The first results of the Study to Evaluate Chemotherapy Plus Osimertinib Against Chemotherapy Plus Placebo in Patients With Non-small Cell Lung Cancer (NSCLC) (COMPEL) trial suggest that osimertinib is a beneficial therapy for epidermal growth factor receptor (EGFR)-mutated NSCLC through multiple lines of therapy.1 The data show patients with EGFR-mutated NSCLC who experienced disease progression on first-line osimertinib showed improved progression-free survival (PFS) and longer overall survival (OS) with osimertinib plus platinum-based chemotherapy vs placebo plus chemotherapy. This was determined based on a descriptive analysis and was not the result of formal hypothesis testing due to reduced sample size.
“There are reasons to continue osimertinib beyond progression: to prolong clinical benefit in case of oligoprogression, to avoid tumor flare-up after osimertinib discontinuation, to maintain disease control in the central nervous system, and maybe also to target cells retaining some sensitivity to osimertinib due to tumor heterogeneity,” said Maurice Pérol, MD, Head of Thoracic Oncology at Centre Léon Bérard, Lyon, France.
Dr. Pérol commented on the trial, which was first presented at the 2025 World Conference on Lung Cancer in September.
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) and preferred treatment for first-line EGFR-mutated NSCLC. However, most patients eventually progress on osimertinib, Dr. Pérol added, and platinum-based chemotherapy plus amivantamab is another treatment option.
“Progression on first-line osimertinib may be heterogeneous, with some cells retaining EGFR signal [dependence] and sensitivity to EGFR TKIs,” said investigator Giula Pasello, MD, PhD, Associate Professor of Oncology at the University of Padova, Padova, Italy. “The combination of osimertinib and platinum-based chemotherapy has shown a manageable safety profile and is currently approved as a first-line treatment for this patient population based on findings of the FLAURA2 study.”
The COMPEL trial randomized 98 patients with locally advanced or metastatic EGFR-mutated NSCLC globally to osimertinib plus chemotherapy vs placebo plus chemotherapy. About a quarter of patients had central nervous system (CNS) metastases at baseline.
The primary end point was PFS as assessed by investigators. Secondary end points included CNS PFS, non-CNS PFS, and OS.
Median PFS in all patients with osimertinib plus chemotherapy was 8.4 months (95% CI, 5.7-11.8 months) vs 4.4 months (95% CI, 3.5-5.6 months) for chemotherapy alone (HR, 0.43; 95% CI, 0.27-0.70). PFS improved in patients without CNS metastases at baseline, and patients on combination therapy had fewer new brain lesions—10% vs 27% for those on chemotherapy alone. The COMPEL trial adds to existing evidence supporting osimertinib’s protective effects in the CNS and suggests that the benefit of combination therapy extends beyond the CNS.
Adverse events were virtually universal, 98% in both arms, with grade 3 and higher events more common in the combination therapy arm at 63% vs 46% for chemotherapy alone. The most common adverse events included anemia, asthenia, and nausea. Safety findings were consistent with the known profiles of each drug in the study.
“Results from this study support continuing osimertinib as a backbone treatment for EGFR-mutated, advanced [NSCLC] through lines of therapy,” Dr. Pasello concluded.
References
1. Peled N, Tufman A, Sequist LV, et al. COMPEL: osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC and progression on first-line osimertinib. ESMO Open. 2025;10(10):105807. Preprint. Posted online September 9, 2025. doi:10.1016/j.esmoop.2025.105807
