Impact of Incidental Germline BRCA1/2 and PALB2 Alterations on EGFR Monotherapy Real-World Outcomes for Patients With Advanced Non-Small-Cell Lung Cancer.

Several studies have sought to determine the prevalence of BRCA1/BRCA2 in patient populations, but few have studied impacts of such alterations on patient outcomes beyond breast, ovarian, prostate and pancreatic cancers. This study assessed patient outcomes from a large real-world evidence (RWE) database for patients with EGFR-mutated advanced non-small-cell lung cancer (aNSCLC) who also had incidental pathogenic germline variants (iPGVs) in BRCA1, BRCA2 or PALB2 identified by a well-validated liquid biopsy. Outcomes from patients included in GuardantINFORM, a RWE database, from Oct 2018-June 2024 with a diagnosis of aNSCLC and an incidental pathogenic germline variant (iPGV) in BRCA1/2 or PALB2 included in OncoKB treated with EGFR monotherapy (gBRCA/PALB2+) were matched in 1:5 using coarsened exact matching to a control cohort without iPGVs (control). Real-world time to treatment discontinuation (rwTTD) and real-world time to next treatment (rwTTNT) were used as proxies for PFS in months. Real-world overall survival (rwOS) was also assessed in months. 106 gBRCA+ patients were matched with 534 control patients for analysis. gBRCA/PALB2+ had numerically shorter rwTTD/rwTTNT (rwTTD: 11.5 vs. 13.9 months, P = .22; rwTTNT: 25.8 months vs. 32.1 months; P = .43). rwOS was 71.4 months for the gBRCA/PALB2+ group whereas the control group had a median of 57.4 months; limited-follow up reduced events available for analysis. Patients with gBRCA/PALB2+ aNSCLC treated with EGFR monotherapy may have subpar outcomes compared with control cohorts. Further research is required to understand the validity of this finding and inform clinical trial development for dual-target inhibition and/or patient selection.