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

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.