The Changing EGFR Landscape
Reviews the decade-long progress in EGFR-targeted therapies and introduces the rationale for first-line dual inhibition.
The MARIPOSA study represents a pivotal phase in advancing precision oncology for patients with EGFR-mutant non–small cell lung cancer (NSCLC). Over the past decade, third-generation tyrosine kinase inhibitors (TKIs) like osimertinib have improved patient outcomes, yet resistance remains nearly universal. The combination of amivantamab, a bispecific antibody targeting EGFR and MET, with the EGFR TKI lazertinib, was developed to proactively overcome the most common mechanisms of resistance that emerge during osimertinib monotherapy. This series underscores how early intervention with dual-targeted therapy can suppress resistance evolution and extend clinical benefit.
With extended follow-up, MARIPOSA data show that amivantamab plus lazertinib leads to markedly lower rates of acquired MET amplifications (~4-fold reduction) and secondary EGFR mutations (~5-fold reduction) compared to osimertinib, without compensatory activation of alternate signaling pathways. These molecular findings correlate with improved median progression-free survival (HR, 0.70; P < .001) and overall survival (HR, 0.75; P < .005), with gains projected to exceed 1 year. Importantly, patients receiving longer durations of amivantamab treatment were even less likely to develop resistance events, supporting the durability of its dual blockade effect.
Beyond the efficacy data, the deck delves into translational insights from circulating tumor DNA (ctDNA) analyses and mutational heterogeneity metrics. The combination reduced overall resistance complexity and heterogeneity index, suggesting a fundamental shift in the biology of resistance development. Clinically, these findings emphasize that upfront dual inhibition may delay disease progression, reduce rebiopsy needs, and optimize sequencing strategies. Taken together, the MARIPOSA update positions amivantamab plus lazertinib as a new benchmark in first-line EGFR-mutant NSCLC therapy, potentially changing the trajectory of long-term disease control
