Efficacy and safety of first-line osimertinib monotherapy versus osimertinib plus platinum-based chemotherapy or amivantamab plus lazertinib in metastatic EGFR-mutated NSCLC: an indirect comparison

Background Osimertinib (Osi) has long represented the standard first-line treatment for metastatic EGFR-mutated non-small cell lung cancer. Recently, two randomized phase 3 trials demonstrated that osimertinib plus platinum-based chemotherapy (Osi+CT) and amivamtamab plus lazertinib (Ami+Laz) improve outcomes compared with Osi alone, although no direct comparison between these regimens are available. This study aimed to indirectly compare progression-free survival (PFS) and overall survival (OS). Materials and methods Three randomized clinical trials (FLAURA, FLAURA-2, and MARIPOSA) were included following PRISMA guidelines. Individual patient data (IPD) were reconstructed from Kaplan-Meier curves using the IPDfromKM algorithm. Hazard ratios (HR) with 95% confidence intervals (CI) and restricted mean survival time (RMST) were calculated for PFS and OS. Subgroup analyses were performed for patients with central nervous system (CNS) metastases and by EGFR mutation subtypes. A network meta-analysis was conducted to evaluate adverse drug reactions. Results In the indirect comparison, Osi+CT and Ami+Laz showed no statistical difference in terms of PFS (HR 0.79, 95% CI 0.61-1.04), with PFS-RMST estimates at 30 months numerically longer with Osi+CT (22.53 vs 20.59 months). No statistically significant differences in OS were observed between regimens (HR 0.95, 95% CI 0.73–1.22). Subgroup PFS analyses according to baseline CNS metastases and EGFR mutation subtypes showed no statistically conclusive differences between regimens. Safety profiles varied: Osi+CT was associated with higher rates of grade ≥ 3 hematologic and gastrointestinal toxicities, while Ami+Laz was linked to higher rates of dermatologic events, infusion-related reactions, hypoalbuminemia, and peripheral edema. Conclusions Despite the inherent limitations of indirect comparisons, these findings suggest that Osi+CT and Ami+Laz provide comparable survival benefits, while distinct toxicity profiles may influence therapeutic decision-making in conjunction with patients’ clinical characteristics and preferences.