FDA Approves J&J's Rybrevant and AZ's Tagrisso Combo for First-Line Lung Cancer

Johnson & Johnson's recent FDA approval for its lung cancer treatment combination involving Rybrevant and Lazcluze has marked a significant milestone but also introduced various challenges. The combination targets newly diagnosed non-small cell lung cancer (NSCLC) patients with specific EGFR mutations at exon 19 or exon 21. The company has a $5 billion peak sales target for this combination, aiming to challenge AstraZeneca’s Tagrisso, which currently dominates the first-line treatment for EGFR-mutant NSCLC with $5.8 billion in global sales in 2023.

The approval follows the phase 3 MARIPOSA trial, where the Rybrevant-Lazcluze combo reduced the risk of disease progression or death by 30% compared to Tagrisso. Patients on the Johnson & Johnson regimen showed a median progression-free survival of 23.7 months, versus 16.6 months for those on Tagrisso. These trial results were presented at the European Society for Medical Oncology congress in October 2023. Despite these promising statistics, industry experts and doctors are keen to see if the combination will extend overall patient survival, a critical factor for broader adoption of the treatment.

Johnson & Johnson is optimistic about achieving an overall survival benefit. The interim analysis of the MARIPOSA trial indicated a positive trend nearing statistical significance. If this survival advantage is confirmed, the company believes it could shift physician preference towards their combination, particularly for younger patients.

However, the treatment faces significant challenges. Unlike Tagrisso, which is administered as a single pill, Rybrevant requires an intravenous infusion, making it less convenient. Additionally, the combination has shown a higher rate of venous thromboembolism (VTE), a condition involving blood clots in veins. The MARIPOSA trial revealed a 10% treatment discontinuation rate due to adverse events for the combo, compared to 3% for Tagrisso.

To address these issues, Johnson & Johnson has developed a subcutaneous version of Rybrevant in collaboration with Halozyme. The phase 3 PALOMA-3 trial showed that subcutaneous Rybrevant achieved comparable tumor reduction to the IV version but significantly lowered infusion-related reactions (13% versus 66%). The administration time for the subcutaneous version was also reduced to approximately five minutes, compared to two to five hours for the IV version. Among patients on prophylactic anticoagulation, the rate of VTE for the subcutaneous version was 7%, closely matching the 9% seen in the Tagrisso group without anticoagulation in the MARIPOSA trial. For first-line usage, the FDA recommends anticoagulation for the initial four months of treatment to mitigate VTE risk.

Notably, subcutaneous Rybrevant demonstrated a statistically significant overall survival benefit over its IV counterpart in the PALOMA-3 second-line trial, potentially strengthening its competitive position against Tagrisso. Earlier this month, the FDA accepted Johnson & Johnson’s filing for subcutaneous Rybrevant under priority review.

Lung cancer experts have suggested that the subcutaneous version could improve Johnson & Johnson's standing in the first-line NSCLC market due to fewer infusion-related reactions and potentially reduced toxicity. Rybrevant, an EGFRxMET bispecific antibody, was initially approved for the less common exon 20 EGFR mutation in NSCLC. Lazcluze, a third-generation EGFR tyrosine kinase inhibitor, was first approved in South Korea under the brand name Laclaza, making it the first novel anti-cancer drug from Korea to receive FDA approval.

With this FDA approval, Johnson & Johnson has a promising yet challenging road ahead to establish Rybrevant and Lazcluze as a preferred treatment option in the competitive lung cancer landscape.