Osimertinib Plus Selumetinib Shows Limited Activity Following First-Line Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer
Clinical Summary:
- Design/Population: A phase 2 module of the ORCHARD platform study evaluated osimertinib plus selumetinib in patients with EGFR-mutated advanced non-small cell lung cancer harboring BRAF alterations following disease progression on first-line osimertinib.
- Key Outcomes: The combination demonstrated minimal clinical activity, with a low objective response rate, and short median progression-free survival. The safety profile was consistent with the known toxicities of the individual agents.
- Clinical Relevance: These findings do not support further evaluation of osimertinib plus selumetinib in patients with BRAF-altered, EGFR-mutated NSCLC after progression on first-line osimertinib.
Results from a phase 2 module of the ORCHARD study demonstrated that osimertinib plus selumetinib showed limited efficacy among patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) harboring acquired BRAF alterations following disease progression on first-line osimertinib.
“ORCHARD was a phase 2, biomarker-matched, platform study designed to characterise resistance mechanisms and evaluate novel drug combinations in patients with EGFR-mutated advanced NSCLC following disease progression on first-line osimertinib,” stated Zofia Piotrowska, MD, Massachusetts General Hospital, Boston, Massachusetts, and coauthors. Here, “we report final results of the module assessing the efficacy and safety of osimertinib plus selumetinib (a MEK inhibitor) in patients with BRAF alterations.”
In this treatment module, 16 patients with BRAF V600E mutations or BRAF fusions received 80 mg of once daily osimertinib plus 75 mg of twice daily selumetinib until disease progression or unacceptable toxicity. The primary end point was investigator-assessed objective response rate (ORR). Key secondary end points included progression-free survival (PFS), overall survival (OS), and safety.
At the data cutoff point, 100% of patients had discontinued study treatment. The confirmed ORR was 7%, with only 1 partial response. Median PFS was 3.4 months, and median OS was 14 months.
No new safety signals were identified and the overall safety profile was consistent with the known toxicities of osimertinib and selumetinib. Grade ≥ 3 adverse events were reported in 69% of patients, most frequently including diarrhea (19%).
“Osimertinib plus selumetinib demonstrated minimal response in patients with EGFR-mutated advanced NSCLC with BRAF alterations following disease progression on first-line osimertinib,” concluded Dr Piotrowska et al. “Overall, the risk-benefit profile suggests further evaluation of this combination is not warranted.”
Source:
Piotrowska Z, Goldberg SB, Goldman JW, et al. Osimertinib plus selumetinib in patients with EGFR-mutated advanced NSCLC with BRAF alterations post-progression on first-line osimertinib: ORCHARD. Eur J Cancer. Published online: May 18, 2026. doi:10.1016/j.ejca.2026.116807
