Dr Califano on MARIPOSA-2 Outcomes by Baseline Resistance Mechanisms in EGFR+ NSCLC

"This [is] an analysis of the progression-free survival [stratified] by molecular aberration, which represents the mechanism of resistance post-osimertinib [in] all patients who were enrolled in the MARIPOSA-2 study. The data [show] is that chemotherapy plus amivantamab is an effective regimen, regardless of the baseline mechanism of resistance post-[osimertinib], and therefore it remains a standard of care in this setting."

Raffaele Califano, MD, a consultant in medical oncology at the Christie and Manchester University Hospital, detailed outcomes based on baseline resistance mechanisms in the phase 3 MARIPOSA-2 trial (NCT04988295), which evaluated amivantamab-vmjw (Rybrevant) in combination with chemotherapy vs chemotherapy alone in patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC) following disease progression on osimertinib (Tagrisso).

The trial enrolled patients with advanced NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease progressed on osimertinib. Baseline circulating tumor DNA (ctDNA) was collected and analyzed using the Guardant360 and FoundationOne CDx platforms to identify putative resistance mechanisms to osimertinib.

Findings from an analysis of outcomes based on osimertinib resistance mechanisms, which were presented at the 2025 ASCO Annual Meeting, showed that amivantamab plus chemotherapy improved PFS in patients with detectable ctDNA at baseline (HR, 0.49; 95% CI, 0.36-0.68; P < .0001) and those harboring TP53 comutations (HR, 0.63; 95% CI, 0.44-0.92; P = .014).

PFS was also improved with the combination in patients with EGFR/MET independent resistance mechanisms (HR, 0.54; 95% CI, 0.31-0.94; P = .025), dependent resistance mechanisms (HR, 0.57; 95% CI, 0.33-0.99; P = .042), and unknown resistance mechanisms (HR, 0.31; 95% CI, 0.17-0.56; P < .001).

Among the ctDNA-evaluable population, MET amplification and EGFR secondary mutations emerged as the most common resistance alterations. Califano noted that across all molecular subgroups, the combination of amivantamab plus chemotherapy demonstrated superior progression-free survival (PFS) outcomes compared with chemotherapy alone.

Importantly, benefit from the amivantamab-based regimen extended beyond biomarker-defined populations, Califano explained. Patients with TP53 co-mutations or unknown resistance mechanisms also experienced improved outcomes, suggesting a broad therapeutic impact regardless of the molecular driver of resistance.

These findings underscore the role of amivantamab plus chemotherapy as a standard-of-care regimen following progression on osimertinib, Califano said.