Compounds with anti-tumor activity against cancer cells bearing egfr or her2 exon 20 mutations

Abstract

The present disclosure provides methods of treating cancer in a patient determined to have an EGFR and/or HER2 exon 20 mutation, such as an insertion mutation, by administering a third-generation tyrosine kinase inhibitor, such as poziotinib or afatinib.

1 - 36 . (canceled) 
     
     
         37 . A method of treating cancer in a subject comprising administering an effective amount of poziotinib to the subject, wherein the subject has a tumor that has been determined to have one or more HER2 exon 20 mutations, wherein the one or more HER2 exon 20 mutations comprise one or more point mutations, insertions, and/or deletions of 1-6 amino acid between amino acids 770-785, wherein the one or more HER2 exon 20 mutations are at residue A775, S779, and/or P780, and/or wherein the one or more HER2 exon 20 mutations are selected from the group consisting of A775insV G776C, A775insYVMA, G776V, G776C V777insV, G776C V777insC, G776del insVV, G776del insVC, and P780insGSP. 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 37 , wherein the HER exon 20 mutation is further defined as a HER2 exon 20 insertion mutation. 
     
     
         41 . The method of  claim 40 , wherein the HER exon 20 insertion mutation is A775insYVMA. 
     
     
         42 . The method of  claim 37 , further comprising administering an mTOR inhibitor. 
     
     
         43 . The method of  claim 42 , wherein the mTOR inhibitor is rapamycin, temsirolimus, everolimus, ridaforolimus or MLN4924. 
     
     
         44 . The method of  claim 42 , wherein the mTOR inhibitor is everolimus. 
     
     
         45 . The method of  claim 42 , wherein the poziotinib and/or the mTOR inhibitor are administered intravenously, subcutaneously, intraosseously, orally, transdermally, in sustained release, in controlled release, in delayed release, as a suppository, or sublingually. 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . The method of  claim 37 , further comprising administering an additional anti-cancer therapy. 
     
     
         50 . The method of  claim 37 , wherein the additional anti-cancer therapy is chemotherapy, radiotherapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy or immunotherapy. 
     
     
         51 . The method of  claim 37 , wherein the cancer is oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, gastrointestinal cancer, central or peripheral nervous system tissue cancer, an endocrine or neuroendocrine cancer or hematopoietic cancer, glioma, sarcoma, carcinoma, lymphoma, melanoma, fibroma, meningioma, brain cancer, oropharyngeal cancer, nasopharyngeal cancer, renal cancer, biliary cancer, pheochromocytoma, pancreatic islet cell cancer, Li-Fraumeni tumors, thyroid cancer, parathyroid cancer, pituitary tumors, adrenal gland tumors, osteogenic sarcoma tumors, multiple neuroendocrine type I and type II tumors, breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer or skin cancer. 
     
     
         52 . The method of  claim 37 , wherein the cancer is non-small cell lung cancer. 
     
     
         53 . The method of  claim 37 , wherein the subject is human. 
     
     
         54 . A pharmaceutical composition comprising poziotinib or afatinib for use in a subject determined to have one or more HER2 exon 20 mutations, wherein the one or more HER2 exon 20 mutations comprise one or more point mutations, insertions, and/or deletions of 1-6 amino acids between amino acids 770-785, wherein the one or more HER2 exon 20 mutations are at residue A775, S779, and/or P780, and/or wherein the one or more HER2 exon 20 mutations are selected from the group consisting of A775insV G776C, A775insYVMA, G776C V777insC, G776del insVV, G776del insVC, and P780insGSP. 
     
     
         55 . The composition of  claim 54 , wherein the HER2 exon 20 mutation is further defined as a HER2 exon 20 insertion mutation. 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . A method of predicting a response to poziotinib alone or in combination with an anti-cancer therapy in a subject having a cancer comprising detecting an HER2 exon 20 mutation selected from the group consisting of A775insV G776C, A775insYVMA, G776C V777insC, G776del insVV, G776del insVC, and P780insGSP in a genomic sample obtained from said subject, wherein if the sample is positive for the presence of the HER2 exon 20 mutation, then the patient is predicted to have a favorable response to the poziotinib or afatinib alone or in combination with an anti-cancer therapy. 
     
     
         60 - 79 . (canceled) 
     
     
         80 . The method of  claim 37 , wherein the one or more HER2 exon 20 mutations comprise one or more point mutations, insertions, and/or deletions of 3-18 between amino acids 770-785. 
     
     
         81 . The method of  claim 37 , wherein the one or more HER2 exon 20 mutations are at residue A775, S779, and/or P780. 
     
     
         82 . The method of  claim 37 , wherein the one or more HER2 exon 20 mutations are selected from the group consisting of A775insV G776C, A775insYVMA, G776V, G776C V777insV, G776C V777insC, G776del insVV, G776del insVC, and P780insGSP