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1. WO2021080983 - METHODS OF TREATING HER2 POSITIVE BREAST CANCER WITH TUCATINIB IN COMBINATION WITH CAPECITABINE AND TRASTUZUMAB

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CLAIMS

1. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy, the subject exhibits progression-free survival of at least 7.5 months following administration of the combination therapy.

2. The method of claim 1, wherein the subject exhibits progression-free survival of at least eight months following administration of the combination therapy.

3. The method of any one of claims 1 or 2, wherein the subject exhibits progression -free survival of at least nine months following administration of the combination therapy.

4. The method of any one of claims 1-3, wherein the subject exhibits progression-free survival of at least ten months following administration of the combination therapy.

5. The method of any one of claims 1-4, wherein the subject has a brain metastasis.

6. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy, the subject exhibits an overall survival of at least eighteen months following administration of the combination therapy.

7. The method of claim 6, wherein the subject exhibits an overall survival of at least nineteen months following administration of the combination therapy.

8. The method of any one of claims 6 or 7, wherein the subject exhibits an overall survival of at least twenty-two months following administration of the combination therapy.

9. The method of any one of claims 6-8, wherein the subject exhibits an overall survival of at least twenty-six months following administration of the combination therapy.

10. The method of any one of claims 6-9, wherein the subject exhibits an overall survival of at least thirty months following administration of the combination therapy.

11. The method of any one of claims 6-10, wherein the subject has a brain metastasis.

12. A method of treating or ameliorating brain metastasis in a subject having HER2 positive breast cancer, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab.

13. The method of claim 12, wherein the time to additional intervention for treatment of the brain metastasis in the subject has been increased.

14. The method of any one of claims 12 or 13, wherein the need for additional intervention for treatment of the brain metastasis in the subject has been prevented.

15. The method of claim 14, wherein the additional intervention is selected from the group consisting of radiation, surgery, and a combination thereof.

16. The method of any one of claims 12-15, wherein regression of an existing brain metastasis in the subject has been promoted.

17. The method of any one of claims 12-16, wherein the size of an existing brain metastasis in the subject has been reduced.

18. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, wherein the subject has brain metastasis, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy, the subject exhibits progression-free survival of at least 6 months following administration of the combination therapy.

19. The method of claim 18, wherein the subject exhibits progression-free survival of at least seven months following administration of the combination therapy.

20. The method of any one of claims 18 or 19, wherein the subject exhibits progression-free survival of at least nine months following administration of the combination therapy.

21. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein the subject exhibits a greater than 40% reduction in the risk of disease progression or death as compared to a subject administered trastuzumab and capecitabine alone.

22. The method of claim 21, wherein the subject administered the combination therapy comprising tucatinib, capecitabine, and trastuzumab exhibits a greater than 45% reduction in the risk of disease progression or death as compared to a subject administered trastuzumab and capecitabine alone.

23. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a

combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein the subject exhibits a greater than 30% reduction in the risk of death as compared to a subject administered trastuzumab and capecitabine alone.

24. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, wherein the subject has a brain metastasis, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein the subject exhibits a greater than 50% reduction in the risk of disease progression or death as compared to a subject administered trastuzumab and capecitabine alone.

25. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy for nine months, the subject has an estimated progression-free survival rate of greater than 40%.

26. The method of claim 25, wherein the subject has an estimated progression-free survival rate of greater than 45%.

27. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy for twelve months, the subject has an estimated progression-free survival rate of greater than 25%.

28. The method of claim 27, wherein the subject has an estimated progression-free survival rate of greater than 30%.

29. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy for fifteen months, the subject has an estimated progression-free survival rate of greater than 20%.

30. The method of claim 29, wherein the subject has an estimated progression-free survival rate of greater than 25%.

31. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy for twenty-four months, the subject has an estimated overall survival rate of greater than 35%.

32. The method of claim 31, wherein the subject has an estimated overall survival rate of greater than 40%.

33. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy for thirty months, the subject has an estimated overall survival rate of greater than 30%.

34. The method of claim 33, wherein the subject has an estimated overall survival rate of greater than 40%.

35. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, wherein the subject has a brain metastasis, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy for nine months, the subject has an estimated progression -free survival rate of greater than 30%.

36. The method of claim 35, wherein the subject has an estimated progression-free survival rate of greater than 40%.

37. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, wherein the subject has a brain metastasis, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, wherein following administration of the combination therapy for twelve months, the subject has an estimated progression -free survival rate of greater than 15%.

38. The method of claim 37, wherein the subject has an estimated progression-free survival rate of greater than 20%.

39. A method for treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab and an effective amount of an anti-diarrheal agent.

40. The method of claim 39, wherein the combination therapy and the anti-diarrheal agent are administered concurrently.

41. The method of claim 39, wherein the anti-diarrheal agent is administered prior to administration of the combination therapy.

42. The method of claim 39-41, wherein the subject is exhibiting symptoms of diarrhea.

43. The method of claim 39-41, wherein the subject is not exhibiting symptoms of diarrhea.

44. A method of reducing the severity or incidents of diarrhea, or preventing diarrhea in a subject having a HER2 positive breast cancer and being treated with an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, the method comprising administering an effective amount of an anti-diarrheal agent prophylactically.

45. The method of claim 44, wherein the combination therapy and the anti-diarrheal agent are administered concurrently.

46. The method of claim 44, wherein the anti-diarrheal agent is administered prior to administration of the combination therapy.

47. A method of reducing the likelihood of a subject developing diarrhea, wherein the subject has a HER2 positive breast cancer and is being treated with an effective amount of a combination therapy comprising tucatinib, capecitabine, and trastuzumab, the method comprising administering an effective amount of an anti-diarrheal agent prophylactically.

48. The method of claim 47, wherein the combination therapy and the anti-diarrheal agent are administered concurrently.

49. The method of claim 47, wherein the anti-diarrheal agent is administered prior to administration of the combination therapy.

50. The method of any one of claims 1-49, wherein the tucatinib is administered to the subject at a dose of about 150 mg to about 650 mg.

51. The method of claim 50, wherein the tucatinib is administered to the subject at a dose of about 300 mg.

52. The method of claim 50 or 51, wherein the tucatinib is administered once or twice per day.

53. The method of claim 52, wherein the tucatinib is administered to the subject at a dose of about 300 mg twice per day.

54. The method of any one of claims 1-53, wherein the tucatinib is administered to the subject orally.

55. The method of any one of claims 1-53, wherein the capecitabine is administered to the subject at a dose of about 500 mg/m2 to about 1500 mg/m2.

56. The method of claim 55, wherein the capecitabine is administered to the subject at a dose of about 1000 mg/m2.

57. The method of claim 55 or 56, wherein the capecitabine is administered to the subject orally.

58. The method of any one of claims 55-57, wherein the capecitabine is administered to the subject twice per day.

59. The method of any one of claims 1-58, wherein the trastuzumab is administered to the subject at a dose of about 400 mg to about 800 mg.

60. The method of claim 59, wherein the trastuzumab is administered to the subject at a dose of about 600 mg.

61. The method of claim 59 or 60, wherein the trastuzumab is administered to the subject subcutaneously.

62. The method of any one of claims 1-58, wherein the trastuzumab is administered to the subject at a dose of about 4 mg/kg to about 10 mg/kg.

63. The method of claim 62, wherein the trastuzumab is administered to the subject at a dose of about 6 mg/kg.

64. The method of claim 62, wherein the trastuzumab is administered to the subject at a dose of about 8 mg/kg.

65. The method of claim 62, wherein the trastuzumab is administered to the subj ect at an initial dose of about 8 mg/kg followed by subsequent doses of about 6 mg/kg.

66. The method of any one of claims 62-65, wherein the trastuzumab is administered intravenously.

67. The method of any one of claims 59-66, wherein the trastuzumab is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

68. The method of claim 67, wherein the trastuzumab is administered once about every 3 weeks.

69. The method of any one of claims 1-68, wherein the tucatinib, capecitabine and trastuzumab are administered to the subject on a 21 day treatment cycle.

70. The method of claim 69, wherein the tucatinib is administered to the subject twice per day on each day of the 21 day treatment cycle.

71. The method of claim 69 or 70, wherein the capecitabine is administered to the subj ect twice per day on each of days 1-14 of the 21 day treatment cycle.

72. The method of any one of claims 69-71, wherein the trastuzumab is administered to the subject once per 21 day treatment cycle.

73. The method of claim 72, wherein the dose of trastuzumab during the first 21 day treatment cycle is 8 mg/kg and the dose of trastuzumab during the subsequent 21 day treatment cycles is 6 mg/kg.

74. The method of any one of claims 1-73, wherein the subject was previously treated with at least one anti cancer therapy for the breast cancer.

75. The method of claim 74, wherein the least one anti cancer therapy is an anti-HER2 antibody or anti-HER2 antibody-drug conjugate.

76. The method of claim 75, wherein the at least one previous anticancer therapy is selected from the group consisting of trastuzumab, pertuzumab, ado-trastuzumab (T-DM1), and combinations thereof.

77. The method of any one of claims 74-76, wherein the subject is refractory to the previous anti cancer therapy.

78. The method of claim 74-77, wherein the subject developed a brain metastasis during the previous anti cancer therapy.

79. The method of any one of claims 1-78, wherein the subject has not been treated with another therapeutic agent for the breast cancer within the past 12 months.

80. The method of any one of claims 1-73, wherein the subject has not previously been treated with another therapeutic agent for the breast cancer.

81. The method of any one of claims 1-73, wherein the subject has not previously been treated with lapatinib, neratinib, afatinib, or capecitabine.