Amivantamab-lazertinib combo improves survival by reducing resistance mechanisms in NSCLC

An updated analysis of MARIPOSA reveals significant reductions in the incidence of MET and EGFR resistance alterations with first-line amivantamab plus lazertinib compared with osimertinib, with no upregulation in other resistance pathways, in patients with nonsmall cell lung cancer (NSCLC).

“A reduction in mutational heterogeneity along with the reductions in MET and EGFR resistance alterations may explain the long-term survival observed with amivantamab plus lazertinib,” said lead author Dr Hidetoshi Hayashi, Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.

In MARIPOSA, patients with treatment-naïve, EGFR-mutant NSCLC were randomly allocated in a 2:2:1 ratio to receive amivantamab plus lazertinib (combination; n=429), osimertinib (n=429), or lazertinib (n=216). The lazertinib monotherapy was included to assess the contribution of components.

Hayashi and his team obtained paired blood samples at baseline and at the end of treatment (EOT) to analyse detectable circulating tumour DNA using the Guardant 360 next-generation sequencing panel. EOT was characterized by disease progression or treatment discontinuation or within 90 days of discontinuation.

Resistance mechanisms

Among participants with matched baseline and EOT samples, 148 were included in the amivantamab plus lazertinib arm and 198 in the osimertinib arm. The combination arm had significantly reduced MET amplification (3.4 percent vs 13.1 percent; p=0.002) and secondary EGFR resistance mutations (1.4 percent vs 7.6 percent; p=0.01) compared with the osimertinib arm.

“Amivantamab plus lazertinib significantly reduced the incidence of acquired MET amplifications by ~4-fold and EGFR resistance mutations by ~5-fold vs osimertinib,” Hayashi said. “No meaningful increases in other molecular escape pathways were observed with amivantamab plus lazertinib.”

Furthermore, treatment with amivantamab for a longer duration resulted in even fewer acquired MET or EGFR mutations. Specifically, 99 out of 101 (98 percent) patients who received ≥6 months of amivantamab did not acquire a MET amplification, and none who received ≥1 months of amivantamab had an EGFR C7975 mutation.

“Subcutaneous delivery of amivantamab and previously demonstrated prophylactic management may prolong the duration of treatment, which may reduce additional opportunities for acquired resistance,” Hayashi said. [J Clin Oncol 2024;42:3593-3605; J Thorac Oncol 2025;20809-20816; Girard N, et al, ELCC 2025]

“These findings suggest that amivantamab plus lazertinib is changing the underlying biology of EGFR-mutant disease, thus contributing to the improved median progression-free survival and overall survival with amivantamab plus lazertinib versus osimertinib observed in MARIPOSA,” Hayashi said.

Progression

Previous studies have shown the near inevitability of progression on osimertinib due to acquired resistance that can be “diverse and polyclonal.” [Br J Cancer 2019;121:725-737; J Clin Oncol 2023;41(suppl 16):9074; Ann Oncol 2018;29(suppl 8):VIII740]

Among the resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs), with or without chemotherapy, the most common are EGFR and MET alterations. [Nat Commun 2023;14:1070; Yang JC-H, et al, WCLC 2024]

“Amivantamab, an EGFR-MET bispecific antibody, was combined with the EGFR TKI lazertinib to proactively address these mechanisms of acquired resistance,” Hayashi said. “Amivantamab is approved in combination with lazertinib for first-line common EGFR-mutant NSCLC and across various EGFR-mutant NSCLC indications.”

In MARIPOSA, first-line treatment with amivantamab plus lazertinib led to significant improvements in progression-free survival in patients with EGFR-mutant NSCLC compared with osimertinib (HR, 0.70, 95 percent CI, 0.58‒0.85; p<0.001). [N Engl J Med 2024;391:1486-1498]

“An earlier report showed that amivantamab plus lazertinib reduced EGFR- and MET-based resistance mechanisms and resistance complexity versus osimertinib, thus proactively addressing osimertinib resistance mechanisms,” Hayashi said. [Besse B, et al, ESMO 2024]