 [95% CI, 0.48 to 0.83] for the durvalumab arm compared to control and 0.42 [95% CI, 0.31 to 0.57] for the durvalumab + olaparib arm compared to control), and for the PD-L1-negative subgroup with smaller improvements (HR 0.89 [95% CI, 0.59 to 1.34] for the durvalumab arm and 0.80 [95% CI, 0.55 to 1.16] for the durvalumab arm and the durvalumab + olaparib arm compared to control, respectively).

[0425] In DUO-E, results in the dual therapy group showed clinical benefit in combination therapy with immune checkpoint inhibitors and standard chemotherapy for newly diagnosed advanced or recurrent endometrial cancer.

[0426] The progression-free survival sensitivity analysis was consistent with the preliminary analysis. The first interim analysis of overall survival favored the study arm and supported the primary endpoint.

[0427] The safety profile of the experimental group was generally consistent with the known profile of each individual regimen. Delivery of standard care was not impaired by delivery of any other treatment, and the frequency of chemotherapy discontinuation was similar across arms.

[0428] For adverse events of particular or potential concern related to devalumab, the events were consistent with the known safety profile of devalumab in combination with chemotherapy, which was primarily driven by chemotherapy. For adverse events of particular concern related to olaparib...The incidence of events, myelodysplastic syndromes, and acute myeloid leukemia was low and consistent with the known safety profile of olaparib.

[0429] Adding durvalumab to standard first-line platinum-based chemotherapy, followed by maintenance durvalumab administration with or without olaparib, significantly improved progression-free survival outcomes in patients with first-line advanced or recurrent endometrial cancer, demonstrating the clinical benefit of integrating immunotherapy with or without a PARP inhibitor into first-line chemotherapy in this context. Adding olaparib to maintenance durvalumab further enhanced the clinical benefit. The safety profile of the experimental groups was generally consistent with the known profile of each individual regimen.

[0430] The combination of olaparib (Lynparza) and durvalumab is indicated for maintenance therapy in adult patients with primary advanced or recurrent endometrial cancer of the mismatch repair intact (pMMR) type who have not progressed on first-line therapy with durvalumab in combination with carboplatin and paclitaxel.

[0431] Predefined exploratory subgroup analyses demonstrated improved PFS, and the addition of maintenance olaparib to the combination of durvalumab and chemotherapy improved outcomes in both pMMR and PD-L1 positive patient populations. Although there was a higher rate of Grade 3 or higher AEs in the durvalumab + olaparib arm, the safety profile of each arm was generally consistent with the known profiles of the respective regimens, pages 41 / 48, CN 122094673 A.

[0432] Example 3: Dvorumab + carboplatin / paclitaxel (CP), followed by Dvorumab ± olaparib as first-line (1L) treatment for endometrial cancer (EC): progression-free survival (PFS) by clinical factors in DUO-E

[0433] Methods

[0434] Patients (pts) with newly diagnosed stage III / IV or recurrent EC were randomized 1:1:1 to CP (CP + Dvorumab placebo [pbo], followed by Dvorumab pbo + olaparib pbo), CP+D (CP + Dvorumab, followed by Dvorumab + olaparib pbo) or CP+D+O (CP + Dvorumab, followed by Dvorumab + olaparib). Post-hoc exploratory PFS subgroup analyses were performed based on key clinical factors: age (<65 years vs. ≥65 years); BMI (<25 vs. ≥25); ECOG PS (0 vs. 1); and prior chemotherapy, surgery, and radiotherapy (yes or no) were reported in the ITT and mismatch repair populations.

[0435] Results

[0436] At the original data cutoff (April 12, 2023), PFS subgroup analyses by age, BMI, ECOG PS, and prior treatment generally showed a benefit of CP+D±O compared to CP in the ITT population (Table 9). PFS subgroup analyses showed a benefit in dMMR patientsConsistent PFS benefit of CP+D compared to CP (HR < 1.00 in all subgroups). In pMMR patients, CP+D generally showed a benefit compared to CP, with the addition of olaparib consistently enhancing PFS (HR < 1.00 for CP+D+O compared to CP in all subgroups).

[0437] Across a range of key clinical factors explored in these analyses, the DUO-E ITT population received a PFS benefit of CP+D±O compared to CP. In dMMR patients, a consistent PFS benefit of CP+D compared to CP was observed across key clinical factors. Across a range of key clinical factors, pMMR patients received a benefit from CP+D compared to CP, with the addition of olaparib consistently enhancing PFS within each subgroup category. These DUO-E subgroup analyses support previous PFS analyses (benefit of CP+D compared to CP) for both the ITT and dMMR populations, and the benefit is enhanced in pMMR patients with the addition of olaparib.

[0438] Table 9. Specification 42 / 48 pages 52 CN 122094673 A

[0439]

[0440] Data loss in 2 patients in both CP and CP+D, and 1 patient in CP+D+O; overweight / obese.

[0441] e, event; n, patient; N, no; Y, yes

[0442] Example 4: First-line (1L) durvalumab + carboplatin / paclitaxel (CP), followed by durvalumab ± olaparib for endometrial cancer (EC) (DUO-E): Objective response rate (ORR), duration of response (DoR), and time to treatment discontinuation or death (TDT) by mismatch repair (MMR) status

[0443] Methods

[0444] Patients with newly diagnosed FIGO stage III (measurable disease before randomization [RECIST 1.1]) or stage IV or recurrent EC and who were untreated with systemic 1L therapy were randomized 1:1:1 to CP + durvalumab placebo (pbo; 6 cycles), followed by durvalumab pbo + olaparib pbo (CP arm); CP + durvalumab (1120 mg IV) q3w), followed by durvalumab (1500 mg IV q4w) + olaparib pbo (CP+D arm); or CP + durvalumab, followed by durvalumab + olaparib (300 mg tablets bid; CP+D+O arm). ORR, DoR, and TDT (exploratory) were evaluated in ITT and MMR populations.

[0445] Results Notice 43 / 48 pages 53 CN 122094673 A

[0446] At the raw data cutoff (April 12, 2023), overall, the ORR of CP+D and CP+D+O compared to CP wasImprovement was achieved (62% and 64% vs 55%); CP+D had longer median (m)DoR and mTDT compared to CP (mDoR: 13.1 [95% CI 6.0–NR] vs 7.7 [5.1–13.5] months [mo]; mTDT: 9.9 [8.8–11.2] vs 8.8 [7.6–9.7] mo), and CP+D+O further increased (mDoR: 21.3 [8.1–29.9] mo; mTDT: 15.1 [12.5–18.6] mo; Table 10). In patients with MMR deficiency (dMMR), CP+D and CP+D+O improved ORR (71% and 73% vs 40%), mDoR (NR and 29.9 [95% CI 9.7–29.9] vs 10.5 [4.6–NR] mo) and mTDT (21.2 [9.3–NR] and 20.6 [13.4–NR] vs 6.7 [5.1–7.9] mo) compared to CP. In pMMR patients, ORR was similar across arms, but CP+D had longer mDoR and mTDT compared to CP (mDoR: 10.6 [95% CI 5.6–NR] vs. 7.6 [5.1–13.1] mo; mTDT: 9.6 [8.1–10.6] vs. 9.3 [8.0–9.9] mo), and CP+D+O further prolonged (mDoR: 18.7 [8.0–NR] mo; mTDT: 13.4 [10.6–15.6] mo).

[0447] Compared to CP (ITT population), CP+dvalumab, followed by dvalumab ± olaparib, improved ORR, DoR, and TDT. In dMMR patients, CP+D consistently improved ORR, DoR, and TDT compared to CP. In pMMR patients, CP+D improved mDoR compared to CP and the addition of olaparib further prolonged mDoR and mTDT compared to CP+D.

[0448] Example 5: Interim analysis of DUO-E results

[0449] The updated DUO-E study design, including endpoints and patients, is shown in Figure 11. † Six cycles of concentration-time curve area under the curve of 5 mg / mL / min or 6 mg / mL / min carboplatin and 175 mg / m2 paclitaxel. bid, twice daily; CP, carboplatin / paclitaxel; D, durvalumab; DCO1, data cutoff point 1; FIGO, International Federation of Gynecology and Obstetrics; IV, intravenous; O, olaparib; q3(4)w, every 3(4) weeks; R, randomization; RECIST, criteria for assessment of response to solid tumors. Figure 12 shows patient characteristic data. Obstetrics and Gynecology Alliance; HRR(m), homologous recombination repair (mutation); MMR, mismatch repair; NGS, next-generation sequencing; PD-L1,Programmed death ligand 1; TAP, tumor region percentage. Percentages may not total 100% due to rounding. Ethnic data were missing for 6 patients; 1 newly diagnosed patient was FIGO stage I, and 1 newly diagnosed patient was FIGO stage II; 1 patient in the CP+D arm had an ECOG PS of 2. Stratification factors (MMR status [intact vs. deficient], disease status [newly diagnosed vs. recurrent], and geographic region [Asian vs. non-Asian]) were based on randomization codes. Based on local testing, an interactive voice response system randomly assigned two patients with an 'unknown' MMR status, as determined by the central laboratory, to the 'deficient' group. “Asia” includes China, India, Japan, Singapore, and the Republic of Korea; † MMR status assessed using the Ventana MMR Immunohistochemistry panel; ‡ PD-L1 expression assessed using the Ventana SP263 assay; § HRRm status evaluated using the Foundation One CDx NGS assay, including harmful or suspected harmful mutations in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Unknown HRRm status includes patients recruited in China who have not undergone HRR testing, and patients whose samples were not available for testing. ECOG PS, Eastern Oncology Collaboration Group performance status:

[0450] Results for the ITT cohort are shown in Figure 13. Optimal objective response was determined based on data obtained before the initiation of any subsequent cancer therapy and up to and including the last RECIST assessment in the absence of progression. The number of patients with measurable disease at baseline was calculated; the advantage of response (complete or partial response). An advantage ratio >1 favored the CP+D or CP+D+O arm; the time from randomization to the start of response; the DoR was the time from the first confirmed complete / partial response to the date of progression or PFS censoring. The percentage of patients who maintained a response was estimated using the Kaplan-Meier method. IQR, interquartile range; NR, not reached. Secondary endpoints in the ITT cohort are shown in Figure 14. The rates of TFST, PFS2, and TSST were estimated using the Kaplan-Meier method. HR was estimated using a Cox proportional hazards model stratified according to MMR and disease state variables. CI was calculated using the probabilistic likelihood method.

[0451] A post-hoc exploratory analysis of the MMR subgroups is shown in Figure 15. For the dMMR subgroup, the median duration of overall survival (OS) follow-up in censored patients was 18.4 months (CP), 19.1 months (CP+D), and 19.9 months (CP+D+O); for the pMMR subgroup, see pages 44 / 48 of the censoring instructions (54 CN).The median follow-up duration in patient A (122094673) was 18.6 months (CP), 18.2 months (CP+D), and 18.4 months (CP+D+O). MMR status was assessed using the Ventana MMR Immunohistochemistry panel. OS rates were estimated using the Kaplan-Meier method. HR and CI were estimated using an unstratified Cox proportional hazards model.

[0452] Figure 16 shows a post-hoc exploratory analysis of the dMMR subset. MMR status was assessed using the Ventana MMR Immunohistochemistry panel. TFST, PFS2, and TSST rates were estimated using the Kaplan-Meier method. HR and CI were estimated using an unstratified Cox proportional hazards model. Stratification factors (disease status, MMR status, and geographic region) were assigned according to randomization codes. HRRm status was evaluated using the Foundation One CDx NGS assay and included harmful or suspected harmful mutations in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Unknown HRRm status included patients recruited in China who had not undergone HRR testing, and patients whose samples were unavailable for testing. PD-L1 status in baseline tumor tissue was determined using the Ventana SP263 assay set. Expression was assessed using the TAP score, calculated based on the proportion of tumor area occupied by tumor cells or immune cells with membrane PD-L1 staining. FIGO staging was determined at the initial diagnosis of endometrial cancer in the study. G, grade; NC, not calculated. Optimal objective response was determined based on data obtained before the initiation of any subsequent cancer therapy and up to and including the last RECIST assessment in the absence of progression. Calculated based on the number of patients with measurable disease at baseline; strength of response (complete or partial response). Odds ratio >1 favored the CP+D or CP+D+O arm; time from randomization to response initiation; DoR was time from the first confirmed complete / partial response to the progression date or PFS censoring date. The percentage of patients maintaining a response was estimated using the Kaplan-Meier method.

[0453] Figure 17 shows a post-hoc exploratory analysis of the pMMR subsets. MMR status was evaluated using the Ventana MMR Immunohistochemistry panel. TFST, PFS2, and TSST rates were estimated using the Kaplan-Meier method. HR and CI were estimated using an unstratified Cox proportional hazards model. Stratification factors (disease status, MMR status, and geographic region) were assigned according to randomization codes. Foundation One CDx was used.HRRm status was evaluated using NGS assays and included harmful or suspected harmful mutations in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Unknown HRRm status included patients recruited in China who had not undergone HRR testing, and patients whose samples were unavailable for testing. PD-L1 status in baseline tumor tissue was determined using the Ventana SP263 assay set. Expression was assessed using the TAP score, calculated based on the proportion of tumor area occupied by tumor cells or immune cells with membrane PD-L1 staining. FIGO staging was determined at the initial diagnosis of the endometrial cancer in the study. Optimal objective response was determined based on data obtained before the initiation of any subsequent cancer therapy and up to and including the last RECIST assessment in the absence of progression. Calculations were based on the number of patients with measurable disease at baseline; the strength of the response (complete or partial response). Odds ratio >1 favored the CP+D or CP+D+O arm; time from randomization to response start; DoR was time from the first confirmed complete / partial response to the progression date or PFS censoring date. The percentage of patients maintaining a response was estimated using the Kaplan-Meier method.

[0454] For the MMR subgroup, the results are shown in Figure 18. MMR status was evaluated using the Ventana immunohistochemical MMR panel. PFS rates were estimated using the Kaplan-Meier method. The CI for median PFS was obtained based on the Brookmeyer-Crowley method; HR and CI were estimated using an unstratified Cox proportional hazards model. CI, confidence interval; CP, carboplatin / paclitaxel; D, duvarubican; DCO, data cutoff; dMMR, MMR deficient; HR, hazard ratio; ITT, intention to treat; NR, not reached; O, olaparib; PFS, progression-free survival; pMMR, MMR intact.

[0455] Finally, Figures 19-20 show additional results from the ITT population and exploratory PFS analysis. Specification 45 / 48 pages 55 CN 122094673 A

[0456]

[0457] References:

[0458] 1. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment ofextensive‑ stage small‑cell lung cancer (CASPIAN): a randomised, controlled, open‑label, phase 3 trial. Lancet 2019;394(10212):1929‑1939. (In eng) .DOI: 10.1016 / s0140‑ 6736(19)32222‑6.

[0459] 2 .Johnson ML , Cho BC , Luft A , et al .Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First‑Line Therapy for Metastatic Non–Small‑Cell Lung Cancer: The Phase III POSEIDON Study.Journal of Clinical Oncology 2023;41(6):1213‑1227. DOI: 10.1200 / jco.22.00975.

[0460] 3 .Oh DY , Lee KH , Lee DW , et al .Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy‑naive patients with advanced biliary tract cancer: an open‑label , single‑centre , phase 2 study.Lancet Gastroenterol Hepatol 2022; 7(6):522‑532.DOI: 10.1016 / S2468‑1253 (22)00043‑7.

[0461] 1.Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022.CA Cancer J Clin 2022;72(1):7‑33. (In eng) .DOI: 10.3322 / caac.21708.

[0462] 2.NCCN.NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines ®) .Uterine neoplasms . Version 1 .2023 . Plymouth Meeting , PA: National Comprehensive Cancer Network, 2022.

[0463] 3 .Aghajanian C , Filiaci V , Dizon DS , et al .A phase II study of frontline paclitaxel / carboplatin / bevacizumab , paclitaxel / carboplatin / temsirolimus , or ixabepilone / carboplatin / bevacizumab in advanced / recurrent endometrial cancer .Gynecol Oncol 2018;150(2):274‑281 . DOI: 10 .1016 / j.ygyno.2018.05.018.

[0464] 4 .Miller D , Filiaci V , Fleming G , et al .Late‑Breaking Abstract 1: Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group study.Gynecol Oncol 2012; 125(3):771.DOI: 10.1016 / j.ygyno.2012.03.034.

[0465] 5 .Pectasides D , Xiros N , Papaxoinis G , et al .Carboplatin and paclitaxel in advanced or metastatic endometrial cancer.Gynecol Oncol 2008; 109(2):250‑4. DOI: 10.1016 / j.ygyno.2008.01.028.

[0466] 6.André T, Berton‑Rigaud D, Curigliano G, et al.549PProgression‑free survival (PFS) and overall survival (OS) in patients (pts) with mismatch repair deficient (dMMR) solid tumors treated with dostarlimab in the GARNET study.Ann Oncol 2022; 33: S799‑800; abstract.DOI: 10.1016 / j.annonc.2022.07.677.

[0467] 7.Antill Y, Kok PS, Robledo K, et al.Clinical activity of durvalumab for patients with advanced mismatch repair‑deficient and repair‑proficient endometrial cancer.A nonrandomized phase 2 clinical trial.J Immunother Cancer 2021; 9(6):e002255.DOI: 10.1136 / jitc‑2020‑002255. Description Page 47 / 48 57 CN 122094673 A

[0468] 8.Marabelle A, Le DT, Ascierto PA, et al.Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability / mismatch repair‑ deficient cancer: results from the Phase II KEYNOTE‑158 study.J Clin Oncol 2020; 38(1):1‑10.DOI: 10.1200 / JCO.19.02105.

[0469] 9.Makker V, Colombo N, Casado Herráez A, et al.Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer.NewEngland Journal of Medicine 2022;386(5):437‑448. DOI: 10.1056 / NEJMoa2108330.

[0470] 10 .Mirza MR , Chase DM , Slomovitz BM , et al .Dostarlimab for primary advanced or recurrent endometrial cancer . N Engl J Med 2023;388:2145‑ 2158.DOI: 10.1056 / NEJMoa2216334.

[0471] 11 .Eskander RN , Sill MW , Beffa L , et al .Pembrolizumab plus chemotherapy in advanced endometrial cancer.N Engl J Med 2023; 388(23):2159‑ 2170.DOI: 10.1056 / NEJMoa2302312.

[0472] 12 .Stewart RA , Pilié PG , Yap TA .Development of PARP and Immune‑ Checkpoint Inhibitor Combinations.Cancer Research 2018;78(24):6717‑6725. DOI: 10.1158 / 0008‑5472.Can‑18‑2652.

[0473] 13 .Li A , Yi M , Qin S , Chu Q , Luo S , Wu K . Prospects for combining immune checkpoint blockade with PARP inhibition.J Hematol Oncol 2019; 12(1): 98.DOI: 10.1186 / s13045‑019‑0784‑8.

[0474] 14.Wanderley CWS, Correa TS, Scaranti M, Cunha FQ, Barroso‑Sousa R . Targeting PARP1 to Enhance Anticancer Checkpoint Immunotherapy Response: Rationale and ClinicalImplications .Front Immunol 2022; 13:816642 .DOI: 10.3389 / fimmu.2022.816642.

[0475] 15.Lee EK, Konstantinopoulos PA.Combined PARP and Immune Checkpoint Inhibition in Ovarian Cancer.Trends Cancer 2019;5(9):524‑528. DOI: 10.1016 / j.trecan.2019.06.004.

[0476] 16.AstraZeneca.Global Policy: bioethics.(www.astrazeneca.com / content / dam / az / PDF / 2019 / Bioethics%20Policy%20final.pdf) . Instruction Manual 48 / 48 Page 58 CN 122094673 A Figure 1 Instruction manual Figure 1 / 46, page 59, CN 122094673 A, Figure 2; Instruction manual Figure 2 / 46, page 60, CN 122094673 A, Figure 3; Instruction manual Figure 3 / 46, page 61, CN 122094673 A, Figure 4A; Instruction manual Figure 4 / 46, page 62, CN 122094673 A, Figure 4B; Instruction manual Figure 5 / 46, page 63, CN 122094673 A, Figure 5; Instruction manual Figure 6 / 46, page 64, CN 122094673 A, Figure 5; Instruction manual Figure 7 / 46, page 65, CN 122094673 A, Figure 6; Instruction manual Figure 8 / 46, page 66, CN 122094673 A, Figure 7; Instruction manual Figure 9 / 46, page 67, CN 122094673 A, Figure 8A; Instruction manual Figure 10 / 46, page 68, CN 122094673 A, Figure 8B. Instruction manual, Figure 9, page 11 / 46, CN 122094673 A; Figure 10A, page 10 / 46, CN 122094673 A; Figure 10B, page 10 / 46, CN 122094673 A; Figure 11, page 12 / 46, CN 122094673 A; Figure 12A, page 15 / 46, CN 122094673 A.Illustrations: Page 16 / 46, Figure 74, CN 122094673 A, Figure 12B; Page 17 / 46, Figure 75, CN 122094673 A, Figure 13A; Page 18 / 46, Figure 76, CN 122094673 A, Figure 13B; Page 19 / 46, Figure 77, CN 122094673 A, Figure 13C; Page 20 / 46, Figure 78, CN 122094673 A, Figure 13D; Page 21 / 46, Figure 79, CN 122094673 A, Figure 14A; Page 22 / 46, Figure 80, CN 122094673 A, Figure 14B; Page 23 / 46, Figure 81, CN 122094673 A, Figure 14C; Page 24 / 46, Figure 82, CN 122094673 A, Figure 15A. The following are figures from the instruction manual: Figure 15B, Figure 16A, Figure 16C, Figure 16D, Figure 16F, Figure 17A, Figure 16B, Figure 16B, Figure 16C, Figure 16B, Figure 17A, Figure 16B, Figure 16B, Figure 16A, Figure 16B, Figure 16C, Figure 16B, Figure 16B, Figure 16C, Figure 16C, Figure 16D, Figure 16F, Figure 16F, Figure 16F, Figure 17A, Figure 17B, Figure 16B, Figure 16B, Figure 16C, Figure 16B, Figure 16B, Figure 16C, Figure 16B, Figure 16C, Figure 16B, Figure 16A ...C, Figure 16B, Figure 16C, Figure 16C, Figure 16B, Figure 16C, Figure 16C, Figure 16B, Figure 16C, Figure 16C, Figure 16C, Figure 16 Instruction manual illustrations, pages 34 / 46, 92 CN 122094673 A, Figure 17C; Instruction manual illustrations, pages 35 / 46, 93 CN 122094673 A, Figure 17D; Instruction manual illustrations, pages 36 / 46, 94 CN 122094673 A, Figure 17E; Instruction manual illustrations, pages 37 / 46, 95 CN 122094673 A, Figure 17F; Instruction manual illustrations, pages 38 / 46, 96 CN 122094673 A, Figure 18A; Instruction manual illustrations, pages 39 / 46, 97 CN 122094673 A, Figure 18B; Instruction manual illustrations, pages 40 / 46.98 CN 122094673 A Figure 19A, Instruction Manual Drawings, Pages 41 / 46 99 CN 122094673 A Figure 19B, Instruction Manual Drawings, Pages 42 / 46 100 CN 122094673 A Figure 20A, Instruction Manual Drawings, Pages 43 / 46 101 CN 122094673 A Figure 20B, Instruction Manual Drawings, Pages 44 / 46 102 CN 122094673 A Figure 20C, Instruction Manual Drawings, Pages 45 / 46 103 CN 122094673 A Figure 20D, Instruction Manual Drawings, Pages 46 / 46 104 CN 122094673 A

Claims

1. A method of treating endometrial cancer in a subject of need, the method comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

2. A method of treating endometrial cancer in a subject of need, the method comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of antiPD-L1 antibody or its antigen-binding fragment.

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

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

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

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

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

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

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

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

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

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

13. The method according to any one of claims 1 to 12, wherein the paclitaxel is at a concentration of 175 mg / m³. 2 Dosage administration.

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

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

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

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

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

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

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

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

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

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

24. The method according to any one of claims 21 to 23, wherein step (a) further comprises applying: 175mg / m 2 Paclitaxel; Carboplatin with an AUC of 5 or 6; and / or 25mg / m 2 Cisplatin.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

45. The method of claim 44, wherein the method comprises administering to the subject suffering from defective mismatch repair (dMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents and a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of antiPD-L1 antibody or its antigen-binding fragment.

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

47. The method of claim 46, wherein the method comprises administering to the subject suffering from intact mismatch repair (pMMR) endometrial cancer: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

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

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

50. The method according to any one of claims 1 to 49, wherein the treatment increases the progression-free survival of the subject compared to patients receiving only durvalumab and chemotherapy.

51. The method of claim 50, wherein the treatment increases progression-free survival by at least 4 months.

52. The method according to any one of claims 1 to 51, wherein the treatment increases the overall survival of the subject compared to patients receiving only durvalumab and chemotherapy.

53. The method of claim 52, wherein the treatment increases overall survival by at least 4 months.

54. A combination for use in treating endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

55. A combination for use in treating endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of antiPD-L1 antibody or its antigen-binding fragment.

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

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

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

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

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

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

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

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

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

65. The combination for use according to claim 64, wherein the dose of paclitaxel is 175 mg / m². 2 .

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

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

68. The combination for use according to claim 67, wherein the application is performed every two to four weeks for a period of nine to twenty-four weeks.

69. The combination for use as described in claim 67 or claim 68, wherein application is performed every three weeks or every four weeks.

70. The combination for use according to claim 69, wherein application is performed every three weeks for a period of twelve to eighteen weeks.

71. The combination for use according to claim 70, wherein application is performed every three weeks for a period of eighteen weeks.

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

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

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

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

76. The combination for use according to any one of claims 73 to 75, wherein (a) further comprises: 175mg / m 2 Paclitaxel; Carboplatin with an AUC of 5 or 6; and / or 25mg / m 2 Cisplatin.

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

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

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

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

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

82. The combination for use according to claim 79, wherein (b) comprises: Administer durvalumab at a dose of 1500 mg; as well as Olaparib was administered at a dose of 300 mg.

83. The combination for use according to any one of claims 79 to 81, wherein (b) comprises: Administer durvalumab at a dose of 1500 mg every 3 weeks; as well as Olaparib was administered twice daily at a dose of 300 mg.

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

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

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

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

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

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

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

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

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

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

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

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

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

97. The combination of claim 96 for use in treating defective mismatch repair (dMMR) endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of antiPD-L1 antibody or its antigen-binding fragment.

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

99. The combination of claim 98 for use in treating intact mismatch repair (pMMR) endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

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

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

102. The combination for use according to any one of claims 54 to 101, wherein treatment with the combination increases the progression-free survival of the subject compared to a patient receiving only durvalumab and chemotherapy.

103. The combination for use according to claim 102, wherein the treatment increases progression-free survival by at least 4 months.

104. The combination for use according to any one of claims 54 to 101, wherein treatment with the combination increases the overall survival of the subject compared to a patient receiving only durvalumab and chemotherapy.

105. The combination for use according to claim 104, wherein the treatment increases overall survival by at least 4 months.

106. Use of the combination in the manufacture of a medicament for treating endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

107. Use of the combination in the manufacture of a medicament for treating endometrial cancer in a subject of need, wherein said combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of antiPD-L1 antibody or its antigen-binding fragment.

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

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

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

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

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

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

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

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

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

117. The use according to claim 116, wherein the dosage of paclitaxel is 175 mg / m². 2 .

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

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

120. The use according to claim 119, wherein the application is performed every two to four weeks for a period of nine to twenty-four weeks.

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

122. The use according to claim 121, wherein the application is performed every three weeks for a period of twelve to eighteen weeks.

123. The use according to claim 122, wherein the application is performed every three weeks for a period of eighteen weeks.

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

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

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

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

128. The use according to any one of claims 125 to 127, wherein (a) further comprises: 175mg / m 2 Paclitaxel; Carboplatin with an AUC of 5 or 6; and / or 25mg / m 2 Cisplatin.

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

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

131. The use according to any one of claims 106 to 130, wherein (b) comprises: The anti-PD-L1 antibody or its antigen-binding fragment was administered at a dose of 1500 mg. as well as The PARP inhibitor was administered at a dose of 300 mg.

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

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

134. The use according to claim 131, wherein (b) comprises: Administer durvalumab at a dose of 1500 mg; as well as Olaparib was administered at a dose of 300 mg.

135. The use according to any one of claims 131 to 134, wherein (b) comprises: Administer durvalumab at a dose of 1500 mg every 3 weeks; as well as Olaparib was administered twice daily at a dose of 300 mg.

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

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

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

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

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

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

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

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

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

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

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

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

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

149. Use of the method of claim 148 in the manufacture of a medicament for treating defective mismatch repair (dMMR) endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of antiPD-L1 antibody or its antigen-binding fragment.

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

151. Use of the method of claim 150 in the manufacture of a medicament for treating intact mismatch repair (pMMR) endometrial cancer in a subject of need, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapeutic agents, a therapeutically effective amount of an antiPD-L1 antibody or its antigen-binding fragment; and (b) A therapeutically effective amount of an anti-PD-L1 antibody or its antigen-binding fragment and a therapeutically effective amount of a PARP inhibitor.

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

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

154. The use according to any one of claims 106 to 153, wherein the combination therapy increases the progression-free survival of the subject compared to patients receiving only durvalumab and chemotherapy.

155. The use according to claim 154, wherein the treatment increases progression-free survival by at least 4 months.

156. The use according to any one of claims 106 to 153, wherein the combination therapy increases the overall survival of the subject compared to patients receiving only durvalumab and chemotherapy.

157. The use according to claim 156, wherein the treatment increases overall survival by at least 4 months.

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