Phase II study of 1st-line durvalumab and platinum–etoposide in advanced large-cell neuroendocrine lung carcinoma (aLCNEC)

BACKGROUND: LCNEC is a rare high-grade neuroendocrine malignancy with poor prognosis and limited evidence to guide systemic therapy. METHODS: Prospective, single-arm phase II study of 1st-line durvalumab 1500 mg + cisplatin or carboplatin and etoposide (EP) q3 weeks for 4 cycles, followed by durvalumab 1500 mg q4 weeks, in aLCNEC. The primary endpoint was 12-month PFS (RECIST v1.1, radiologist-assessed); secondary endpoints were ORR, OS, and safety. Sample size followed a single-stage Fleming design (one-sided α = 0.10, power 80%) testing a 12-month PFS rate ≤ 5% (H0) vs ≥ 18% (H1). The study closed early due to slow accrual after twelve of twenty-two planned patients were enrolled. RESULTS: Twelve patients were treated (median age 68y; 66.7% male; 91.7% smokers; 91.7% stage IVB). After median follow-up of 12.8 months (95% CI 8.5-21.3), 92% had progressed and 75% had died. Median PFS was 4.4 months (95% CI 3.1-12.9); 12-month PFS was 25.0% (95% CI 6.0-50.5), exceeding the ≤ 5% null hypothesis (H0) and compatible with the ≥ 18% target (H1). Median OS was 12.8 months (95% CI 5.2-NR); 12-month OS was 58.3% (95% CI 27.0-80.1). ORR was 50.0%, and DCR was 91.7%. All three patients with untreated brain metastases achieved complete intracranial response. Toxicities were mainly grade 1-2; 41.7% had grade 3 adverse events; three discontinued durvalumab for immune-related toxicity; and no treatment-related deaths occurred. CONCLUSIONS: This first prospective evaluation of durvalumab + EP in aLCNEC, though underpowered, demonstrates efficacy and safety consistent with design expectations.