A Mutant-Selective EGFR Inhibitor in NSCLC
AZD9291 is a third-generation EGFR–tyrosine kinase inhibitor (TKI) that has been shown in preclinical models to be effective against both EGFR-TKI sensitizing and resistance T790M mutations. In a phase 1 safety and preliminary efficacy study, 199 patients with EGFR-mutant NSCLC who had progressed on prior EGFR-TKI therapy due to acquired resistance, were treated with AZD9291 in dose-escalation (N = 31) and dose-expansion (N = 168) cohorts. Among 177 evaluable patients, the confirmed plus unconfirmed overall response rate (c + uORR) was 51%, including RECIST responses and effects on brain metastases. In 132 patients with confirmed T790 mutation, the c + uORR was 64%. The overall disease control rate in the T790M+ patients was 96%. No dose-limiting toxicities were noted with AZD9291, with the majority of adverse events being diarrhea, nausea, and rash. This agent holds promise as treatment for patients with EGFR T790M+ NSCLC who have a poor response to existing EGFR-TKIs, but is probably of less value in patients whose tumors do not harbor the T790M mutation. As with any new agent, judicious use in only the most appropriate patients is advisable.