Long-term safety of first-line osimertinib plus platinum-pemetrexed in EGFR-mutated advanced NSCLC: FLAURA2.

Abstract

In the phase 3 FLAURA2 trial (NCT04035486), adding platinum-pemetrexed to first-line osimertinib significantly improved survival versus osimertinib monotherapy. We report a long-term longitudinal safety analysis, including incidence and temporal patterns of treatment-emergent adverse events (AEs). Patients with EGFR-mutated advanced NSCLC were randomized to either osimertinib plus platinum-pemetrexed (for four cycles, followed by osimertinib plus pemetrexed maintenance), or osimertinib monotherapy. A post-hoc analysis of the combination arm, tailored to individual patients' exposure to each study treatment, was conducted to characterize the safety of three distinct treatment periods: induction (triple-combination therapy; n = 276), pemetrexed-maintenance (osimertinib-plus-pemetrexed; n = 201), and osimertinib-only (n = 206). In the combination arm, median (range) duration of each period was 2.8 (0.1-4.1), 12.4 (0.7-56.1), and 17.8 (0.4-56.8) months, respectively. Onset frequency of any-grade/grade ≥ 3 AEs causally related to treatment was highest during induction (93%/43%), decreasing progressively across the pemetrexed-maintenance (90%/25%) and osimertinib-only (58%/14%) periods. New AEs indicative of hematological, gastrointestinal, and skin/nail toxicity (mostly grade 1/2) were reported most frequently during induction, with reductions in frequency thereafter. Onset frequency of AEs indicative of renal toxicity was higher during pemetrexed maintenance (19%; all grade 1/2) than induction (7%; one grade 3). Rates of AEs leading to osimertinib discontinuation were low across periods (≤8%). By characterizing safety according to individual treatment exposure, this novel analysis provides insight into the longitudinal safety of the FLAURA2 regimen. With prolonged treatment, grade ≥ 3 AE onset frequency progressively declined over successive treatment periods, while AE profiles remained consistent with the known safety profiles of the individual agents. Median durations of the pemetrexed-maintenance and osimertinib-only periods exceeded 12 and 17 months, respectively. This reinforces the favorable long-term benefit-risk profile of the FLAURA2 regimen. gov: NCT04035486.