Clinical Insights: Metastatic EGFR+ NSCLC from MARIPOSA and PALOMA-3
Key Points
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The MARIPOSA and FLAURA2 trials showed combination regimens improved overall survival (OS) in EGFR-mutated advanced non–small cell lung cancer (NSCLC).
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Repeat brain MRIs in MARIPOSA demonstrated the central nervous system (CNS) activity of amivantamab plus lazertinib, providing some of the most robust data on brain metastases in the field.
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Amivantamab plus lazertinib can lead to adverse effects, but proactive strategies have significantly improved tolerability over time.
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Trials like PALOMA-3 and COPERNICUS are building on MARIPOSA data by exploring novel amivantamab formulations.
Panelists Discuss 2025 Advances in EGFR-Positive Advanced NSCLC
In 2024, the FDA approved two combinations for EGFR-mutated advanced NSCLC: osimertinib plus chemotherapy, based on FLAURA2 findings, and amivantamab plus lazertinib, based on MARIPOSA’s results. Both regimens demonstrated an OS advantage over standard of care osimertinib monotherapy.
At the IASLC/ASCO 2025 North America Conference on Lung Cancer, Joshua Sabari, MD, of NYU Langone Health, led a roundtable discussion on these two regimens and their impact. Dr. Sabari was joined by four experts in EGFR-mutated advanced NSCLC: Alexander Spira, MD, PhD, FACP, FASCO, of NEXT Oncology; Danny Nguyen, MD, of City of Hope; Edgardo Santos, MD, FACP, FASCO, of Florida Society of Clinical Oncology; and Eric Singhi, MD, of The University of Texas MD Anderson Cancer Center.
The panelists also discussed ongoing studies that are refining amivantamab delivery and tolerability. Overall, their discussion provided insights into how emerging data are influencing clinical decision-making in 2025.
Comparing MARIPOSA and FLAURA2: Efficacy and CNS Outcomes
Dr. Sabari began by asking how the new combinations’ positive data may change osimertinib monotherapy’s role. For most patients with metastatic EGFR-mutated NSCLC, combination therapy is likely to become the preferred treatment, but osimertinib alone may still offer a “deescalated” option for patients who are older, more frail, or live far from treatment centers, Dr. Singhi said.
The panel discussed efficacy data that influence the choice between the MARIPOSA and FLAURA2 regimens. The data favor both combinations over osimertinib alone across subgroups, including patients with high-risk features such as liver metastases or TP53 co-mutation. Both combinations also showed improved survival for patients with CNS metastases. However, the MARIPOSA trial included baseline and repeat brain MRIs for all patients, allowing for prospective analysis of intracranial progression-free survival. The more robust data may favor using amivantamab plus lazertinib for patients with known CNS involvement.
Additionally, the MARIPOSA regimen was specifically designed to overcome the most common treatment resistance patterns in EGFR-mutated advanced NSCLC, such as MET amplification. In MARIPOSA, circulating tumor DNA data showed amivantamab was associated with approximately seven- to eight-fold reductions in EGFR-mediated resistance and a three- or four-fold reduction in MET-mediated resistance, suggesting that amivantamab is altering the disease biology, Dr. Sabari said.
Managing Adverse Effects With FLAURA2 and MARIPOSA Regimens
For the FLAURA2 regimen, both osimertinib and chemotherapy have well-documented adverse event profiles, and combining the two drugs did not introduce new safety signals. Standard management of toxicities related to EGFR inhibitors can be used with standard strategies for chemotherapy-related toxicities, including growth factor support for cytopenias and steroids for nausea.
The MARIPOSA regimen’s proactive management strategies have significantly improved tolerability. Common adverse events associated with amivantamab plus lazertinib include infusion-related reactions (IRRs), venous thromboembolism (VTE), and cutaneous toxicities.
For IRRs, the phase 2 SKIPPirr trial evaluated prophylactic strategies and reported that giving 8 mg of oral dexamethasone before the first infusion significantly reduced the incidence of IRRs. In addition, implementing prophylactic anticoagulation medications dramatically reduced the rate of events. For rash and other skin toxicities, the phase 2 COCOON trial showed that an enhanced prophylactic regimen significantly reduced the incidence of dermatologic adverse events and their impact on quality of life. The enhanced regimen consists of oral doxycycline or minocycline, clindamycin 1%, chlorhexidine 4%, and a ceramide-based moisturizer.
Generally, EGFR-mediated toxicities linked to amivantamab plus lazertinib start to subside after the first 4 treatment cycles. Furthermore, dose interruptions in MARIPOSA participants did not compromise efficacy, so oncologists should not hesitate to hold amivantamab doses to ease adverse effects and keep patients on treatment, Dr. Santos said.
Evaluating Subcutaneous Amivantamab in COPERNICUS and PALOMA-3
A subcutaneous formulation of amivantamab is in development and is being compared with intravenous (IV) amivantamab in trials including PALOMA-3. The subcutaneous form reduced VTE risk, substantially reduce IRRs, and improve treatment logistics compared with IV amivantamab. Early PALOMA-3 data also suggest that subcutaneous amivantamab may improve efficacy, although it’s not clear what mechanism of action is driving the additional benefit, Dr. Spira said.
The COPERNICUS trial is evaluating subcutaneous amivantamab with either lazertinib or platinum-based chemotherapy. Dr. Singhi, one of the study investigators, reiterated the improved logistics of subcutaneous amivantamab, especially less time spent in clinics for patients. Although IRR and VTE risks are reduced with the subcutaneous formulation, EGFR- and MET-mediated toxicities still occur and require proper follow-up, Dr. Nguyen said.
Ultimately, the panelists urged doctors to refer patients with EGFR-mutated advanced NSCLC to trials like COPERNICUS so the field keeps moving forward, improving survival via novel agents or strategies to manage adverse effects.