Durvalumab plus etoposide–platinum in patients with epidermal growth factor receptor (EGFR)-mutated advanced NSCLC and neuroendocrine transformation after first-line osimertinib: ORCHARD

Abstract

Background: ORCHARD (NCT03944772) was an open-label, phase 2 platform study that evaluated resistance mechanisms and post-progression treatments 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 module investigating durvalumab plus etoposide–platinum in patients with neuroendocrine transformation to small cell lung cancer or large cell neuroendocrine carcinoma. Methods: Patients received durvalumab 1,500 mg intravenously every three weeks (Q3W) plus etoposide–platinum Q3W for up to four cycles. Durvalumab continued until PD, unacceptable toxicity or another discontinuation criterion was met. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary endpoints were progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. Results: Fourteen patients received treatment and were evaluable for efficacy/safety (data cutoff: January 21, 2025). Confirmed ORR was 43 % (80 % confidence interval [CI]: 24–63) (six partial responses). Median duration of response was 4.3 months (95 % CI: 3.0–not calculable); one patient had a response lasting 10 months. Progression-free survival (PFS) events were observed in 13 patients (93 %) and 11 patients (79 %) died. Median PFS was 4.2 months (95 % CI: 3.0–5.6) and median overall survival was 10.2 months (95 % CI: 4.3–16.8). Nine patients (64 %) reported grade ≥3 adverse events (AEs), most commonly neutropenia and decreased neutrophil count (four patients each), and one patient discontinued all three study drugs due to an AE (not treatment-related). Conclusions: Durvalumab plus etoposide–platinum demonstrated a modest treatment response in neuroendocrine-transformed EGFR-mutated NSCLC. AEs were concordant with the known safety profiles of the combination, and no new safety signals were observed. Trial registration: ClinicalTrials.gov, NCT03944772.