Real-World Eligibility for FLAURA, FLAURA2, and MARIPOSA in Patients with EGFR-Mutated Advanced NSCLC: A Retrospective Single-Center Study

Introduction: First-line treatment options for EGFR-mutated NSCLC have expanded beyond osimertinib monotherapy following the FLAURA2 and MARIPOSA trials, which demonstrated improved long-term outcomes with combination strategies, albeit with increased toxicities. Given that randomized controlled trials (RCTs) typically enroll highly selected patients (pts), evaluating the representativeness of these cohorts in real-world (RW) practice is essential to inform RCT applicability. Methods: We retrospectively identified patients with EGFR-mutated advanced NSCLC treated with first-line osimertinib at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, between January 2019 and August 2025. Clinical characteristics were collected, and eligibility for FLAURA, FLAURA2, and MARIPOSA was assessed according to the respective trial criteria. For survival analyses, patients were classified as trial-eligible or trial-ineligible according to FLAURA eligibility criteria, as all patients received first-line osimertinib. Results: Overall, 135 pts were included in the analysis; median age was 67 years (IQR 57–76), 17% had ECOG PS 2, and 11% harbored uncommon EGFR mutations. Only 31 patients (23%) met eligibility criteria for all three trials, whereas 91 (67%) were ineligible for all. The most frequent exclusion criteria included symptomatic CNS disease or spinal cord compression, ECOG PS 2, and EGFR mutation assessment by cytology or liquid biopsy. Both real-world progression free survival (rwPFS) and overall survival (OS) were numerically longer in trial-eligible than trial-ineligible patients (20.1 vs. 18.2 months and 29.9 vs. 22.3 months, respectively). Patients with negative prognostic characteristics such as ECOG PS ≥ 2, uncommon EGFR mutations, and liver metastases had significantly shorter OS, while other predefined risk factors showed only numerical trends. Conclusions: A substantial proportion of patients treated with first-line osimertinib in routine practice would not have met the eligibility criteria of pivotal EGFR-mutated NSCLC trials. Trial-ineligible patients had numerically shorter survival, likely reflecting adverse baseline characteristics. These findings highlight the limitations of direct extrapolation of RCT results to real-world populations.