MARIPOSA Trial: CNS Benefit and Reducing Resistance Mutations

The MARIPOSA study introduced a key advancement in monitoring and managing CNS involvement in EGFR-mutated non–small cell lung cancer. Unique to this study was the requirement for scheduled brain imaging throughout treatment. Although osimertinib is known for strong CNS penetration, the addition of amivantamab and lazertinib demonstrated improved progression-free survival in the brain. Although the exact mechanism is not fully understood, the benefit may stem from improved systemic disease control or from direct CNS activity of the larger antibody molecules—contrary to previous assumptions about limited CNS penetration. This finding is clinically significant, especially in efforts to avoid whole-brain radiation, which can have lasting negative effects on patients.

Mechanistically, the MARIPOSA regimen targets both EGFR and MET through the bispecific antibody amivantamab. This dual-target approach is designed not only to enhance EGFR inhibition but also to address MET amplification—a common mechanism of resistance that can emerge after EGFR tyrosine kinase inhibitor (TKI) therapy or even be present at diagnosis. By combining amivantamab with a TKI like lazertinib, the regimen aims to preemptively block these resistance pathways. The strategy appears successful: the trial showed a reduction in the emergence of both EGFR secondary mutations and MET amplifications, supporting the scientific rationale behind the combination therapy.

These molecular findings reinforce the effectiveness of the MARIPOSA regimen and validate its design, translating into clinically meaningful outcomes. Importantly, no new concerning resistance patterns, such as increased TP53 or RB1 mutations, were observed, suggesting that the therapy does not induce more aggressive disease. This alignment of scientific intent with clinical results strengthens the case for broader adoption of the regimen and highlights a promising shift in how EGFR-mutated NSCLC is approached—particularly for patients at higher risk of CNS progression and treatment resistance.