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

Autores de IIS La Fe

• Guillermo Suay Montagud

  Autor

• Patricia Capdevila Gaudens

  Autor

• Francisco De Asís Aparisi Aparisi

  Autor

• Óscar José Juan Vidal

  Autor

Participantes ajenos a IIS La Fe

• Cases-Esteban S.
• García-Márquez A.
• Garde-Noguera J.
• Espinosa-Olarte P.
• Arnal M.
• Sandiego-Contreras S.
• Escoin-Pérez C.
• Martín-Martorell P.
• García J.
• Blasco-Cordellat A.
• Blasco-Mollá S.
• Benítez-Fuentes J.D.
• Ávila-Andrade C.D.
• Borregón M.

Grupos

• Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Abstract

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. © 2026 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/

Keywords

• EGFR; local ablative therapy; NSCLC; oligoprogression; osimertinib; real-world evidence