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

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.