Combination therapy involving diaryl macrocyclic compounds

Abstract

The present disclosure relates to methods and compositions for treating cancer with a diaryl macrocycle in combination with a KRAS inhibitor, such as an inhibitor of KRAS G12C.

1 . A method for treating cancer in a host animal, the method comprising the step of administering to the host animal a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the cancer is selected from the group consisting of ALCL, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, triple negative breast, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, stomach cancer, and lung cancer. 
     
     
         3 . The method of  claim 1 , wherein the cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, colorectal cancer, metastatic colorectal cancer, pancreatic cancer, metastatic pancreatic cancer, uterine cancer, or metastatic uterine cancer. 
     
     
         4 . The method of  claim 3 , wherein the cancer is non-small cell lung cancer. 
     
     
         5 . The method of  claim 3 , wherein the cancer is colorectal cancer. 
     
     
         6 . The method of  claim 1 , wherein the compound that inhibits FAK, SRC, and JAK2 is administered at the same time as, before, or after the at least one agent that inhibits KRAS G12C. 
     
     
         7 . The method of  claim 1 , wherein IL-6 secretion from the cancer is decreased. 
     
     
         8 . The method of  claim 1 , wherein the at least one agent that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C or a small molecule inhibitor of KRAS G12C. 
     
     
         9 . The method of  claim 1 , wherein the at least one agent that inhibits KRAS G12C is a biological agent that inhibits KRAS G12C. 
     
     
         10 . The method of  claim 9 , wherein the biological agent that inhibits KRAS G12C is an antibody, an antibody fragment, a peptide, an oligonucleotide, a ribonucleic acid, or an siRNA. 
     
     
         11 . The method of  claim 1 , wherein the at least one agent that inhibits KRAS G12C is a small molecule inhibitor of KRAS G12C. 
     
     
         12 . The method of  claim 1 , wherein the at least one agent that inhibits KRAS G12C is AMG-510, MRTX849, JNJ-74699157, ARS-1620, MRTX1257, RM-007, or ADT-007. 
     
     
         13 . The method of  claim 12 , wherein the at least one agent that inhibits KRAS G12C is AMG-510, or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 12 , wherein the at least one agent that inhibits KRAS G12C is MRTX849, or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 1 , wherein the compound that inhibits FAK, SRC and JAK2 is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, or about 160 mg; and the at least one agent that inhibits KRAS G12C is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 800 mg to about 1.5 g, or at least 800 mg, or at least 600 mg, or about 960 mg, or about 600 mg. 
     
     
         16 . The method of  claim 1 , wherein the compound that inhibits FAK, SRC and JAK2 is administered at a dose of about 0.1 mg/kg to about 1 g/kg, or about 0.5 mg/kg to about mg/kg, or about 0.5 mg/kg to about 25 mg/kg, or about 1.0 mg/kg to about 10 mg/kg, or about 1.0 mg/kg to about 5 mg/kg, or about 0.1 mg/kg to about 5 mg/kg, or about 0.1 mg/kg to about 1 mg/kg, or about 0.1 mg/kg to about 0.6 mg/kg, or about 1.25 mg/kg to about 3.75 mg/kg, or about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg, or about 4.0 mg/kg and the at least one agent that inhibits KRAS G12C is administered at a dose of about 0.1 mg/kg to about 1 g/kg, or about 0.5 mg/kg to about 50 mg/kg, or about 0.5 mg/kg to about 25 mg/kg, or about 1.0 mg/kg to about 10 mg/kg, or about 1.0 mg/kg to about 5 mg/kg, or about 0.1 mg/kg to about 5 mg/kg, or about 0.1 mg/kg to about 1 mg/kg, or about 0.1 mg/kg to about 0.6 mg/kg, or about 1.25 mg/kg to about 3.75 mg/kg, or about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg, or about 4.0 mg/kg. 
     
     
         17 . The method of  claim 1 , wherein the host animal is a human patient in need of such treatment who has not received a prior treatment. 
     
     
         18 . The method of  claim 1 , wherein the host animal is a human patient in need of such treatment who has received at least one prior treatment of one or more chemotherapeutic agents or immunotherapies. 
     
     
         19 . The method of  claim 1 , wherein the host animal is a human patient in need of such treatment who has received at least one prior treatment of one or more chemotherapeutic agents or immunotherapies, and developed an acquired resistance to the treatment, and/or developed bypass resistance to the treatment, and/or developed bypass resistance to the treatment regulated by FAK, SRC or JAK2. 
     
     
         20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound that inhibits FAK, SRC, and JAK2, in combination with a therapeutically effective amount of at least one agent that inhibits KRAS G12C, and a pharmaceutically acceptable excipient, wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.