PURPOSE: In the CASPIAN trial, first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small cell lung cancer (ES-SCLC). We report exploratory analyses of CASPIAN outcomes by programmed cell death ligand-1 (PD-L1) expression and tissue tumor mutational burden (tTMB). EXPERIMENTAL DESIGN: Patients were randomized (1:1:1) to durvalumab (1,500 mg) plus EP, durvalumab plus tremelimumab (75 mg) plus EP, or EP alone. Treatment effects in PD-L1 and tTMB subgroups were estimated using an unstratified Cox proportional hazards model. RESULTS: The PD-L1 and tTMB biomarker-evaluable populations (BEP) comprised 54.4% (438/805) and 35.2% (283/805) of the intention-to-treat population, respectively. PD-L1 prevalence was low: 5.7%, 25.8%, and 28.3% had PD-L1 expression on ≥1% tumor cells (TC), ≥1% immune cells (IC), and ≥1% TCs or ICs, respectively. OS benefit with durvalumab plus EP versus EP was similar across PD-L1 subgroups, with HRs all falling within the 95% confidence interval (CI) for the PD-L1 BEP (0.47‒0.79). OS benefit with durvalumab plus tremelimumab plus EP versus EP was greater in PD-L1 ≥1% versus <1% subgroups, although CIs overlapped. There was no evidence of an interaction between tTMB and treatment effect on OS (durvalumab plus EP vs. EP, P = 0.916; durvalumab plus tremelimumab plus EP vs. EP, P = 0.672). CONCLUSIONS: OS benefit with first-line durvalumab plus EP in patients with ES-SCLC was observed regardless of PD-L1 or tTMB status. PD-L1 expression may prove to be a useful biomarker for combined treatment with PD-(L)1 and CTLA-4 inhibition, although this requires confirmation with an independent dataset. See related commentary by Rolfo and Russo, p. 652.

Asklepios Lung Clinic Member of the German Center for Lung Research Munich Gauting Germany

AstraZeneca Cambridge United Kingdom

AstraZeneca Gaithersburg Maryland

AstraZeneca Waltham Massachusetts

Cancer and Hematology Centers of Western Michigan Grand Rapids Michigan

Clinic of Medical Oncology UMHAT St Marina Varna Bulgaria

David Geffen School of Medicine at UCLA Los Angeles California

Department of Medical Oncology Hospital Universitario 12 de Octubre Lung Cancer Unit CNIO H120 Complutense University and Ciberonc Madrid Spain

Department of Medicine Section of Hematology Oncology Thoracic Oncology Unit University of Chicago Chicago Illinois

Dnipropetrovsk Medical Academy Dnipro Ukraine

Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Istanbul University Cerrahpaşa Cerrahpaşa School of Medicine Istanbul Turkey

Karl Landsteiner Institute of Lung Research and Pulmonary Oncology Klinik Floridsdorf Vienna Austria

Odessa Regional Oncological Dispensary Odessa Ukraine

Okayama University Hospital Okayama Japan

Omsk Regional Cancer Center Omsk Russian Federation

Petrov Research Institute of Oncology St Petersburg Russian Federation

Samsung Changwon Hospital Sungkyunkwan University School of Medicine Changwon Republic of South Korea

Semmelweis University Budapest Hungary

Thomayer Hospital 1st Faculty of Medicine Charles University Prague Czech Republic

Clin Cancer Res. 2024 Feb 16;30(4):652-654. doi: 10.1158/1078-0432.CCR-23-3087. PubMed

Transl Cancer Res. 2025 Jan 31;14(1):24-28. doi: 10.21037/tcr-24-1711. PubMed

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