Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial

Summary Background Most patients with small-cell lung cancer (SCLC) have extensive-stagedisease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stageSCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposideplus either cisplatin or carboplatin ( platinum– etoposide) in treatment-naive patients with ES-SCLC. Methods This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteriain Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumabplus platinum– etoposide; durvalumabplus tremelimumabplus platinum– etoposide; or platinum– etoposidealone. All drugs were administered intravenously. Platinum– etoposideconsisted of etoposide80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL per min or cisplatin 75–80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum– etoposideplus durvalumab1500 mg with or without tremelimumab75 mg every 3 weeks followed by maintenance durvalumab1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum– etoposideevery 3 weeks plus prophylactic cranial irradiation(investigator's discretion) in the platinum– etoposidegroup. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumabplus platinum– etoposidegroup versus the platinum– etoposidegroup from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov , NCT03043872 , and is ongoing. Findings Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumabplus platinum– etoposidegroup and 269 to the platinum– etoposidegroup. Durvalumabplus platinum– etoposidewas associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5–14·8) in the durvalumabplus platinum– etoposidegroup versus 10·3 months (9·3–11·2) in the platinum– etoposidegroup, with 34% (26·9–41·0) versus 25% (18·4–31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumabplus platinum– etoposidegroup and 166 (62%) of 266 in the platinum– etoposidegroup; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. Interpretation First-line durvalumabplus platinum– etoposidesignificantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. Funding AstraZeneca.