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The FDA approved for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations, the agency announced Monday.

This is the first U.S. approval for lazertinib -- a highly selective, brain-penetrant, third-generation oral EGFR tyrosine kinase inhibitor. The combination is the first multitargeted, chemotherapy-free regimen approved in this setting.

The approval was based on results from the phase III MARIPOSA study, in which the combination significantly improved median progression-free survival (PFS) by about 7 months over the current standard, single-agent osimertinib (Tagrisso).

"The unique combination of Rybrevant and Lazcluze demonstrated superior efficacy in the first-line treatment of certain patients with EGFR-mutated advanced NSCLC as shown with the MARIPOSA study," said Alexander Spira, MD, PhD, of the Virginia Cancer Specialists Research Institute, and a MARIPOSA study investigator, in a from the company.

"Patients will now have the option of a potential new first-line standard of care with significant clinical benefits over osimertinib," he added. "This first-line therapy uses a targeted approach aiming to achieve the best possible patient outcomes while reserving chemotherapy for later stages of treatment when resistance becomes more complex."

The MARIPOSA study involved 1,074 patients with EGFR-mutated advanced or metastatic NSCLC who had received 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 (included to show the contribution of the single agent alone).

The combination reduced the risk of disease progression or death by 30% compared with osimertinib (HR 0.70, 95% CI 0.58-0.85, P<0.001), with median PFS values of 23.7 months versus 16.6 months. Median PFS in the lazertinib monotherapy arm reached 18.5 months.

While response rates were similar between the combination and osimertinib arms (86% vs 85%), lazertinib plus amivantamab yielded more durable responses (median 25.8 months vs 16.8 months).

Interim overall survival data also showed a trend favoring the combination over osimertinib (HR 0.80, 95% CI 0.61-1.05).

The most common adverse reactions with lazertinib plus amivantamab included rash, nail toxicity, infusion-related reactions (amivantamab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19 infection, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity.

The FDA noted that a serious safety signal of venous thromboembolic events was observed with the combination and recommended that prophylactic anticoagulation should be administered for the first 4 months of therapy.

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