TREATMENT OF EGFR-MUTANT CANCER
Disclosed herein are methods for treating an EGFR-mutant cancer in a patient in need thereof by administering to the patient a therapeutically effective amount of at least one RET inhibitor (e.g., Compound 1 and/or pharmaceutically acceptable salts thereof) and a therapeutically effective amount of at least one EGFR inhibitor (e.g., osimertinib and/or pharmaceutically acceptable salts thereof), as well as combination therapies including at least one RET inhibitor and at least one EGFR inhibitor.
1 . A method for treating an EGFR-mutant cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one RET inhibitor and a therapeutically effective amount of at least one EGFR inhibitor.
2 . The method of claim 1 , wherein the at least one RET inhibitor is chosen from Compound 1 and pharmaceutically acceptable salts thereof.
3 . The method of claim 1 , wherein the at least one RET inhibitor is chosen from alectinib, apatinib, BOS172738 (DS-5010), cabozantinib (XL184), dovitinib (TKI258), GSK3179106, GSK3352589, lenvatinib, LOXO-292, TPX-0046, SL-1001, nintedanib, ponatinib, sitravatinib (MGCD516), sorafenib, sunitinib, regorafenib (BAY 73-4506), RXDX-105, vandetanib, XL999, and pharmaceutically acceptable salts of any of the foregoing.
4 . The method of claim 1 , wherein the at least one RET inhibitor is a selective RET inhibitor.
5 . The method of any one of claims 1 to 4 , wherein the at least one EGFR inhibitor is a selective EGFR inhibitor.
6 . The method of any one of claims 1 to 4 , wherein the at least one EGFR inhibitor is a third generation EGFR inhibitor.
7 . The method of any one of claims 1 to 4 , wherein the at least one EGFR inhibitor is chosen from osimertinib and pharmaceutically acceptable salts thereof.
8 . The method of any one of claims 1 to 7 , wherein the EGFR-mutant cancer is characterized by at least one EGFR mutation chosen from T790M, C797S, and L792H.
9 . The method of any one of claims 1 to 8 , wherein the EGFR-mutant cancer is further characterized by at least one RET-fusion.
10 . The method of claim 9 , wherein the EGFR-mutant cancer is further characterized by CCDC6-RET fusion.
11 . The method of any one of claims 1 to 10 , wherein the EGFR-mutant cancer is lung cancer.
12 . The method of claim 11 , wherein the lung cancer is chosen from small cell lung cancer and non-small cell lung cancer.
13 . The method of any one of claims 1 to 12 , wherein the patient is a human.
14 . The method of any one of claims 1 to 13 , wherein the patient has been previously treated with at least one EGFR inhibitor.
15 . The method of any one of claims 1 to 14 , wherein the patient has acquired resistance to at least one EGFR inhibitor.
16 . The method of any one of claims 1 , 2 , and 4 - 15 , wherein:
the at least one RET inhibitor is chosen from Compound 1 and pharmaceutically acceptable salts thereof;
the at least one RET inhibitor is orally administered to the patient once daily; and
the therapeutically effective amount of the at least one RET inhibitor is 200 mg to 400 mg of Compound 1 or the weight equivalent of a pharmaceutically acceptable salt thereof.
17 . The method of claim 16 , wherein the therapeutically effective amount of the at least one RET inhibitor is 200 mg to 300 mg of Compound 1 or the weight equivalent of a pharmaceutically acceptable salt thereof.
18 . The method of any one of claims 7 to 17 , wherein
the at least one EGFR inhibitor is chosen from osimertinib and pharmaceutically acceptable salts thereof;
the at least one EGFR inhibitor is orally administered to the patient once daily; and
the therapeutically effective amount of the at least one EGFR inhibitor is 80 mg of osimertinib or the weight equivalent of a pharmaceutically acceptable salt thereof.
19 . A combination therapy comprising at least one RET inhibitor and at least one EGFR inhibitor.
20 . The combination therapy of claim 19 , wherein the at least one RET inhibitor is chosen from Compound 1 and pharmaceutically acceptable salts thereof.
21 . The combination therapy of claim 19 , wherein the at least one RET inhibitor is chosen from alectinib, apatinib, BOS172738 (DS-5010), cabozantinib (XL184), dovitinib (TK1258), GSK3179106, GSK3352589, lenvatinib, LOXO-292, TPX-0046, SL-1001, nintedanib, ponatinib, sitravatinib (MGCD516), sorafenib, sunitinib, regorafenib (BAY 73-4506), RXDX-105, vandetanib, XL999, and pharmaceutically acceptable salts of any of the foregoing.
22 . The combination therapy of claim 19 , wherein the at least one RET inhibitor is a selective RET inhibitor.
23 . The combination therapy of any one of claims 19 to 22 , wherein the at least one EGFR inhibitor is a selective EGFR inhibitor.
24 . The combination therapy of any one of claims 19 to 22 , wherein the at least one EGFR inhibitor is a third generation EGFR inhibitor.
25 . The combination therapy of claim 20 , wherein Compound 1 is present in an amount of 200 mg to 400 mg.
26 . The combination therapy of claim 20 , wherein Compound 1 is present in an amount of 200 mg to 300 mg.
27 . The combination therapy of any one of claims 19 to 22 , 25 , or 26 , wherein the at least one EGFR inhibitor is chosen from osimertinib and pharmaceutically acceptable salts thereof.
28 . The combination therapy of claim 27 , wherein osimertinib is present in an amount of 80 mg.
29 . A method for treating a patient suffering from an EGFR-mutant cancer, the method comprising:
(a) obtaining a biological sample from the patient;
(b) detecting the presence or absence of at least one RET-fusion in the biological sample; and
(c) administering a combination therapy to the patient if at least one RET-fusion is detected, wherein the combination therapy comprises at least one EGFR inhibitor and at least one RET inhibitor.
30 . The method of claim 29 , wherein the at least one RET inhibitor is chosen from Compound 1 and pharmaceutically acceptable salts thereof.
31 . The method of claim 29 , wherein the at least one RET inhibitor is chosen from alectinib, apatinib, BOS172738 (DS-5010), cabozantinib (XL184), dovitinib (TK1258), GSK3179106, GSK3352589, lenvatinib, LOXO-292, TPX-0046, SL-1001, nintedanib, ponatinib, sitravatinib (MGCD516), sorafenib, sunitinib, regorafenib (BAY 73-4506), RXDX-105, vandetanib, XL999, and pharmaceutically acceptable salts of any of the foregoing.
32 . The method of claim 29 , wherein the at least one RET inhibitor is a selective RET inhibitor.
33 . The method of any one of claims 29 to 32 , wherein the at least one EGFR inhibitor is chosen from osimertinib and pharmaceutically acceptable salts thereof.
34 . The method of any one of claims 29 to 32 , wherein the at least one EGFR inhibitor is a selective EGFR inhibitor.
35 . The method of any one of claims 29 to 32 , wherein the at least one EGFR inhibitor is a third generation EGFR inhibitor.
36 . The method of any one of claims 29 to 35 , wherein the EGFR-mutant cancer is characterized by at least one EGFR mutation chosen from T790M, C797S, and L792H.
37 . The method of any one of claim 29 to 36 , wherein the at least one RET-fusion is a CCDC6-RET fusion.
38 . The method of any one of claims 29 to 37 , wherein the EGFR-mutant cancer is lung cancer.
39 . The method of claim 38 , wherein the lung cancer is chosen from small cell lung cancer and non-small cell lung cancer.
40 . The method of any one of claims 29 to 39 , wherein the patient is a human.
41 . The method of any one of claims 29 to 40 , wherein the patient has been previously treated with at least one EGFR inhibitor.
42 . The method of any one of claims 29 to 41 , wherein the patient has acquired resistance to at least one EGFR inhibitor.