In a phase III, international, randomised MARIPOSA study, first-line treatment with amivantamab plus lazertinib significantly prolonged progression-free survival (PFS) as compared with osimertinib monotherapy with hazard ratio (HR) for disease progression or death of 0.70 (p < 0.001) in patients with previously untreated or osimertinib-pretreated EGFR–mutated advanced non-small cell lung cancer (NSCLC).
PFS curves separated at 6 months and widened over time. Regarding PFS, a benefit with amivantamab plus lazertinib was also observed across key prespecified subgroups, such as those defined according to a history of metastases in central nervous system (CNS). Predominant adverse events were EGFR-related. The findings are published by Dr. Byoung C. Cho of the Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, South Korea, and colleagues on 26 June 2024 in The New England Journal of Medicine.
The authors wrote in the background that the current first-line treatment for Ex19del and L858R advanced NSCLC is osimertinib, which is a third-generation EGFR tyrosine kinase inhibitor (EGFR TKI). Resistance to third-generation EGFR TKIs develops in nearly all patients. The mechanisms of resistance are diverse and polyclonal and the most common measurable resistance mechanisms are secondary EGFR pathway alterations and MET pathway activation. Amivantamab is an EGFR-MET bispecific antibody with immune cell–directing activity and unique mechanisms of action. Lazertinib is a highly selective, CNS-penetrant, third-generation EGFR TKI that has shown efficacy in both activating EGFR and T790M mutations.
Amivantamab was combined with lazertinib initially in patients whose disease had progressed during or after treatment with osimertinib. Amivantamab plus lazertinib had clinical activity across a wide range of secondary EGFR and MET alterations, including in patients without an identified mechanism of resistance. It was hypothesised that first-line treatment with amivantamab plus lazertinib could proactively address downstream resistance mechanisms and improve clinical outcomes.
Amivantamab plus lazertinib was evaluated in patients with previously untreated EGFR-mutated advanced NSCLC in the phase I CHRYSALIS study. All 20 enrolled patients had a response, and at a median follow-up of 33.6 months, 50% of the patients had an ongoing response and were continuing to receive treatment. At 36 months, 51% of the patients were free from disease progression, and 85% were alive.
The investigators conducted the phase III, international, randomised MARIPOSA study to assess the efficacy and safety of amivantamab plus lazertinib as compared with osimertinib alone in first-line treatment for patients with EGFR-mutated advanced NSCLC. In a third group in this study, lazertinib monotherapy was administered to patients to evaluate the contribution of the components in the combination treatment.
Patients with previously untreated EGFR-mutated (Ex19del or L858R), locally advanced or metastatic NSCLC were assigned in a 2:2:1 ratio to receive amivantamab plus lazertinib in an open-label fashion, osimertinib in a blinded fashion, or lazertinib in a blinded fashion, to assess the contribution of treatment components. The primary endpoint was PFS in the amivantamab plus lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review.
Overall, 1074 patients underwent randomisation, of whom 429 to amivantamab plus lazertinib, 429 to osimertinib and 216 to lazertinib. The median PFS was significantly longer in the amivantamab plus lazertinib group than in the osimertinib group, 23.7 versus 16.6 months (HR for disease progression or death 0.70, 95% confidence interval [CI] 0.58 to 0.85; p < 0.001).
An objective response was observed in 86% of the patients (95% CI 83 to 89) in the amivantamab plus lazertinib group and in 85% of those (95% CI 81 to 88) in the osimertinib group. Among patients with a confirmed response (336 in the amivantamab plus lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI 20.1 to could not be estimated) and 16.8 months (95% CI 14.8 to 18.5). In a planned interim overall survival analysis of amivantamab plus lazertinib as compared with osimertinib, the HR for death was 0.80 (95% CI 0.61 to 1.05).
Grade 3 or higher adverse events (AEs) were reported in 75% of the patients treated with amivantamab plus lazertinib and in 43% of those treated with osimertinib, with paronychia and rash being the most common events. Serious AEs were reported in 49% of the patients treated with amivantamab plus lazertinib and in 33% of those treated with osimertinib. Infusion-related reactions occurred in 63% of the patients treated with amivantamab plus lazertinib, with most events occurring on cycle 1 day 1. Venous thromboembolic AEs were reported in 37% of the patients in the amivantamab plus lazertinib group and in 9% of those in the osimertinib group, with pulmonary embolism and deep-vein thrombosis being the most common events.
The incidence of discontinuation of all agents due to treatment-related AEs was 10% with amivantamab plus lazertinib and 3% with osimertinib. The most common AEs leading to the discontinuation of any study agent were infusion-related reactions and paronychia. AEs leading to death occurred in 8% of patients in the amivantamab plus lazertinib group and in 7% in the osimertinib group. Cardiopulmonary-, cerebrovascular-, and infection-related deaths predominated in these two groups.
Most venous thromboembolic AEs in the amivantamab plus lazertinib group occurred during the first 4 months of treatment. One possible explanation could be a transitory prothrombotic state caused by a mechanism of rapid tumour-cell death by amivantamab plus lazertinib. In ongoing studies of amivantamab plus lazertinib (PALOMA-3 and COCOON), prophylactic anticoagulation is recommended for the first 4 months of treatment.
The study findings were previously presented in part at the ESMO 2023 Congress in Madrid, Spain.
The study was supported by Janssen Research and Development.
Reference
Cho BC, Lu S, Felip E, et al. for the MARIPOSA Investigators. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. NEJM; Published online 26 June 2024. DOI: 10.1056/NEJMoa2403614