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Building IP: BMY Patent Grant"Methods Of Treating A Tumor Using An Anti-PD-1 AntibodyMethods Of Treating A Tumor Using An Anti-PD-1 AntibodyDOCUMENT IDUS 11566073 B2 DATE PUBLISHED2023-01-31 INVENTOR INFORMATION NAMECITYSTATEZIP CODECOUNTRYEdwards; Robin Newtown PA N/A US Geese; William J. Pipersville PA N/A US Greenawalt; Danielle M. Philadelphia PA N/A US APPLICANT INFORMATION NAME Bristol-Myers Squibb Company CITY Princeton STATE NJ ZIP CODE N/A COUNTRY US AUTHORITY N/A TYPE obligated-assignee ASSIGNEE INFORMATION NAME Bristol-Myers Squibb Company CITY Princeton STATE NJ ZIP CODE N/A COUNTRY US TYPE CODE 02 APPLICATION NO16/617725 DATE FILED2018-06-01 DOMESTIC PRIORITY (CONTINUITY DATA)us-provisional-application US 62513831 20170601 AbstractThis disclosure provides a method for treating a subject afflicted with tumor, which method comprises administering to the subject an antibody or an antigen-binding portion thereof that specifically binds to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the tumor is derived from a non-small cell lung cancer (NSCLC). In some embodiments, the tumor expresses Programmed Death Ligand 1. In some embodiments, the subject carries a wild-type STK11 gene. Background/SummaryFIELD OF THE INVENTION (1) This disclosure relates to methods for treating a tumor comprising administering to the subject an anti-Programmed Death-1 (PD-1) antibody, wherein the subject carries wild-type STK11. BACKGROUND OF THE INVENTION (2) Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Further, the immune system demonstrates considerable plasticity and a memory component. The successful harnessing of all these attributes of the adaptive immune system would make immunotherapy unique among all cancer treatment modalities. (3) PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2), that are expressed on antigen-presenting cells as well as many human cancers and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1. (4) Nivolumab (formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions (U.S. Pat. No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56). (5) NSCLC is the leading cause of cancer death in the U.S. and worldwide (NCCN GUIDELINES®, Version 3.2014—Non-Small Cell Lung Cancer, available at: nccn.org/professionals/physician_gls/pdf/nscl.pdf, last accessed May 14, 2014). NSCLCs are relatively insensitive to chemotherapy but patients with Stage IV disease who have a good performance status (PS) benefit from treatment with chemotherapeutic drugs, including platinum agents (e.g., cisplatin, carboplatin), taxanes agents (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel), vinorelbine, vinblastine, etoposide, pemetrexed and gemcitabine, and various combinations of these drugs. SUMMARY OF THE INVENTION (6) The present disclosure provides a method for treating a subject afflicted with a tumor comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) administering to the subject an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity (“anti-PD-1 antibody”) if the STK11 gene is wild-type. In other aspects, the present disclosure relates to methods for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a wild-type STK11 gene. In other aspects, the present disclosure relates to methods for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the STK11 gene is wild-type. In some embodiments, the method further comprises detecting a mutation status of a marker gene selected from the group consisting of KRAS, TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof. (7) In other aspects, the present disclosure relates to methods for treating a subject afflicted with a tumor comprising (i) determining a mutation status of marker gene in the subject; and (ii) administering to the subject an anti-PD-1 antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof. In other aspects, the present disclosure relates to methods for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a mutated marker gene, wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof. In other aspects, the present disclosure relates to methods for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of a marker gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof. In some embodiments, TP53 is mutated. In some embodiments, CDKN2A is mutated. In some embodiments, PTPND, CUBN, and HERC1 are mutated. (8) In some embodiments, the marker gene comprises a non-synonymous mutation. In certain embodiments, the marker gene comprises a nonsense, frameshift, or splicing mutation. (9) In some embodiments, the tumor is derived from a lung cancer. In certain embodiments, the tumor is derived from a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC). In certain embodiments, the tumor is derived from an NSCLC. In particular embodiments, the tumor is derived from a non-squamous cell NSCLC. In other embodiments, the tumor is derived from a squamous cell NSCLC. (10) In some embodiments, the methods further comprise detecting PD-L1 expression in the tumor prior to administration. In some embodiments, the tumor expresses PD-L1 in a diffuse pattern. In some embodiments, the tumor expresses PD-L1 in a heterogeneous pattern. (11) In some embodiments, the mutation status of the STK11 gene is determined by sequencing the STK11 gene. (12) In some embodiments, the tumor has a tumor mutational burden (TMB) status that is a high TMB. In some embodiments, the tumor TMB status is determined by sequencing nucleic acids in the tumor and identifying a genomic alteration in the sequenced nucleic acids. (13) In some embodiments, the tumor exhibits high inflammation. In some embodiments, the inflammation is measured according to the expression of STK11. (14) In some embodiments, the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1. In some embodiments, the anti-PD-1 antibody binds to the same epitope as nivolumab. In some embodiments, the anti-PD-1 antibody is a chimeric, humanized or human monoclonal antibody or a portion thereof. In some embodiments, the anti-PD-1 antibody comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype. In some embodiments, the anti-PD-1 antibody is nivolumab. (15) In some embodiments, the anti-PD-1 antibody is administered at a dose ranging from at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight once about every 1, 2 or 3 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose. In some embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose or about 240 mg. (16) In some embodiments, the administering treats the tumor. In some embodiments, the administering reduces the size of the tumor. In some embodiments, the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial administration. In some embodiments, the subject exhibits a partial response after the administration. In some embodiments, the subject exhibits a complete response after the administration. (17) In other aspects, this disclosure provides a kit for treating a subject afflicted with a tumor, the kit comprising: (a) a dosage ranging from about 4 mg to about 500 mg of an anti-PD-1 antibody; and (b) instructions for using the anti-PD-1 antibody in any method disclosed herein. In some embodiments, the kit further comprises an anti-PD-L1 antibody. Embodiments (18) E1. A method for treating a subject afflicted with a tumor comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) administering to the subject an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity (“anti-PD-1 antibody”) if the STK11 gene is wild-type. (19) E2. A method for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a wild-type STK11 gene. (20) E3. A method for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the STK11 gene is wild-type. (21) E4. The method of any one of E1 to E3, further comprising detecting a mutation status of a marker gene selected from the group consisting of KRAS, TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof. (22) E5. A method for treating a subject afflicted with a tumor comprising (i) determining a mutation status of marker gene in the subject; and (ii) administering to the subject an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity (“anti-PD-1 antibody”) if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof. (23) E6. A method for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a mutated marker gene, wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof. (24) E7. A method for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of a marker gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof. (25) E8. The method of any one of E4 to E7, wherein TP53 is mutated. (26) E9. The method of any one of E4 to E8, wherein CDKN2A is mutated. (27) E10. The method of any one of E4 to E9, wherein PTPND, CUBN, and HERC1 are mutated. (28) E11. The method of any one of E4 to E10, wherein the marker gene comprises a non-synonymous mutation. (29) E12. The method of any one of E4 to E11, wherein the marker gene comprises a nonsense, frameshift, or splicing mutation. (30) E13. The method of any one of E1 to E12, wherein the tumor is derived from a lung cancer. (31) E14. The method of E13, wherein the tumor is derived from a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC). (32) E15. The method of E14, wherein the tumor is derived from an NSCLC. (33) E16. The method of E15, wherein the tumor is derived from a non-squamous cell NSCLC. (34) E17. The method of E15, wherein the tumor is derived from a squamous cell NSCLC. (35) E18. The method of any one of E1 to E17, further comprising detecting PD-L1 expression in the tumor prior to administration. (36) E19. The method of E18, wherein the tumor expresses PD-L1 in a diffuse pattern. (37) E20. The method of E19, wherein the diffuse pattern of PD-L1 expression is characterized by a PD-L1 H-score of from about 60 to about 500, from about 80 to about 480, from about 100 to about 460, from about 120 to about 440, from about 140 to about 420, from about 160 to about 400, from about 180 to about 380, from about 200 to about 360, from about 200 to about 340, from about 200 to about 320, or from about 200 to about 300. (38) E21. The method of E19, wherein the diffuse pattern of PD-L1 expression is characterized by a PD-L1 H-score of at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 225, at least about 250, at least about 275, or at least about 300. (39) E22. The method of E21, wherein the diffuse pattern of PD-L1 expression is characterized by a PD-L1 H-score of at least about 200. (40) E23. The method of E18, wherein the tumor expresses PD-L1 in a heterogeneous pattern. (41) E24. The method of E23, wherein the heterogeneous pattern of PD-L1 expression is characterized by a PD-L1 H-score of from about 1 to about 50, from about 5 to about 45, from about 10 to about 40, or from about 15 to about 35, and wherein the PD-L1 expression is restricted to one or more distinct portions of the tumor. (42) E25. The method E23, wherein the heterogeneous pattern of PD-L1 expression is characterized by a PD-L1 H-score of at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, or at least about 40. (43) E26. The method of E25, wherein the heterogeneous pattern of PD-L1 expression is characterized by a PD-L1 H-score of at least about 15. (44) E27. The method of any one of E1, 3, 4, and 13 to E26, wherein the mutation status of the STK11 gene is determined by sequencing the STK11 gene. (45) E28. The method of any one of E18 to E27, wherein PD-L1 expression is detected using an immunohistochemistry (IHC) assay. (46) E29. The method of E28, wherein the IHC assay is an automated IHC assay. (47) E30. The method of E28 or E29, wherein the IHC assay is performed using an anti-PD-L1 monoclonal antibody that specifically binds to the PD-L1 and wherein the anti-PD-L1 monoclonal antibody is selected from the group consisting of 28-8, 28-1, 28-12, 29-8, 5H1, and any combination thereof. (48) E31. The method of any one of E18 to E30, wherein at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% of tumor cells express PD-L1. (49) E32. The method of any one of E1 to E31, wherein the tumor has a tumor mutational burden (TMB) status that is a high TMB. (50) E33. The method of E32, wherein the tumor TMB status is determined by sequencing nucleic acids in the tumor and identifying a genomic alteration in the sequenced nucleic acids. (51) E34. The method of E33, wherein the genomic alteration comprises one or more somatic mutations. (52) E35. The method of E33 or E34, wherein the genomic alteration comprises one or more non-synonymous mutations. (53) E36. The method of any one of E33 to E35, wherein the genomic alteration comprises one or more missense mutations. (54) E37. The method of any one of E33 to E36, wherein the genomic alteration comprises one or more alterations selected from the group consisting of a base pair substitution, a base pair insertion, a base pair deletion, a copy number alteration (CNAs), a gene rearrangement, and any combination thereof. (55) E38. The method of any one of E32 to E37, wherein the high TMB has a score of at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, at least 245, at least 250, at least 255, at least 260, at least 265, at least 270, at least 275, at least 280, at least 285, at least 290, at least 295, at least 300, at least 305, at least 310, at least 315, at least 320, at least 325, at least 330, at least 335, at least 340, at least 345, at least 350, at least 355, at least 360, at least 365, at least 370, at least 375, at least 380, at least 385, at least 390, at least 395, at least 400, at least 405, at least 410, at least 415, at least 420, at least 425, at least 430, at least 435, at least 440, at least 445, at least 450, at least 455, at least 460, at least 465, at least 470, at least 475, at least 480, at least 485, at least 490, at least 495, or at least 500. (56) E39. The method of any one of E32 to E38, wherein the high TMB has a score of at least 215, at least 220, at least 221, at least 222, at least 223, at least 224, at least 225, at least 226, at least 227, at least 228, at least 229, at least 230, at least 231, at least 232, at least 233, at least 234, at least 235, at least 236, at least 237, at least 238, at least 239, at least 240, at least 241, at least 242, at least 243, at least 244, at least 245, at least 246, at least 247, at least 248, at least 249, or at least 250. (57) E40. The method of any one of E32 to E39, wherein the high TMB has a score of at least 243. (58) E41. The method of any one of E32 to E40, further comprising comparing the subject's TMB status to a reference TMB value. (59) E42. The method of E41, wherein the subject's TMB status is within the highest fractile of the reference TMB value. (60) E43. The method of E41, wherein the subject's TMB status is within the top tertile of the reference TMB value. (61) E44. The method of any one of E32 to E43, wherein the TMB status is determined by genome sequencing. (62) E45. The method of any one of E32 to E43, wherein the TMB status is determined by exome sequencing. (63) E46. The method of any one of E32 to E45, wherein the TMB status is determined by genomic profiling. (64) E47. The method of any one of E1 to E46, wherein the tumor exhibits high inflammation. (65) E48. The method of E47, wherein the inflammation is measured according to the expression of STK11. (66) E49. The method of any one of E1 to E48, wherein the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1. (67) E50. The method of any one of E1 to E49, wherein the anti-PD-1 antibody binds to the same epitope as nivolumab. (68) E51. The method of any one of E1 to E50, wherein the anti-PD-1 antibody is a chimeric, humanized or human monoclonal antibody or a portion thereof. (69) E52. The method of any one of E1 to E51, wherein the anti-PD-1 antibody comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype. (70) E53. The method of any one of E1 to E52, wherein the anti-PD-1 antibody is nivolumab. (71) E54. The method of any one of E1 to E53, wherein the anti-PD-1 antibody is pembrolizumab. (72) E55. The method of any one of E1 to E54, wherein the anti-PD-1 antibody is administered at a dose ranging from at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight once about every 1, 2 or E3 weeks. (73) E56. The method of E55, wherein the anti-PD-1 antibody is administered at a dose of at least about 3 mg/kg body weight once about every 2 weeks. (74) E57. The method of any one of E1 to E56, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose. (75) E58. The method of any one of E1 to E54 and 57, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose of at least about 200, at least about 220, at least about 240, at least about 260, at least about 280, at least about 300, at least about 320, at least about 340, at least about 360, at least about 380, at least about 400, at least about 420, at least about 440, at least about 460, at least about 480, at least about 500 or at least about 550 mg. (76) E59. The method of any one of E1 to E54, 57, and 58, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose of about 240 mg. (77) E60. The method of any one of E1 to E54, and 57 to E59, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose about once every 1, 2, 3 or E4 weeks. (78) E61. The method of any one of E1 to E60, wherein the anti-PD-1 antibody is administered for as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs. (79) E62. The method of any one of E1 to E61, wherein the anti-PD-1 antibody is formulated for intravenous administration. (80) E63. The method of any one of E1 to E62, wherein the anti-PD-1 antibody is administered at a subtherapeutic dose. (81) E64. The method of any one of E1 to E63, wherein the administering treats the tumor. (82) E65. The method of any one of E1 to E64, wherein the administering reduces the size of the tumor. (83) E66. The method of E65, wherein the size of the tumor is reduced by at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size prior to the administration. (84) E67. The method of any one of E1 to E66, wherein the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial administration. (85) E68. The method of any one of E1 to E67, wherein the subject exhibits stable disease after the administration. (86) E69. The method of any one of E1 to E67, wherein the subject exhibits a partial response after the administration. (87) E70. The method of any one of E1 to E67, wherein the subject exhibits a complete response after the administration. (88) E71. A kit for treating a subject afflicted with a tumor, the kit comprising: (a) a dosage ranging from about 4 mg to about 500 mg of an anti-PD-1 antibody; and (b) instructions for using the anti-PD-1 antibody in the method of any of E1 to E70. (89) E72. The kit of E71, further comprising an anti-PD-L1 antibody. |
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