Pulse Afatinib for ERBB2 Exon 20 Insertion–Mutated Lung Adenocarcinomas

Abstract

IntroductionGenomic aberrations involving the erb-b2 receptor tyrosine kinase 2 gene (ERBB2) are driver oncogenes in approximately 2% of lung adenocarcinomas. However, the use of daily dosing of ERBB2 tyrosine kinase inhibitors (TKIs)—including afatinib—has been fraught with plasma concentrations that barely achieve preclinical model inhibition, significant patient-reported toxicities, and limited clinical activity. We hypothesized that alternative dosing strategies could improve tolerability and efficacy. MethodsWe profiled lung cancer cell lines against TKIs and retrospectively evaluated the toxicity of and response to pulse afatinib (280 mg once weekly) in lung cancers with ERBB2 mutations. ResultsAn ERBB2 exon 20 insertion–mutated lung cancer cell line had a 50% inhibitory concentration in response to afatinib that was higher than the reported plasma concentration of afatinib, 40 mg daily. Three patients with advanced ERBB2-mutated lung adenocarcinomas were treated with off-label pulse afatinib. The 280-mg weekly dose was well tolerated with no reported rash and minimal diarrhea. One TKI-naive patient achieved a partial response for 5 months and another achieved stable disease for 11 months. ConclusionsPulse afatinib at a weekly dosing scheme induced antitumor activity in ERBB2 exon 20 insertion–mutated lung adenocarcinomas. Future clinical trials of alternative dosing schemes of ERBB TKIs as monotherapy or in combination with other therapies are warranted for ERBB2-mutated tumors.