Lung cancer with EGFR PACC mutations: a practical review of available treatment options and novel therapies on the horizon

Abstract: Epidermal growth factor receptor (EGFR)-P-loop and αC-helix compressing (PACC) mutations are a recently proposed structural-functional category of mutations that represent more than 10% of all EGFR mutations in non-small cell lung cancer (NSCLC), including G719X, S768I, K745_E746insIPVAIK, L747X, E709X, E709_T7109delinsD mutations, among others. EGFR PACC mutations show a distinct pattern of response to EGFR tyrosine kinase inhibitors (TKIs) in preclinical models, favoring 2nd generation EGFR TKIs such as afatinib. While treatment options for EGFR-mutated lung cancer continue to expand, the available clinical data is predominantly from patients whose tumors harbor the most common classical mutations (exon 19 deletions/indels and L858R mutations). Most available EGFR TKIs and combination treatments for NSCLC do not have regulatory approval specific to EGFR PACC mutations. However, a growing body of evidence exists to support optimal treatment for patients with tumors with EGFR PACC mutations. In this review, we highlight a case example that illustrates key treatment considerations, including balancing efficacy, toxicity, and patient preferences when selecting the optimal palliative therapy. We discuss key treatment considerations for EGFR PACC mutated NSCLC to inform the use of afatinib (the only approved therapy with an indication that includes two EGFR PACC mutations, G719X and S768I), osimertinib, or combination therapies in the upfront setting; limitations of the available data; and ongoing clinical trials specific to the EGFR PACC mutation subgroup that may further refine our understanding of treatment for patients with these tumors.