On August 19, 2024, the U.S. Food and Drug Administration (FDA) approved lazertinib (Lazcluze™) in combination with amivantamab-vmjw (Rybrevant®) for first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution variants, as detected by an FDA-approved test.
Efficacy was evaluated in MARIPOSA (NCT04487080), a randomized, active-controlled, multicenter trial of 1,074 patients with exon 19 deletion– or exon 21 L858R substitution variant–positive locally advanced or metastatic NSCLC and no prior systemic therapy for advanced disease. Patients were randomized 2:2:1 to receive lazertinib in combination with amivantamab, osimertinib monotherapy, or lazertinib monotherapy (an unapproved regimen for NSCLC) until they experienced disease progression or unacceptable toxicity.
The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review for lazertinib with amivantamab versus osimertinib. Overall survival (OS) was a key secondary outcome measure. Lazertinib with amivantamab demonstrated a statistically significant improvement in PFS compared to osimertinib with a hazard ratio of 0.70 (95% CI: 0.58, 0.85; p = 0.0002). The median PFS was 23.7 months (95% CI = 19.1, 27.7) in the lazertinib with amivantamab arm and 16.6 months (95% CI = 14.8, 18.5) in the osimertinib arm. Although the OS results were immature at the current analysis, with 55% of pre-specified deaths for the final analysis reported, the researchers did not observe a trend toward a detriment.
The most common adverse reactions reported in at least 20% of patients were rash, nail toxicity, infusion 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 four 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. See the prescribing information for lazertinib and amivantamab for specific dosing information.
The FDA conducted the review under Project Orbis, an initiative of the Oncology Center of Excellence (OCE), which provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with the Australian Therapeutic Goods Administration, Brazilian Health Regulatory Agency, Health Canada, Switzerland’s Swissmedic, and United Kingdom’s Medicines and Healthcare Products Regulatory Agency. The application reviews are ongoing at the other regulatory agencies.
The applicant used the Assessment Aid to facilitate the FDA’s review. The FDA granted the application priority review. FDA’s expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.
For assistance with single-patient applications for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.