First-line osimertinib in advanced EGFR-mutated NSCLC: real-world outcomes, clinicogenomic correlates, and oligoprogression management in a multicenter Spanish cohort

Background First-line osimertinib is standard for advanced EGFR -mutated non-small-cell lung cancer (NSCLC), but upfront combinations (FLAURA2, MARIPOSA) are reshaping this paradigm. Trial practice gaps and the optimal management of oligoprogressive disease (OPD) remain unclear. We evaluated real-world effectiveness, progression patterns, and the role of local ablative therapy (LAT) in a Western European cohort. Patients and methods Multicenter retrospective cohort from eastern Spain including patients with advanced EGFR -mutated NSCLC treated with first-line osimertinib. Outcomes were objective response rate (ORR), real-world progression-free survival (rwPFS), real-world overall survival (rwOS) and access to second-line therapy. Prespecified analyses examined exon 19 deletion versus p.Leu858Arg, baseline central nervous system metastases, OPD treated with LAT while continuing osimertinib, re-biopsy at progression, and time toxicity. Results Among 268 patients, median age was 72 years, 27.6% had Eastern Cooperative Oncology Group performance status ≥2, and 42.5% had brain metastases. Osimertinib achieved an ORR of 73.5%, rwPFS of 17.5 months, and rwOS of 28.1 months, but only 50.1% of patients who progressed initiated second-line therapy. Among 180 patients with documented progression, 51 (28.3%) had OPD and 82.4% received LAT. Exploratory analyses suggested clinically meaningful improvements in median PFS and median OS versus the overall cohort. Re-biopsy identified resistance mechanisms (e.g. MET amplification, small-cell transformation), and time toxicity measures were modest. Conclusions In routine practice, first-line osimertinib shows robust effectiveness but lower rwOS than expected and substantial post-progression attrition. These findings underscore the need for risk-adapted treatment strategies and support prospective evaluation of OPD management approaches, including integration of LAT alongside contemporary systemic options.