Johnson & Johnson's combination therapy of Rybrevant (amivantamab) and Lazcluze (lazertinib) has demonstrated a significant overall survival benefit compared to AstraZeneca's Tagrisso (osimertinib) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). This finding, from the Phase 3 MARIPOSA trial, suggests a potential shift in the standard of care for this patient population.
The MARIPOSA trial, a head-to-head study, involved nearly 1,100 patients with previously untreated locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitutions. The results indicated that patients receiving the Rybrevant and Lazcluze combination lived significantly longer than those treated with Tagrisso alone. J&J anticipates the combination to extend median overall survival by at least one year more than Tagrisso.
Clinical Significance
"This is an absolute game changer," said Biljana Naumovic, president of U.S. Oncology Solid Tumor at Johnson & Johnson Innovative Medicine. The observed survival improvement is considered clinically meaningful and statistically significant, meeting the study's pre-specified secondary endpoint. This outcome could lead to wider adoption of the J&J regimen as a first-line treatment option.
Tagrisso, a third-generation EGFR tyrosine kinase inhibitor, has been a cornerstone in the treatment of EGFR-mutated NSCLC. AstraZeneca's FLAURA trial previously demonstrated a median overall survival of nearly 39 months with Tagrisso. The new data from MARIPOSA suggests that the Rybrevant/Lazcluze combination can further extend survival in this patient population.
Mechanism of Action
Rybrevant is a bispecific antibody targeting both EGFR and MET, while Lazcluze is an oral third-generation EGFR tyrosine kinase inhibitor. This dual-targeting approach addresses a common mechanism of resistance to EGFR inhibitors, potentially leading to more durable responses.
Challenges and Considerations
Despite the promising results, the Rybrevant/Lazcluze regimen presents some challenges. In the MARIPOSA trial, 10% of patients discontinued therapy due to side effects, compared to 3% in the Tagrisso arm. The combination was also associated with a higher incidence of venous thromboembolism, prompting the FDA to require prophylactic anticoagulation during the initial months of treatment. Furthermore, Rybrevant requires intravenous infusions every two weeks after a lead-in period, whereas Tagrisso is administered orally once daily.
Competition and Future Directions
AstraZeneca has also explored combining Tagrisso with chemotherapy in the first-line setting. Data from the FLAURA2 trial demonstrated a benefit in progression-free survival with the addition of chemotherapy, providing an alternative strategy for managing EGFR-mutated NSCLC. The optimal sequencing and combination strategies for EGFR-targeted therapies remain an area of active investigation.
J&J has filed a subcutaneous version of Rybrevant with the FDA, which, if approved, could mitigate some of the administration challenges associated with the intravenous formulation. This subcutaneous version demonstrated improved patient convenience and a reduced risk of clotting in the PALOMA-3 trial.
Market Impact
J&J anticipates peak annual sales of Rybrevant exceeding $5 billion. The overall survival data from MARIPOSA could significantly impact the treatment landscape for EGFR-mutated NSCLC, potentially shifting market share from Tagrisso to the Rybrevant/Lazcluze combination. However, the ultimate adoption will depend on a comprehensive assessment of efficacy, safety, and patient convenience.
