METHODS OF TREATING HER2 POSITIVE BREAST CANCER WITH TUCATINIB IN COMBINATION WITH AN ANTI-HER2 ANTIBODY-DRUG CONJUGATE

1 . A method of treating or ameliorating a HER2 positive breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination therapy comprising tucatinib and an anti-HER2 antibody-drug conjugate.

2 . A method of treating or ameliorating cancer in a subject in need thereof, the method comprising:

(a) identifying the subject as having a HER2 positive breast cancer; and

(b) administering to the subject a therapeutically effective amount of a combination therapy comprising tucatinib and an anti-HER2 antibody-drug conjugate.

3 . 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 and an anti-HER2 antibody-drug conjugate, 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.

4 . The method of claim 3 , wherein the subject exhibits progression-free survival of at least eight months following administration of the combination therapy.

5 . The method of any one of claim 3 or 4 , wherein the subject exhibits progression-free survival of at least nine months following administration of the combination therapy.

6 . The method of any one of claims 3 - 5 , wherein the subject exhibits progression-free survival of at least ten months following administration of the combination therapy.

7 . The method of any one of claims 1 - 6 , wherein the subject has a brain metastasis.

8 . 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 and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy, the subject exhibits an overall survival of at least eighteen months following administration of the combination therapy.

9 . The method of claim 8 , wherein the subject exhibits an overall survival of at least nineteen months following administration of the combination therapy.

10 . The method of any one of claim 8 or 9 , wherein the subject exhibits an overall survival of at least twenty-two months following administration of the combination therapy.

11 . The method of any one of claims 8 - 10 , wherein the subject exhibits an overall survival of at least twenty-six months following administration of the combination therapy.

12 . The method of any one of claims 8 - 11 , wherein the subject exhibits an overall survival of at least thirty months following administration of the combination therapy.

13 . The method of any one of claims 8 - 12 , wherein the subject has a brain metastasis.

14 . A method of treating or ameliorating a 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 and an anti-HER2 antibody-drug conjugate.

15 . The method of claim 14 , wherein the time to additional intervention for treatment of the brain metastasis in the subject has been increased.

16 . The method of any one of claim 14 or 15 , wherein the need for additional intervention for treatment of the brain metastasis in the subject has been prevented.

17 . The method of any one of claim 15 or 16 , wherein the additional intervention is selected from the group consisting of radiation, surgery, and a combination thereof.

18 . The method of any one of claims 14 - 17 , wherein regression of an existing brain metastasis in the subject has been promoted.

19 . The method of any one of claims 14 - 18 , wherein the size of an existing brain metastasis in the subject has been reduced.

20 . 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 and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy, the subject exhibits progression-free survival of at least 6 months following administration of the combination therapy.

21 . The method of claim 20 , wherein the subject exhibits progression-free survival of at least seven months following administration of the combination therapy.

22 . The method of any one of claim 20 or 21 , wherein the subject exhibits progression-free survival of at least nine months following administration of the combination therapy.

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 and an anti-HER2 antibody-drug conjugate, wherein the subject exhibits a greater than 40% reduction in the risk of disease progression or death as compared to a subject administered the anti-HER2 antibody-drug conjugate alone.

24 . The method of claim 23 , wherein the subject administered the combination therapy comprising tucatinib and the anti-HER2 antibody-drug conjugate exhibits a greater than 45% reduction in the risk of disease progression or death as compared to a subject administered the anti-HER2 antibody-drug conjugate 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 and an anti-HER2 antibody-drug conjugate, wherein the subject exhibits a greater than 30% reduction in the risk of death as compared to a subject administered the anti-HER2 antibody-drug conjugate alone.

26 . 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 and an anti-HER2 antibody-drug conjugate, wherein the subject exhibits a greater than 50% reduction in the risk of disease progression or death as compared to a subject administered the anti-HER2 antibody-drug conjugate alone.

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 and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy for nine months, the subject has an estimated progression-free survival rate of greater than 40%.

28 . The method of claim 27 , wherein the subject has an estimated progression-free survival rate of greater than 45%.

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 and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy for twelve months, the subject has an estimated progression-free survival rate of greater than 25%.

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

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 and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy for fifteen months, the subject has an estimated progression-free survival rate of greater than 20%.

32 . The method of claim 31 , wherein the subject has an estimated progression-free survival rate of greater than 25%.

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 and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy for twenty-four months, the subject has an estimated overall survival rate of greater than 35%.

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, the method comprising administering to the subject an effective amount of a combination therapy comprising tucatinib and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy for thirty months, the subject has an estimated overall survival rate of greater than 30%.

36 . The method of claim 35 , wherein the subject has an estimated overall 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 and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy for nine months, the subject has an estimated progression-free survival rate of greater than 30%.

38 . The method of claim 37 , wherein the subject has an estimated progression-free survival rate of greater than 40%.

39 . 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 and an anti-HER2 antibody-drug conjugate, wherein following administration of the combination therapy for twelve months, the subject has an estimated progression-free survival rate of greater than 15%.

40 . The method of claim 39 , wherein the subject has an estimated progression-free survival rate of greater than 20%.

41 . 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 and an anti-HER2 antibody-drug conjugate and an effective amount of an anti-diarrheal agent.

42 . The method of claim 41 , wherein the combination therapy and the anti-diarrheal agent are administered concurrently.

43 . The method of claim 42 , wherein the anti-diarrheal agent is administered prior to administration of the combination therapy.

44 . The method of claim 41 - 43 , wherein the subject is exhibiting symptoms of diarrhea.

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

46 . 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 and an anti-HER2 antibody-drug conjugate, the method comprising administering an effective amount of an anti-diarrheal agent prophylactically.

47 . The method of claim 46 , wherein the combination therapy and the anti-diarrheal agent are administered concurrently.

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

49 . 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 and an anti-HER2 antibody-drug conjugate, the method comprising administering an effective amount of an anti-diarrheal agent prophylactically.

50 . The method of claim 49 , wherein the combination therapy and the anti-diarrheal agent are administered concurrently.

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

52 . The method of any one of claims 1 - 51 , wherein the tucatinib is administered to the subject at a dose of about 150 mg to about 650 mg.

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

54 . The method of claim 52 or 53 , wherein the tucatinib is administered once or twice per day.

55 . The method of any one of claims 1 - 54 , wherein the tucatinib is administered twice daily.

56 . The method of claim 55 , wherein the tucatinib is administered to the subject at a dose of about 300 mg twice per day.

57 . The method of any one of claims 1 - 56 , wherein the tucatinib is administered to the subject orally.

58 . The method of any one of claims 1 - 57 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject at a dose of about 150 mg to about 400 mg.

59 . The method of claim 58 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject at a dose of about 200 mg.

60 . The method of claim 58 or 59 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject subcutaneously.

61 . The method of any one of claims 1 - 60 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject at a dose of about 1 mg/kg to about 5 mg/kg.

62 . The method of claim 61 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject at a dose of about 3.6 mg/kg.

63 . The method of claim 61 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject at a dose of about 4 mg/kg.

64 . The method of claim 61 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject at an initial dose of about 4 mg/kg followed by subsequent doses of about 3.6 mg/kg.

65 . The method of any one of claims 61 - 64 , wherein the anti-HER2 antibody-drug conjugate is administered intravenously.

66 . The method of any one of claims 1 - 65 , wherein the anti-HER2 antibody-drug conjugate is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks.

67 . The method of claim 66 , wherein the anti-HER2 antibody-drug conjugate is administered once about every 3 weeks.

68 . The method of any one of claims 1 - 67 , wherein the tucatinib and the anti-HER2 antibody-drug conjugate are administered to the subject on a 21 day treatment cycle.

69 . The method of claim 68 , wherein the tucatinib is administered to the subject twice per day on each day of the 21 day treatment cycle.

70 . The method of any one of claims 68 - 69 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject once per 21 day treatment cycle.

71 . The method of claim 70 , wherein the dose of the anti-HER2 antibody-drug conjugate during the first 21 day treatment cycle is 4 mg/kg and the dose of the anti-HER2 antibody-drug conjugate during the subsequent 21 day treatment cycles is 3.6 mg/kg.

72 . The method of any one of claims 1 - 71 , wherein the HER2 positive breast cancer is unresectable or metastatic.

73 . The method of any one of claims 1 - 72 , wherein the subject was previously treated with at least one anticancer therapy.

74 . The method of claim 73 , wherein the least one anticancer therapy is an anti-HER2 antibody or anti-HER2 antibody-drug conjugate.

75 . The method of claim 73 , wherein the at least one previous anticancer therapy is selected from the group consisting of trastuzumab, trastuzumab and a taxane, pertuzumab, ado-trastuzumab, and combinations thereof.

76 . The method of any one of claims 73 - 75 , wherein the subject is refractory to the previous anticancer therapy.

77 . The method of claim 71 - 76 , wherein the subject developed a brain metastasis during the previous anticancer therapy.

78 . The method of any one of claims 1 - 77 , wherein the subject has not been treated with another therapeutic agent for the breast cancer within the past 12 months.

79 . The method of any one of claims 1 - 78 , wherein the subject was previously treated with two or more anti-HER2-based regimens.

80 . The method of any one of claims 1 - 79 , 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 - 80 , wherein the subject has not previously been treated with lapatinib, neratinib, afatinib, or capecitabine.

82 . The method of any one of claims 1 - 81 , wherein the subject has not been previously treated with an anti-HER2 and/or an anti-EGFR tyrosine kinase inhibitor.

83 . The method of claim 82 , wherein the wherein the anti-HER2/EGFR tyrosine kinase inhibitor is selected from the group consisting of tucatinib, lapatinib, neratinib, or afatinib.

84 . The method of any one of claims 1 - 83 , wherein the subject has not been previously treated with an anti-HER2 antibody-drug conjugate.

85 . The method of claim 84 , wherein the anti-HER2 antibody-drug conjugate is selected from the group consisting of ado-trastuzumab, or trastuzumab deruxtecan.

86 . The method of any one of claims 1 - 85 , wherein the subject has not been previously treated with an anthracycline.

87 . The method of claim 86 , wherein the anthracycline is selected from the group consisting of doxorubicin, epirubicin, mitoxantrone, idarubicin, liposomal doxorubicin, and combinations thereof.

88 . A method for treating a HER2 positive breast cancer in a subject that has exhibited an adverse event after starting treatment with a combination therapy comprising tucatinib and anti-HER2 antibody-drug conjugate at an initial dosage level, comprising administering to the subject at least one component of the combination therapy at a reduced dosage level.

89 . The method of claim 88 , wherein the tucatinib is administered to the subject at an initial dose of about 150 mg to about 650 mg.

90 . The method of any one of claim 88 or 89 , wherein the tucatinib is administered to the subject at an initial dose of about 300 mg.

91 . The method of any one of claims 88 - 90 , wherein the tucatinib is administered to the subject at a reduced dose of about 125 mg to about 275 mg.

92 . The method of any one of claims 88 - 91 , wherein the tucatinib is administered to the subject at a reduced dose of about 250 mg.

93 . The method of any one of claims 88 - 91 , wherein the tucatinib is administered to the subject at a reduced dose of about 200 mg.

94 . The method of any one of claims 88 - 91 , wherein the tucatinib is administered to the subject at a reduced dose of about 150.

95 . The method of claim 88 - 94 , wherein the anti-HER2 antibody-drug conjugate is administered to the subject at an initial dose of about 3 mg/kg to about 7 mg/kg.

96 . The method of any one of claims 88 - 95 , wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan.

97 . The method of any one of claims 88 - 95 , wherein the anti-HER2 antibody-drug conjugate is ado-trastuzumab emtansine.

98 . The method of claim 96 , wherein the trastuzumab deruxtecan is administered to the subject at an initial dose of about 5.4 mg/kg.

99 . The method of claim 96 or 98 , wherein the trastuzumab deruxtecan is administered to the subject at a reduced dose of about 4.4 mg/kg.

100 . The method of claim 96 or 98 , wherein the trastuzumab deruxtecan is administered to the subject at a reduced dose of about 3.2 mg/kg.

101 . The method of claim 97 , wherein the ado-trastuzumab emtansine is administered to the subject at an initial dose of about 3.6 mg/kg.

102 . The method of claim 97 or 101 , wherein the ado-trastuzumab emtansine is administered to the subject at a reduced dose of about 3 mg/kg.

103 . The method of claim 97 or 101 , wherein the ado-trastuzumab emtansine is administered to the subject at a reduced dose of about 2.4 mg/kg.

104 . The method of any one of claims 1 - 95 , wherein the anti-HER2 antibody-drug conjugate is ado-trastuzumab emtansine.

105 . The method of any one of claims 1 - 95 , wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan.

106 . The method of any one of claims 1 - 105 , wherein the administration of the tucatinib, or a salt or solvate thereof, increases the overall amount of HER2 in a solid tumor.

107 . The method of claim 106 , wherein the overall amount of HER2 in the solid tumor is determined by western blot analysis.

108 . The method of any one of claims 1 - 107 , wherein the administration of the tucatinib, or a salt or solvate thereof, increases the amount of membrane-bound HER2 in a solid tumor.

109 . The method of claim 108 , wherein the amount of membrane-bound HER2 in the solid tumor is determined by quantitative fluorescence activated cell sorting (qFACS).

110 . The method of any one of claims 1 - 109 , wherein the administration of the tucatinib, or a salt or solvate thereof, increases dwell time of HER2 at the cell surface.

111 . The method of any one of claims 1 - 110 , wherein the administration of the tucatinib, or a salt or solvate thereof, increases internalization of membrane-bound HER2.

112 . The method of any one of claims 1 - 111 , wherein the administration of the tucatinib, or a salt or solvate thereof, increases lysosomal degradation of HER2.