A landmark international Phase 3 trial published in The New England Journal of Medicine has demonstrated that combining osimertinib with platinum-based chemotherapy and pemetrexed significantly improves overall survival in patients with EGFR mutated advanced non-small cell lung cancer compared with osimertinib alone.
Osimertinib, a third generation EGFR tyrosine kinase inhibitor, selectively targets key EGFR mutations including T790M, L858R, and exon 19 deletions commonly found in NSCLC. Its high specificity, with approximately 200-fold greater affinity for mutant EGFR over wild type receptors, helps reduce off target toxicity and overcome resistance seen with earlier generation TKIs.
The findings come from the FLAURA2 global study, which enrolled 557 previously untreated patients harboring either EGFR exon 19 deletion or L858R mutation. Participants were randomized to receive either osimertinib monotherapy (80 mg daily) or osimertinib in combination with cisplatin or carboplatin and pemetrexed. After extended follow up, the combination therapy achieved a median overall survival of 47.5 months compared with 37.6 months for osimertinib alone, representing a 23% reduction in the risk of death (hazard ratio 0.77; 95% CI, 0.61–0.96; P = 0.02). These results indicate a meaningful survival advantage with the addition of chemotherapy in the first line setting for EGFR mutated NSCLC.
While the combination approach improved outcomes, it was associated with higher toxicity. Grade 3 or higher adverse events occurred in 70% of patients receiving the combination compared with 34% in the monotherapy arm. Treatment discontinuation due to side effects was 12% with combination therapy compared with 7% with osimertinib alone. Most adverse effects were reversible and manageable with appropriate supportive care.
Supporting evidence from recent studies, including work by Sampath and colleagues, suggests that combining osimertinib with consolidative radiotherapy is both safe and effective, offering a potentially less complex alternative to multi agent targeted regimens. Ongoing randomized trials are expected to further validate this approach.
Currently, osimertinib remains the standard of care for EGFR mutated advanced NSCLC. However, the FLAURA2 results may redefine first line treatment, particularly for patients with aggressive disease or high tumor burden. Experts anticipate these findings will influence future clinical guidelines and precision oncology strategies, expanding the role of combination therapy in this patient population.
Reference:
- Jänne PA, Planchard D, Kobayashi K, Yang JCH, Liu Y, Valdiviezo N, et al. Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC. New England Journal of Medicine [Internet]. [cited 2025 Oct 18];0(0). Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2510308
- Osimertinib [Internet]. [cited 2025 Oct 18]. Available from: https://go.drugbank.com/drugs/DB09330
- Sampath S, Rashdan S, Iyengar P, Mickel TA, Zhang S, Ahn C, et al. Osimertinib plus consolidative radiotherapy for advanced EGFR mutant non–small cell lung cancer: a multicentre, single-arm, phase 2 trial. eClinicalMedicine [Internet]. 2025 Sept 1 [cited 2025 Oct 18];87. Available from: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00367-0/fulltext