Osimertinib plus Chemotherapy Improves Outcomes in Advanced EGFR-Mutant NSCLC

Osimertinib, a third-generation epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI), is the standard of care for patients with advanced EGFR-mutated non–small-cell lung cancer (NSCLC) with classic activating mutations. Despite initial responses to osimertinib, patients eventually develop resistance to this targeted therapy and median progression-free survival (PFS) with osimertinib is approximately 19 months. Because combining earlier generation TKIs with chemotherapy could have an additive effect, there was interest in evaluating osimertinib with chemotherapy in the frontline setting.

In an industry-funded, open-label, phase 3 study, 557 patients with EGFR-mutated advanced NSCLC were randomly assigned to osimertinib alone or with pemetrexed plus cisplatin or carboplatin. Patients assigned to chemotherapy received intravenous pemetrexed and cisplatin or carboplatin every 21 days for four cycles followed by osimertinib and maintenance pemetrexed every 21 days until progression or toxicity.

Median PFS — the primary outcome — was longer with combination therapy than with osimertinib monotherapy (25.5 vs. 16.7 months; hazard ratio, 0.62; P<0.001). PFS benefits were maintained across all prespecified subgroups, including EGFR mutation type and the presence or absence of central nervous system metastases. Objective response was noted in 83% of patients on osimertinib-chemotherapy and 76% of those on osimertinib alone. Overall survival results were immature.

Grade 3 or higher treatment-related adverse events occurred in 64% of patients on osimertinib-chemotherapy, driven primarily by chemotherapy side effects, and 27% on osimertinib alone.