Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: Analyses of the CASPIAN phase 3 study Journal Article
| Authors: | Xie, M.; Vuko, M.; Rodriguez-Canales, J.; Zimmermann, J.; Schick, M.; O’Brien, C.; Paz-Ares, L.; Goldman, J. W.; Garassino, M. C.; Gay, C. M.; Heymach, J. V.; Jiang, H.; Barrett, J. C.; Stewart, R. A.; Lai, Z.; Byers, L. A.; Rudin, C. M.; Shrestha, Y. |
| Article Title: | Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: Analyses of the CASPIAN phase 3 study |
| 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. © The Author(s) 2024. |
| Keywords: | immunohistochemistry; adult; controlled study; human tissue; protein expression; treatment outcome; treatment response; aged; middle aged; young adult; human cell; major clinical study; overall survival; genetics; clinical trial; mortality; cancer staging; antineoplastic agent; neoplasm staging; cd8 antigen; biomarkers; biological marker; metabolism; ticilimumab; cancer immunotherapy; gene expression; gene expression profiling; etoposide; randomized controlled trial; antineoplastic combined chemotherapy protocols; lung neoplasms; molecular dynamics; cohort analysis; pathology; tumor marker; monoclonal antibody; lung tumor; immunology; antibodies, monoclonal; immunotherapy; major histocompatibility antigen class 2; therapy effect; phase 3 clinical trial; cell density; ctla-4; cd4 antigen; cancer tissue; drug therapy; therapy; antigen presenting cell; predictive value; small-cell lung cancer; small cell lung cancer; small cell lung carcinoma; major histocompatibility antigen class 1; programmed death 1 ligand 1; tumor microenvironment; pd-l1; procedures; cd8alpha antigen; antibodies, monoclonal, humanized; humans; prognosis; human; male; female; article; rna sequencing; durvalumab; biomarkers, tumor; tumor mutational burden; molecular fingerprinting; molecular subtyping; antigen presentation machinery; sclc subtypes; t-cell inflamed signature; cd8a gene |
| Journal Title: | Molecular Cancer |
| Volume: | 23 |
| ISSN: | 1476-4598 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2024-05-30 |
| Start Page: | 115 |
| Language: | English |
| DOI: | 10.1186/s12943-024-02014-x |
| PUBMED: | 38811992 |
| PROVIDER: | scopus |
| PMCID: | PMC11137956 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
