%0 Journal Article
%T Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study.
%A Xie M
%A Vuko M
%A Rodriguez-Canales J
%A Zimmermann J
%A Schick M
%A O'Brien C
%A Paz-Ares L
%A Goldman JW
%A Garassino MC
%A Gay CM
%A Heymach JV
%A Jiang H
%A Barrett JC
%A Stewart RA
%A Lai Z
%A Byers LA
%A Rudin CM
%A Shrestha Y
%J Mol Cancer
%V 23
%N 1
%D 2024 May 30
%M 38811992
%F 41.444
%R 10.1186/s12943-024-02014-x
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.<BR><B>BACKGROUND: </B>ClinicalTrials.gov, NCT03043872.