MARIPOSA-2: How Baseline Mechanisms of Osimertinib Resistance Influence Outcomes in NSCLC

Raffaele Califano, MD, of the Christie NHS Foundation Trust and The University of Manchester, joined Lung Cancers Today at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting to discuss a new analysis of MARIPOSA-2.

The phase 3 MARIPOSA-2 study randomized patients 2:2:1 to receive amivantamab and lazertinib plus chemotherapy, chemotherapy alone, or amivantamab plus chemotherapy. The study included patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) who had disease progression on osimertinib.

Dr. Califano explained that previously reported study findings of MARIPOSA-2 showed that adding amivantamab or amivantamab and lazertinib to chemotherapy improves progression-free survival (PFS) compared with standard chemotherapy alone.

The data presented at ASCO 2025 focused on evaluating patient outcomes based on their baseline mechanism of resistance to osimertinib, specifically examining patients who received amivantamab plus chemotherapy or chemotherapy alone. Dr. Califano and colleagues identified baseline mechanisms of resistance to osimertinib by performing next-generation sequencing on blood circulating tumor DNA (ctDNA).

“In patients with detectable ctDNA, the most common mechanism of resistance was MET amplification in approximately 15% of patients, or secondary EGFR resistance mutations,” Dr. Califano said.

The researchers also evaluated how these baseline mechanisms of resistance influenced treatment outcomes.

“When we analyzed the impact of these molecular aberrations in terms of PFS, we saw that with a medium follow-up of 8.7 months in patients with detectable ctDNA, the combination of chemo plus amivantamab achieved a longer progression-free survival when compared to chemotherapy alone,” Dr. Califano said.

In addition, amivantamab plus chemotherapy significantly improved the median PFS compared with chemotherapy for patients with EGFR/MET-independent resistance mechanisms, as well as those with unknown resistance mechanisms.

“The combination of chemotherapy plus amivantamab improves progression-free survival over standard chemotherapy regardless of the baseline mechanism of the resistance to osimertinib, and this confirms that the MARIPOSA-2 regimen remains a standard of care in this setting,” Dr. Califano concluded.