Introduction
The U.S. Food and Drug Administration (FDA) has granted approval for the combination of lazertinib (Lazcluze) and amivantamab-vmjw (Rybrevant) as a first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring specific epidermal growth factor receptor (EGFR) mutations. This approval marks a significant advancement in the treatment landscape for NSCLC patients with exon 19 deletions or exon 21 L858R substitution mutations, detected through FDA-approved tests.
Current Regulatory Status
This approval was part of an expedited review process under Project Orbis, an FDA Oncology Center of Excellence initiative that allows for concurrent submission and review of oncology drugs among international regulatory partners. The review involved collaboration with agencies from Australia, Brazil, Canada, Switzerland, and the United Kingdom, with ongoing assessments in these countries. The application was also granted priority review status, underscoring its potential to address a significant unmet medical need.
Drug Details
Lazertinib is an oral EGFR tyrosine kinase inhibitor, while amivantamab is a bispecific antibody targeting both EGFR and MET receptors. The combination of these drugs is designed to target multiple pathways involved in the growth and survival of cancer cells with EGFR mutations, offering a more comprehensive approach to treating this subset of NSCLC.
Technology
Amivantamab-vmjw leverages a bispecific antibody platform that simultaneously targets EGFR and MET, which are often implicated in resistance mechanisms in NSCLC. The dual targeting approach aims to prevent or overcome resistance to treatment, a common challenge in managing advanced NSCLC.
Trial Details
The FDA’s approval is based on data from the MARIPOSA trial (NCT04487080), a randomized, active-controlled, multicenter study that enrolled 1,074 patients with locally advanced or metastatic NSCLC harboring exon 19 or exon 21 mutations. Patients were randomized to receive either the lazertinib and amivantamab combination, osimertinib monotherapy, or lazertinib monotherapy, although the latter regimen is not approved for NSCLC. The trial’s primary endpoint was progression-free survival (PFS), with overall survival (OS) as a key secondary outcome.
Efficacy Data
The study specifically targeted patients with EGFR mutation-positive NSCLC, a subtype known for its poor prognosis and limited treatment options after resistance develops. The combination of lazertinib and amivantamab showed a statistically significant improvement in PFS compared to osimertinib, with a hazard ratio of 0.70, indicating a 30% reduction in the risk of disease progression or death. The median PFS for the combination was 23.7 months, compared to 16.6 months for osimertinib.
Conclusion
The FDA’s approval of the lazertinib and amivantamab combination represents a pivotal advancement in the treatment of EGFR mutation-positive NSCLC, offering new hope for patients facing this challenging diagnosis. With the continued global collaboration through Project Orbis and the ongoing development of targeted therapies, the future of NSCLC treatment is poised for significant progress. Full prescribing information for both Lazcluze and Rybrevant will be available on the FDA’s official website.
Dr. Vinoth Khandelwal, Ph.D.
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