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Clinical factors and molecular co-alterations impact outcomes in patients receiving first-line osimertinib for EGFR-mutated non-small cell lung cancer.

Clinical factors and molecular co-alterations impact outcomes in patients receiving first-line osimertinib for EGFR-mutated non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Sun, F., Banwait, M. K., Singhal, S., Herrmann, A., Piotrowska, Z., Yun, K., Bazhenova, L., Ullah, A. T., Guo, E. W., Wakelee, H. A., Neal, J. W., Das, M. S., Ramchandran, K. J., Roy, M., Diehn, M., Myall, N. J. 2025; 208: 108747

Abstract

Until recently, osimertinib was the preferred first-line therapy for nearly all patients with EGFR-mutated advanced NSCLC. However, with approval of the FLAURA2 and MARIPOSA regimens, identifying molecular or clinical factors that confer higher risk for inferior outcomes to first-line osimertinib may better inform upfront treatment selection for newly-diagnosed patients.This real-world, multicenter retrospective study across 4 U.S. academic centers included adult patients with metastatic NSCLC and classic sensitizing EGFR mutations (exon 19 deletion, L858R mutation) receiving first-line osimertinib monotherapy who had tissue-based next-generation sequencing performed at diagnosis. Survival analyses for time-to-treatment discontinuation (TTD) on osimertinib and overall survival (OS) were conducted by number of co-alterations, individual gene alterations, previously defined molecular pathways, and clinical factors.A total of 219 patients were included (median age 68, 62 % female, 51 % with baseline CNS metastases). TP53 was most frequently co-altered (58 %), followed by EGFR amplification (13 %), CDKN2A (10 %), RB1 (9 %), and PIK3CA (8 %). Number of de novo co-alterations and presence of co-alterations by molecular pathway did not significantly predict TTD or OS. Co-alteration of both TP53 and PIK3CA, but not TP53 alone, demonstrated significantly shorter median OS compared to the TP53 and PIK3CA wild-type population (21.9 vs 39.5 months, p = 0.046), with similar numerical trend for median TTD. On multivariate analysis, L858R mutation and CNS and bone metastases remained significant predictors for inferior clinical outcomes.Co-alteration of TP53 and PIK3CA may represent a high-risk molecular subgroup of EGFR-mutated NSCLC, however both clinical and molecular features should be considered in risk stratification.

View details for DOI 10.1016/j.lungcan.2025.108747

View details for PubMedID 40957338