Ret inhibitor for use in treating cancer having a ret alteration

Abstract

Disclosed herein is the treatment of a subject afflicted with a cancer having an activating RET alteration by administering an effective amount of a selective RET inhibitor, e.g., Compound 1 or pharmaceutically acceptable salts thereof, including, e.g., administering an amount of 300 mg to 400 mg of the selective RET inhibitor once daily.

1 . A method of treating a subject afflicted with a cancer having an activating rearranged during transfection (RET) alteration, the method comprising administering to the subject a therapeutically effective amount of 300 to 400 mg of Compound 1 or a pharmaceutically acceptable salt thereof once daily. 
     
     
         2 . The method of  claim 1 , wherein the amount administered is 300 mg. 
     
     
         3 . The method of  claim 1  or  2 , wherein the amount administered is 400 mg. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the cancer is chosen from papillary thyroid carcinoma (PTC), medullary thyroid cancer (MTC), pheochromocytoma (PCC), pancreatic ductal adenocarcinoma, multiple endocrine neoplasia (MEN2A and MEN2B), metastatic breast cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), chronic myelomonocytic leukemia (CMML), colorectal cancer, ovarian cancer, inflammatory myofibroblastic tumor, and cancer of the salivary gland. 
     
     
         5 . The method of any one of  claims 1 - 3 , wherein the cancer is chosen from esophageal cancer, skin cancer (non-melanoma), endometrial cancer, head and neck cancer, bladder cancer, prostate cancer, hematological cancer, leukemia, soft tissue sarcoma, renal cell carcinoma (RCC), non-Hodgkin lymphoma, hepatobiliary cancer, adrenocortical carcinoma, myelodysplasia (MDS), uterine sarcoma, germ cell tumor, cervical cancer, central nervous system cancer, bone cancer, ampullary carcinoma, gastrointestinal stromal tumor, small bowel cancer, mesothelioma, rectal cancer, paraganglioma, and intrahepatic bile duct cancer. 
     
     
         6 . The method of any one of  claims 1 - 3 , wherein the cancer is chosen from adenocarcinoma, spitzoid neoplasm, lung adenocarcinoma, adenosquamous carcinoma, colon cancer, metastatic colon cancer, metastatic papillary thyroid cancer, diffuse sclerosing variant of papillary thyroid cancer, primary myelofibrosis with secondary acute myeloid leukemia, diffuse gastric cancer, thyroid gland carcinoma, and bronchioles lung cell carcinoma. 
     
     
         7 . The method of any one of  claims 1 - 3 , wherein the cancer is chosen from hepatobiliary cancer, ampullary carcinoma, small bowel cancer, intrahepatic bile duct cancer, metastatic colon cancer, brain cancer associated with lung cancer, brain metastasis associated with lung cancer, and retropentoneal paraganglioma. 
     
     
         8 . The method of any one of  claims 1 - 3 , wherein the cancer is chosen from medullary thyroid cancer (MTC) and non-small cell lung cancer (NSCLC). 
     
     
         9 . The method of  claim 8 , wherein the cancer is chosen from sporadic MTC, metastatic RET-altered NSCLC, tyrosine kinase inhibitor (TKI)-refractory KIF5B-RET NSCLC, and KIF5B-RET NSCLC. 
     
     
         10 . The method of any one of  claims 1 - 3 , wherein the cancer is chosen from a brain cancer associated with a lung cancer. 
     
     
         11 . The method of  claim 10 , wherein the brain cancer is brain metastasis. 
     
     
         12 . The method of any one of  claims 1 - 11 , wherein the activating RET alteration comprises a RET mutation or a RET gene rearrangement (fusion). 
     
     
         13 . The method of any one of  claims 1 - 11 , wherein the activating RET alteration is a RET mutation. 
     
     
         14 . The method of  claim 12  or  13 , wherein the RET mutation is a point mutation. 
     
     
         15 . The method of any one of  claims 12 - 14 , wherein the RET mutation is a resistance mutation. 
     
     
         16 . The method of any one of  claims 12 - 15 , wherein the RET alteration is a RET mutation chosen from Table 1. 
     
     
         17 . The method of any one of  claims 12 - 16 , wherein the RET mutation is V804M, M918T, C634R, or C634W. 
     
     
         18 . The method of any one of  claims 1 - 4 ,  8 ,  9 , and  12 - 16 , wherein the cancer is RET-altered medullary thyroid cancer (MTC). 
     
     
         19 . The method of  claim 18 , wherein the cancer is familial MTC. 
     
     
         20 . The method of  claim 18 , wherein the cancer is sporadic MTC. 
     
     
         21 . The method of any one of  claims 1 - 3  and  12 - 19 , wherein the cancer is MTC having a M918T mutation. 
     
     
         22 . The method of any one of  claims 1 - 3  and  12 - 19 , wherein the cancer is MTC having a C634R mutation. 
     
     
         23 . The method of any one of  claims 1 - 3  and  12 - 19 , wherein the cancer is MTC having a V804M mutation. 
     
     
         24 . The method of any one of  claims 1 - 3 ,  6 , and  12 - 16 , wherein the cancer is paraganglioma. 
     
     
         25 . The method of  claim 24 , wherein the cancer is retropentoneal paraganglioma. 
     
     
         26 . The method of any one of  claims 1 - 3 ,  6 ,  12 - 16 ,  24 , and  25 , wherein the paraganglioma has a R77H mutation. 
     
     
         27 . The method of any one of  claims 1 - 11 , wherein the activating RET alteration is a gene-rearrangement (fusion). 
     
     
         28 . The method of  claim 27 , wherein the activating RET alteration is a fusion with a RET fusion partner chosen from Table 2. 
     
     
         29 . The method of  claim 27  or  28 , wherein the fusion is KIF5B-RET, CCDC6-RET, KIAA1468-RET, or NCOA4-RET. 
     
     
         30 . The method of any one of  claims 1 - 4  and  27 - 29 , wherein the cancer is RET-altered NSCLC. 
     
     
         31 . The method of  claim 30 , wherein the cancer is NSCLC having a KIF5B-RET fusion. 
     
     
         32 . The method of  claim 30 , wherein the cancer is NSCLC having a CCDC6-RET fusion. 
     
     
         33 . The method of  claim 30 , wherein the cancer is NSCLC having a KIAA1468-RET fusion. 
     
     
         34 . The method of  claim 30 , wherein the cancer is NSCLC having a RET fusion identified as FISH positive. 
     
     
         35 . The method of  claim 29  or  30 , wherein the RET alteration is KIF5B-RET V804L (cabozantinib resistant). 
     
     
         36 . The method of  claim 29  or  30 , wherein the RET alteration is CCDC6-RET V804M (ponatinib resistant). 
     
     
         37 . The method of any one of  claims 1 - 4  and  27 - 29 , wherein the cancer is RET-altered PTC. 
     
     
         38 . The method of  claim 37 , wherein the cancer is PTC having a CCDC6-RET fusion. 
     
     
         39 . The method of  claim 37 , wherein the cancer is PTC having a NCOA4-RET fusion. 
     
     
         40 . The method of any one of  claims 1 - 3  and  27 - 29 , wherein the cancer is RET-altered intrahepatic bile duct carcinoma. 
     
     
         41 . The method of  claim 40 , wherein the cancer is intrahepatic bile duct carcinoma having a NCOA4-RET fusion. 
     
     
         42 . The method of any one of  claims 1 - 41 , wherein the subject has not received prior treatment with a multikinase RET inhibitor. 
     
     
         43 . The method of any one of  claims 1 - 41  wherein the subject has received one or more prior treatments with a multikinase RET inhibitor. 
     
     
         44 . The method of  claim 43 , wherein the multikinase RET inhibitor is chosen from lenvatinib, vandetanib, cabozantinib, and RXDX-105. 
     
     
         45 . The method of any one of  claims 1 - 41 , wherein the subject has not received prior treatment with platinum. 
     
     
         46 . The method of any one of  claims 1 - 41 , wherein the subject has received prior treatment with platinum. 
     
     
         47 . The method of any one of  claims 1 - 41 , wherein the subject has received prior treatment with a selective RET inhibitor. 
     
     
         48 . The method of any one of  claims 1 - 47 , wherein the subject has not received prior chemotherapy. 
     
     
         49 . The method of any one of  claims 1 - 47 , wherein the subject has received prior chemotherapy. 
     
     
         50 . The method of  claim 49 , wherein the prior chemotherapy is chosen from carboplatin, pemetrexed, abraxane, cisplatin, bevacizumab, and combinations thereof. 
     
     
         51 . The method of any one of  claims 1 - 42 , wherein the subject has not received prior immunotherapy. 
     
     
         52 . The method of any one of  claims 1 - 42 , wherein the subject has received prior immunotherapy. 
     
     
         53 . The method of  claim 52 , wherein the prior immunotherapy is chosen from ipilimumab, pembrolizumab, nivolumab, MPDL3280A, MEDI4736, and combinations thereof. 
     
     
         54 . A method of treating a subject afflicted with a brain cancer associated with a RET-altered lung cancer, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The method of  claim 54 , wherein the brain cancer is brain metastasis. 
     
     
         56 . A method of treating a subject afflicted with a cancer having an activating RET mutation, the comprising administering to the subject a physiologically effective amount of a RET inhibitor, wherein administration of the RET inhibitor is associated with a sustained down-regulation of at least one effect marker in the subject. 
     
     
         57 . The method of  claim 56 , wherein the RET inhibitor is orally administered. 
     
     
         58 . The method of  claim 56  or  57 , wherein the RET inhibitor is Compound 1 or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of any one of  claims 56 - 58 , wherein the effect marker is chosen from DUSP6 mRNA expression, SPRY4 mRNA expression, carcinoembryonic antigen level, and calcitonin level. 
     
     
         60 . The method of any one of  claims 56 - 58 , wherein the effect marker is KIF5B ctDNA level or TP53 ctDNA level. 
     
     
         61 . The method of any one of  claims 56 - 59 , wherein the amount administered to the subject produces a greater than 95% down-regulation of at least one effect marker. 
     
     
         62 . The method of any one of  claims 56 - 59 , wherein the amount administered to the subject produces a greater than 94%, greater than 93%, greater than 92%, greater than 91%, greater than 90%, greater than 89%, greater than 88%, greater than 87%, greater than 86% greater than 85%, greater than 80%, greater than 75%, greater than 70%, greater than 65%, greater than 60%, greater than 55%, or greater than 50% down-regulation in at least one effect marker. 
     
     
         63 . The method of  claim 61 , wherein the amount administered to the subject produces a greater than 89%, greater than 88%, greater than 87%, greater than 86%, greater than 85%, greater than 80%, greater than 75%, or greater than 70% down-regulation in at least one effect marker. 
     
     
         64 . The method of any one of  claims 56 - 59 , wherein at least two effect markers are down-regulated.