Resistance Biology: MARIPOSA vs. FLAURA2 Reshaping Debate

The debate examined whether amivantamab-lazertinib or osimertinib-chemotherapy more favorably reshapes resistance biology, with the MARIPOSA team citing data showing lower rates of MET amplification (7.3% vs. 13.1%) and secondary EGFR mutations (1.4% vs. 7.6%) compared to osimertinib monotherapy, alongside a potential immune-activating effect of amivantamab and a possible curve-flattening signal suggesting disease course modification. Team Thriller countered that although amivantamab does shift resistance patterns, the actionability of that shift is uncertain; MET amplification and on-target EGFR mutations arising after FLAURA2-based therapy may actually be more targetable with emerging fourth-generation EGFR inhibitors and MET-directed therapies than the bypass pathway resistance seen with amivantamab-lazertinib. A key unresolved point was that MARIPOSA did not allow crossover, making it impossible to know whether sequencing osimertinib followed by an amivantamab-based regimen could ultimately yield comparable or superior outcomes, a question that remains critical as the treatment landscape rapidly evolves.