Real-world outcomes of second-line carboplatin plus pemetrexed after first-line osimertinib in EGFR-mutant advanced NSCLC: An international multicentre cohort study

Background: First-line osimertinib is one of the standards of care for EGFR-mutant advanced non-small cell lung cancer (NSCLC), but most patients eventually progress. After progression, carboplatin plus pemetrexed remains the most widely used second-line therapy, yet robust real-world data in this setting are scarce. Methods: We conducted a retrospective multicentre cohort study from four European countries in patients with EGFR-mutant advanced NSCLC who received second-line carboplatin plus pemetrexed following osimertinib. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), safety, and exploratory analyses of associations between baseline factors and outcomes. Results: We identified a total of 252 patients. Median PFS and OS were 5.3 months (95 % CI 4.7–5.9) and 9.6 months (95 % CI 8.2–11.1), respectively. The ORR was 40.7 %, with grade ≥ 3 adverse events reported in 19.3 % of patients. ECOG ≥ 2 and liver metastases independently predicted worse OS; ECOG ≥ 2 and a history of smoking were associated with shorter PFS. Early progression on osimertinib (<18 months) correlated with shorter OS (8.3 vs 14.7 months; HR 1.66, P = 0.005). Neither the timing between osimertinib discontinuation and chemotherapy initiation nor EGFR mutation subtype influenced efficacy. Conclusions: In real-world European practice, second-line carboplatin plus pemetrexed provides modest benefit post-osimertinib, with outcomes strongly influenced by ECOG status, metastatic burden, and prior osimertinib duration. Despite a clinically diverse cohort, outcomes were consistent with historical reports. These data help define benchmarks for future trials and underscore the need for personalised sequencing strategies, particularly in high-risk subgroups.