Osimertinib plus selumetinib in patients with EGFR-mutated advanced NSCLC with BRAF alterations post-progression on first-line osimertinib: ORCHARD

Background ORCHARD (NCT03944772) was a phase II, biomarker-matched, platform study designed to characterise resistance mechanisms and evaluate novel drug combinations in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) following disease progression on first-line osimertinib. We report final results of the module assessing the efficacy and safety of osimertinib plus selumetinib (a MEK inhibitor) in patients with BRAF alterations. Methods Patients with BRAF fusions or BRAF V600E mutations received osimertinib 80 mg once daily plus selumetinib 75 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Results Overall, 16 patients received osimertinib plus selumetinib. At data cut-off, (25 November 2024) all patients had discontinued study treatment. The ORR was 7 % (80 % confidence interval [CI], ' 1–25); one patient had a partial response. Median PFS was 3.4 months (95 % CI, 1.3–5.4) and median OS was 14.0 months (95 % CI, 6.2–not calculable). Eleven patients (69 %) had grade ≥ 3 adverse events, most commonly diarrhoea (19 %). Conclusion Osimertinib plus selumetinib demonstrated minimal response in patients with EGFR -mutated advanced NSCLC with BRAF alterations following disease progression on first-line osimertinib. The safety profile of the combination was consistent with the known profiles of the two individual drugs; no new safety signals were identified. Overall, the risk–benefit profile suggests further evaluation of this combination is not warranted.