First-Line Combination Therapy for EGFR-Mutated NSCLC

Osimertinib is the preferred first-line treatment for most patients with non–small-cell lung cancer (NSCLC) who harbor common EGFR mutations. Unfortunately, despite initial deep response, many patients experience progressive disease in less than 1.5 years. Several drug combinations, including osimertinib plus pemetrexed chemotherapy, have shown promise compared with osimertinib alone.

The phase 3 industry-supported MARIPOSA study compared amivantamab plus lazertinib to osimertinib alone in patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 19 deletion or L858R substitution mutations. Amivantamab is a bispecific antibody targeting EGFR and MET; lazertinib is a third-generation, central nervous system–penetrant, mutant-selective EGFR tyrosine kinase inhibitor.

A total of 1074 patients were randomized to one of three arms: amivantamab administered intravenously once weekly in the first 4-week cycle and once every 2 weeks in subsequent cycles, plus daily oral lazertinib; oral osimertinib plus placebo; oral lazertinib plus placebo. At a median follow-up of 22 months, progression-free survival (PFS) in the amivantamab-lazertinib arm compared with the osimertinib arm (the primary outcome) was significantly longer with combination therapy (median, 23.7 vs. 16.6 months; hazard ratio, 0.70; P<0.001). Lazertinib alone resulted in a median PFS of 18.5 months.

Grade ≥3 adverse events were more common with amivantamab-lazertinib than osimertinib alone (75% vs. 43%); treatment discontinuation occurred in 10% and 3%, respectively. The most common toxicities were paronychia and rash. Venous thromboembolic events were more frequent with combination therapy, thus prompting a recommendation for prophylactic anticoagulation in the first 4 months of treatment.