Osimertinib plus Gefitinib in Patients with EGFR -Mutated Advanced Non–Small Cell Lung Cancer and EGFR (C797X) Mutation Following First-Line Osimertinib: ORCHARD

Abstract Purpose: ORCHARD (NCT03944772) was a phase II, open-label study evaluating resistance mechanisms and postprogression therapies in patients with epidermal growth factor receptor (EGFR)–mutated advanced non–small cell lung cancer (NSCLC) with progressive disease (PD) on first-line osimertinib. We report final data from the osimertinib plus gefitinib module in patients with EGFR C797X, a known resistance mechanism to osimertinib. Patients and Methods: Patients received once-daily osimertinib 80 mg plus gefitinib 250 mg until PD, unacceptable toxicity, or another discontinuation criterion. The primary endpoint was objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumors 1.1. Results: Thirty-one patients were treated and evaluable for response/safety (data cutoff: May 10, 2024). Eight patients had a partial response, for a confirmed ORR of 26% [80% confidence interval (CI), 16–39]; the median duration of response was 4.2 months (95% CI, 2.8–5.5). Thirty patients (97%) experienced a progression-free survival (PFS) event, and 19 patients (61%) died. Median PFS was 5.1 months (95% CI, 3.9–6.8), and median overall survival was 19 months (95% CI, 14.6–25). Eleven patients (35%) had grade ≥3 adverse events. Safety was consistent with the known adverse event profiles of the individual drugs, with no new safety signals. Several resistance mechanisms (EGFR T790M, BRAF, and PIK3CA mutations) were identified following PD on osimertinib–gefitinib. Conclusions: Osimertinib–gefitinib demonstrated modest clinical benefit in patients with EGFR-mutated advanced NSCLC harboring an EGFR C797X mutation identified following PD on first-line osimertinib. The risk–benefit profile indicates that further evaluation of this regimen is not warranted in this population.