ORCHARD final data: osimertinib plus gefitinib gives modest benefit in EGFR C797X, and the authors advise against further study

Background

Osimertinib is standard first-line treatment for EGFR-mutated advanced non-small cell lung cancer (NSCLC), and the disease eventually progresses in most patients who receive it. EGFR C797X is a known resistance mechanism to osimertinib: the substitution affects the cysteine residue that osimertinib binds covalently, which is the rationale that has been proposed for pairing it with a reversible inhibitor such as gefitinib. ORCHARD evaluated resistance mechanisms after first-line osimertinib and the therapies given after progression.

Study design

ORCHARD is a phase II, open-label study in patients with EGFR-mutated advanced NSCLC and progressive disease on first-line osimertinib. In the module reported here, patients with EGFR C797X received osimertinib 80 mg once daily plus gefitinib 250 mg once daily, continued until progressive disease, unacceptable toxicity, or another discontinuation criterion was met. The primary endpoint was objective response rate assessed by the investigator according to RECIST 1.1.

Findings

Thirty-one patients were treated and were evaluable for response and safety at the data cutoff of 10 May 2024. Eight patients had a partial response, for a confirmed objective response rate of 26% (80% CI 16 to 39). The median duration of response was 4.2 months (95% CI 2.8 to 5.5).

By the cutoff, 30 patients (97%) had a progression-free survival event and 19 patients (61%) had died. Median progression-free survival was 5.1 months (95% CI 3.9 to 6.8) and median overall survival was 19.0 months (95% CI 14.6 to 25.0).

Safety

Eleven patients (35%) had grade 3 or higher adverse events. The authors reported that safety was consistent with the known adverse-event profiles of osimertinib and gefitinib given individually, with no new safety signals.

Resistance after the combination

Several resistance mechanisms were identified in patients who progressed on osimertinib plus gefitinib, including EGFR T790M, BRAF and PIK3CA mutations.

What comes next

The authors concluded that osimertinib plus gefitinib demonstrated modest clinical benefit in patients with EGFR C797X identified after progression on first-line osimertinib, and that the risk-benefit profile indicates further evaluation of this regimen in this population is not warranted.