September 17, 2026 | OncLive Staff
The frequency of treatment-related adverse effects (TRAEs) declined progressively across three mutually exclusive treatment periods among patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) who received osimertinib (Tagrisso) plus platinum-pemetrexed, according to a post-hoc analysis of the phase 3 FLAURA2 trial (NCT04035486) presented in a poster session at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).1
Among the 276 patients in the combination arm who received at least 1 dose of osimertinib and at least 1 dose of platinum-pemetrexed, TRAEs of any grade occurred in 93% of patients during the induction period (grade ≥3, 43%), 90% during the pemetrexed-maintenance period (grade ≥3, 25%), and 58% during the osimertinib-only period (grade ≥3, 14%). At a median follow-up of 42.6 months (range, 0.1-60.4), the median duration of the induction, pemetrexed-maintenance, and osimertinib-only periods was 2.8 (range, 0.1-4.1), 12.4 (range, 0.7-56.1), and 17.8 (range, 0.4-56.8) months, respectively.
Previously reported findings from FLAURA2 showed that adding platinum-pemetrexed to osimertinib significantly improved progression-free survival (PFS; HR, 0.62; 95% CI, 0.49-0.79; P < .001)2 and overall survival (OS; HR, 0.77; 95% CI, 0.61-0.96; P = .02)3 compared with osimertinib monotherapy. Median osimertinib exposure was longer with the combination than with monotherapy (30.5 vs 21.2 months), and the combination arm exhibited an extended osimertinib-only treatment period.3
How was the post-hoc safety analysis conducted?
Because the number and type of treatments patients received changed over the course of FLAURA2, investigators characterized safety according to 3 mutually exclusive periods defined by patient-level treatment exposure: induction (osimertinib plus platinum and pemetrexed), pemetrexed-maintenance (osimertinib plus pemetrexed), and osimertinib-only.1 AEs were coded using MedDRA version 27.1 and graded for severity per CTCAE version 5.0, with events reported according to maximum severity. AEs of clinical interest were selected based on the most frequently reported events in FLAURA2 and on toxicities that overlap between osimertinib and platinum-pemetrexed; AEs indicative of fatigue, venous thromboembolic events, and febrile neutropenia were also assessed. The data cutoff for this analysis was June 12, 2025.
Of the 276 patients evaluated, 276, 201, and 206 were assessed during the induction, pemetrexed-maintenance, and osimertinib-only periods, respectively. Most patients (n = 201 of 276) transitioned from induction into pemetrexed maintenance, with 143 of those patients subsequently moving into the osimertinib-only period; an additional 63 patients transitioned directly from induction to osimertinib-only treatment.
What did the analysis show for AEs of clinical interest?
Onset frequencies of AEs indicative of anemia, neutropenia, and thrombocytopenia were highest during the induction period, with total incidences of 38%, 35%, and 29%, respectively, and each declining in the pemetrexed-maintenance (25%, 28%, and 15%) and osimertinib-only periods (11%, 13%, and 9%). Grade 3 hematologic AEs were common during induction, grade 4 events were infrequent, and no grade 5 events were reported in any category.
AEs indicative of gastrointestinal and skin/nail toxicity followed a similar pattern, with the highest onset frequencies during induction. For example, diarrhea (32%), nausea (37%), and rash (41%), which declined markedly by the osimertinib-only period. These events were predominantly grade 1 or 2, with few grade 3 events and none of grade 4 or 5.
Onset frequency of AEs indicative of renal toxicity, by contrast, was higher during the pemetrexed-maintenance period (19%) than during induction (7%) or the osimertinib-only period (10%). Renal AEs were predominantly grade 1 or 2, with only a single grade 3 event, reported during induction, and no grade 4 or 5 events.
What were the findings on discontinuation and dose modifications?
Onset frequencies of AEs leading to osimertinib discontinuation were consistently low throughout the study, at 4%, 3%, and 8% during the induction, pemetrexed-maintenance, and osimertinib-only periods, respectively. Onset frequencies of AEs leading to osimertinib dose reduction were similarly low across all periods, at 5%, 3%, and 4%. AEs leading to platinum dose reduction occurred in 18% of patients during induction, and AEs leading to pemetrexed dose reduction occurred in 17% and 14% of patients during the induction and pemetrexed-maintenance periods, respectively.
What are the clinical implications of these findings?
Investigators concluded that characterizing safety according to individual treatment exposure provides clinically meaningful insight into the longitudinal safety of the FLAURA2 regimen that can support informed treatment decisions, patient counseling, and shared decision-making throughout a patient’s treatment course. With prolonged treatment, the frequency of grade 3 or higher AE onset declined progressively across successive treatment periods, and AE profiles remained consistent with the known safety profiles of osimertinib, platinum agents, and pemetrexed individually. A separate post-hoc analysis of FLAURA2 presented at the same meeting showed that the PFS and OS benefit of osimertinib plus platinum-pemetrexed over osimertinib monotherapy was maintained regardless of baseline TP53 mutation status.4 Together with previously reported survival outcomes, the investigators noted that these long-term safety findings continue to support osimertinib plus platinum-pemetrexed as a preferred first-line treatment option for patients with EGFR-mutated advanced NSCLC.1
References
Lee CK, Jänne PA, Yang JC-H, et al. Long-term safety outcomes with osimertinib plus platinum-pemetrexed in EGFR-mutated advanced NSCLC: FLAURA2. Presented at: 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, Republic of Korea. Abstract PT2.03.03.
Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948.
Jänne PA, et al. Overall survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):27-38.
FLAURA2 Data Show Osimertinib-Chemotherapy Benefit Holds Regardless of Baseline TP53 Status in EGFR+ NSCLC. OncLive. Published September 15, 2026. Accessed September 16, 2026. https://www.onclive.com/view/flaura2-data-show-osimertinib-chemotherapy-benefit-holds-regardless-of-baseline-tp53-status-in-egfr-nsclc
