The U.S. Food and Drug Administration (FDA) has approved the EGFR inhibitor lazertinib (Lazcluze) in combination with the EGFR/MET-targeting bispecific antibody amivantamab-vmjw (Rybrevant) for the first-line treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) and EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
MARIPOSA
Efficacy of the combination was evaluated in MARIPOSA (ClinicalTrials.gov identifier NCT04487080), a randomized, active-controlled, multicenter trial of 1,074 patients with EGFR exon 19 deletion or exon 21 L858R substitution mutation–positive locally advanced or metastatic NSCLC who had received no prior systemic therapy for advanced disease. Patients were randomly assigned 2:2:1 to receive lazertinib in combination with amivantamab, osimertinib monotherapy, or lazertinib monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity.
The major efficacy outcome measure was progression-free survival as assessed by blinded independent central review for the comparison between lazertinib with amivantamab and osimertinib; overall survival was a key secondary outcome measure. Lazertinib with amivantamab demonstrated a statistically significant improvement in progression-free survival compared to osimertinib, with a hazard ratio of 0.70 (95% confidence interval [CI] = 0.58–0.85, P = .0002). The median progression-free survival was 23.7 months (95% CI = 19.1–27.7 months) in the lazertinib with amivantamab arm and 16.6 months (95% CI = 14.8–18.5 months) in the osimertinib arm. While overall survival results were immature at the time of the current analysis, with 55% of prespecified deaths for the final analysis reported, no trend towards a detriment was observed.
The most common adverse reactions (occurring in ≥ 20% of patients receiving the combination regimen) were rash, nail toxicity, infusion-related reactions (related to amivantamab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19 infection, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. A serious safety signal of venous thromboembolic events was observed with lazertinib in combination with amivantamab, and prophylactic anticoagulation should be administered for the first 4 months of therapy.
The recommended lazertinib dose is 240 mg orally once daily administered in combination with amivantamab with or without food. The recommended amivantamab dose is based on baseline body weight.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, Switzerland’s Swissmedic, and the United Kingdom’s Medicines and Healthcare products Regulatory Agency. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review.
