Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Until recently, the primary treatment for advanced NSCLC has been chemotherapy, which typically causes significant tumor shrinkage in ~20% of patients, with significant toxicities. In recent years, however, the treatment of NSCLC has been revolutionized by two major changes: the development of targeted agents, such as tyrosine kinase inhibitors (TKIs) targeting mutant forms of epidermal growth factor receptor (EGFR); and immunotherapy. While these TKIs have been shown to dramatically prolong the lives of patients bearing “typical” EGFR mutations, approximately 20% of patients with EGFR mutations have “atypical” muta...

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Until recently, the primary treatment for advanced NSCLC has been chemotherapy, which typically causes significant tumor shrinkage in ~20% of patients, with significant toxicities. In recent years, however, the treatment of NSCLC has been revolutionized by two major changes: the development of targeted agents, such as tyrosine kinase inhibitors (TKIs) targeting mutant forms of epidermal growth factor receptor (EGFR); and immunotherapy. While these TKIs have been shown to dramatically prolong the lives of patients bearing “typical” EGFR mutations, approximately 20% of patients with EGFR mutations have “atypical” mutations in EGFR exon 18 or exon 20 for which standard TKIs are much less effective. Recently, our laboratory identified poziotinib as a novel therapy for tumors bearing EGFR exon 20 mutations that have remained refractory to all therapies. Based on this study a phase II trial testing poziotinib in EGFR exon 20 mutant patients has been conducted at MD Anderson with initial results that indicate high anti-tumor activity with confirmed objective response rate in 43% of 44 evaluable patients. However, the responses to poziotinib were not as durable as the ones provided by traditional TKI therapy for classical EGFR mutations and many patients experienced toxicities like rash and diarrhea related to the inhibition of non-mutant EGFR on normal cells. Through a multidisciplinary effort involving structural studies and pre-clinical testing, this proposal aims to identify novel compounds that are more potent and more EGFR-mutant selective to enhance the anti-tumor activity and reduce adverse effects for patients with EGFR exon 18 and exon 20 mutant cancers. Novel compounds identified in through this effort would have significant impact on the treatment of more than 6000 NSCLC patients in the US annually (and greater than 50,000 worldwide) with atypical exons 18 and 20 mutations.

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