The U.S. Food and Drug Administration (FDA) has granted approval for the combination of Rybrevant (amivantamab) and Lazcluze (lazertinib) as a first-line treatment option for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring specific EGFR mutations—exon 19 deletions or exon 21 L858R substitutions. This decision followed a Priority Review process and was supported by the Phase 3 MARIPOSA trial results, which demonstrated that this combination therapy significantly reduces the risk of disease progression or death compared to osimertinib, with a notably longer median duration of response.
Rybrevant and Lazcluze Show Superior Progression-Free Survival Over Osimertinib
A New Standard in EGFR-Mutated NSCLC Treatment
This approval marks the first time a multitargeted, chemotherapy-free regimen has been approved as a superior alternative to osimertinib for the first-line treatment of EGFR-mutated NSCLC. Rybrevant is a bispecific antibody that targets both EGFR and MET, engaging the immune system to attack cancer cells, while Lazcluze is a third-generation EGFR tyrosine kinase inhibitor (TKI) designed to penetrate the brain effectively. This combination uniquely targets the most common EGFR mutations in NSCLC.
The Global Burden of Lung Cancer
Lung cancer remains the leading cause of cancer-related deaths worldwide, claiming 1.8 million lives annually. NSCLC accounts for 80 to 85 percent of all lung cancer cases. Among patients with EGFR-mutated NSCLC, up to 39 percent never receive a second-line treatment due to rapid disease progression and limited treatment options. The five-year survival rate for those with advanced EGFR-mutated NSCLC treated with the current standard of care, TKI monotherapy, remains below 20 percent. Resistance to TKI monotherapy further complicates subsequent treatment efforts.
Findings from the MARIPOSA Study
The FDA's approval was based on compelling data from the Phase 3 MARIPOSA trial, which involved 1,074 patients. The study evaluated the efficacy of Rybrevant in combination with Lazcluze compared to osimertinib and Lazcluze monotherapy in the first-line treatment of patients with locally advanced or metastatic NSCLC with specific EGFR mutations.
The primary endpoint was progression-free survival (PFS), assessed by an independent central review. The results showed that the combination of Rybrevant and Lazcluze reduced the risk of disease progression or death by 30 percent compared to osimertinib, with a median PFS of 23.7 months versus 16.6 months. Additionally, the median duration of response was nine months longer with the Rybrevant and Lazcluze combination, at 25.8 months compared to 16.7 months with osimertinib.
About Rybrevant
Rybrevant (amivantamab), a fully-human bispecific antibody targeting EGFR and MET with immune system engagement capabilities, is approved as a monotherapy in the U.S., Europe, and other global markets for the treatment of adult patients with locally advanced or metastatic NSCLC characterized by EGFR exon 20 insertion mutations who have experienced disease progression following platinum-based chemotherapy. In its subcutaneous formulation, Rybrevant is combined with recombinant human hyaluronidase PH20 (rHuPH20), utilizing Halozyme’s ENHANZE drug delivery technology.
In addition to its monotherapy approval, Rybrevant is authorized in the U.S. in combination with chemotherapy (carboplatin and pemetrexed) as a first-line treatment for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) recommended the approval of Rybrevant for this indication in April 2024.
Furthermore, Rybrevant is now approved in combination with Lazcluze for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations. Applications for marketing authorization and extension of indication have been submitted to the European Medicines Agency (EMA) for Lazcluze in combination with Rybrevant, based on the MARIPOSA study findings.
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