COMPEL: Osimertinib+Platinum-Based Chemotherapy in Patients with EGFRm Advanced NSCLC and Progression on 1L Osimertinib

Introduction: Osimertinib is a 3 rd generation, CNS-active EGFR-TKI that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations, and is a preferred 1L treatment for EGFR-mutated NSCLC. Despite the clinical benefits of osimertinib and its protective effects against CNS progression, disease progression occurs in most patients. COMPEL (NCT04765059) was a global, randomised, double-blind study that evaluated the benefits of osimertinib+chemotherapy (CTx) vs placebo+chemotherapy (CTx) in patients with EGFRm advanced NSCLC, following extracranial progression on 1L osimertinib. Methods: Adult patients progressing on 1L osimertinib without CNS progression were randomised 1:1 to receive either osimertinib 80 mg QD or placebo QD in combination with CTx (cisplatin 75 mg/m 2 or carboplatin AUC5+pemetrexed 500 mg/m 2 for 4 cycles Q3W), followed by osimertinib 80 mg QD or placebo QD in combination with maintenance pemetrexed (500 mg/m 2 Q3W) until progression or another discontinuation criterion was met. The primary endpoint was PFS. Results: Overall, 98 patients were randomised, of whom 48 in each arm received treatment. Baseline characteristics were generally similar between treatment arms. Median PFS was 8.4 months (m) (95% CI 5.7, 11.8) with osimertinib+CTx vs 4.4 m (95% CI 3.5, 5.6) with placebo+CTx; HR 0.43 (95% CI 0.27, 0.70). Median OS was 15.9 m (95% CI 12.4, 20.8) with osimertinib+CTx vs 9.8 m (95% CI 8.4, 17.2) with placebo+CTx; HR 0.71 (95% CI 0.42, 1.23). The most frequent Grade≥3 AE were anaemia (13% vs 13%), neutropenia (15% vs 4%), neutrophil count decreased (10% vs 6%) and wbc count decreased (10% vs 4%), in the osimertinib+CTx vs placebo+CTx arms, respectively. Conclusions: In patients with extracranial disease progression on 1L osimertinib, COMPEL demonstrated a PFS benefit with continued osimertinib+CTx vs placebo+CTx, and a positive trend towards improvement in OS. These results suggest that resistance to 1L osimertinib is heterogeneous, with some clonal tumour cells maintaining sensitivity for longer periods. The combination of osimertinib+CTx had a manageable safety and tolerability profile, consistent with the individual safety profiles for each drug. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany