MARIPOSA: Amivantamab Plus Lazertinib in EGFR-Mutated NSCLC
Key Points
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The MARIPOSA trial led to the approval of amivantamab plus lazertinib for advanced non-small cell lung cancer (NSCLC) with common EGFR mutations.
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Amivantamab plus lazertinib is associated with cutaneous toxicities, venous thromboembolism, and infusion-related reactions, but effective management strategies have been developed.
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Amivantamab plus lazertinib may bypass some mechanisms of resistance to EGFR and MET therapies.
Recent Changes in the EGFR-Mutated NSCLC Treatment Landscape
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with four lung cancer experts at the 2025 American Society of Clinical Oncology Annual Meeting to discuss clinical insights from the MARIPOSA trial on amivantamab plus lazertinib for untreated, advanced NSCLC with common EGFR mutations.
Prior to 2024, osimertinib monotherapy was the frontline standard of care for patients with EGFR-mutated NSCLC. In 2024, two new regimens were approved: osimertinib plus carboplatin-pemetrexed chemotherapy, based on the FLAURA2 study, and amivantamab plus lazertinib, based on the MARIPOSA study. Amivantamab is a bispecific antibody targeting the EGFR and MET pathways, whereas lazertinib is a third-generation tyrosine kinase inhibitor (TKI) that acts against EGFR.
MARIPOSA Trial Design and Findings
The pivotal MARIPOSA trial enrolled patients with metastatic NSCLC with exon 19 deletion or L858R mutation to receive either amivantamab plus lazertinib (n=429), osimertinib alone (n=429), or lazertinib alone (n=216).
In the first report, patients treated with amivantamab plus lazertinib had significantly longer progression-free survival (PFS) at 23.7 months compared with those treated with osimertinib at 16.6 months (hazard ratio [HR], 0.70; 95% CI, 0.58-0.85; P < .001). The objective response rates were 86% (95% CI, 83-89) with amivantamab plus lazertinib and 85% (95% CI, 81-88) with osimertinib. In the final overall survival (OS) analysis, after a median follow-up of 37.8 months, the 3-year OS rate was 60% with amivantamab plus lazertinib versus 51% with osimertinib (HR, 0.75; 95% CI, 0.61-0.92; P = .005).
MARIPOSA also required central nervous system (CNS) monitoring in all patients. Over 50% of patients with EGFR-mutated NSCLC will develop brain metastases, but imaging is typically only done after identification of CNS involvement said Helena Yu, MD, of Memorial Sloan Kettering Cancer Center. As such, the MARIPOSA data may improve understanding of asymptomatic CNS progression and how amivantamab crosses the blood-brain barrier.
Managing Adverse Events of Amivantamab Plus Lazertinib
In MARIPOSA, common adverse events reported with amivantamab plus lazertinib included infusion-related reactions, cutaneous toxicities, and venous thromboembolism. However, preventative strategies have been developed that effectively manage these effects.
Anticoagulant therapy for the first 4 months of amivantamab plus lazertinib treatment is the standard thromboprophylaxis for eligible patients. Infusion-related reactions, which typically occur only during the first infusion, can be managed by premedicating patients with steroids in the 2 days preceding the infusion, said Estelamari Rodriguez, MD, MPH, of the University of Miami Health System.
Because of the dual inhibition of EGFR with amivantamab plus lazertinib, the cutaneous toxicities can be more distinct than other anti-EGFR agents, said Susan Scott, MD, of the Johns Hopkins Hospital. After the approval of amivantamab plus lazertinib for EGFR-mutated NSCLC, the phase 2 COCOON study described an enhanced dermatologic management regimen that significantly reduced the incidence of dermatologic adverse events. According to the study, patients receiving amivantamab plus lazertinib should be prescribed an oral antibiotic, a topical antibiotic for the scalp, an antiseptic for the fingernails and toenails, and a ceramide-based moisturizer.
If any of the toxicities associated with amivantamab plus lazertinib are too severe or persist despite management strategies, physicians can consider dose reductions or holds. “I generally start [dose reductions] with the amivantamab and try to keep the lazertinib at full dose,” said Joshua Sabari, MD, NYU Langone Health. MARIPOSA data also showed that dose holds did not compromise the PFS benefit, Dr. Sabari said.
Overcoming Mechanisms of Resistance in EGFR-Mutated NSCLC
Treatment Resistance is a significant challenge when treating EGFR-mutated disease. Classic mechanisms of resistance to osimertinib include EGFR C797S mutation, MET amplification, and bypass track alterations. Analysis of resistance mechanisms in a subset of MARIPOSA patients with early disease progression showed a “tremendous reduction” in EGFR-mediated and MET-mediated resistance with amivantamab plus lazertinib compared with osimertinib, Dr. Sabari said.