Molecular Classification and Biomarkers of Outcome With Immunotherapy in Extensive-Stage Small-Cell Lung Cancer: Analyses of the CASPIAN Phase 3 Study

Authors

Mingchao Xie
Miljenka Vuko
Jaime Rodriguez-Canales
Johannes Zimmermann
Markus Schick
Cathy O'Brien
Luis Paz-Ares
Jonathan W Goldman
Marina Chiara Garassino
Carl M Gay
John V Heymach
Haiyi Jiang
J Carl Barrett
Ross A Stewart
Zhongwu Lai
Lauren A Byers
Charles M Rudin
Yashaswi Shrestha

Publication Date

5-30-2024

Journal

Molecular Cancer

Abstract

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial.

METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry.

RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry.

CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT03043872.

Keywords

Humans, Small Cell Lung Carcinoma, Biomarkers, Tumor, Lung Neoplasms, Female, Male, Immunotherapy, Antineoplastic Combined Chemotherapy Protocols, Middle Aged, Aged, Antibodies, Monoclonal, Treatment Outcome, Neoplasm Staging, Antibodies, Monoclonal, Humanized, Prognosis, Adult

Comments

PMID: 38811992