Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (<pT2) in the neoadjuvant setting. In LCCC1520 (NCT02690558), a phase 2 single-arm trial of neoadjuvant chemo-immunotherapy (gemcitabine and cisplatin plus pembrolizumab; NAC-ICI) for MIBC, 22/39 patients responded (pathologic downstaging as primary outcome), as previously described. Here, we report post-hoc correlative analyses. Treatment was associated with changes in tumor mutational profile, immune gene signatures, and RNA subtype switching. Clinical response was associated with an increase in plasma IL-9 from pre-treatment to initiation of cycle 2 of therapy. Tumors harbored diverse predicted antigen landscapes that change across treatment and are associated with APOBEC, tobacco, and other etiologies. Higher pre-treatment tumor PD-L1 and TIGIT RNA expression were associated with complete response. IL-8 signature and Stroma-rich subtype were associated with improved response to NAC-ICI versus neoadjuvant ICI (ABACUS trial, NCT02662309). Plasma IL-9 represents a potential predictive biomarker of NAC-ICI response, while tumor IL-8 signature and stroma-rich subtype represent potential predictive biomarkers of response benefit of NAC-ICI over neoadjuvant ICI. Future efforts must include additional independent biomarker discovery and validation, ultimately to improve the selection of patients for ICI-related treatments.
Nature communications. 2024 May 24*** epublish ***
Wolfgang Beckabir, Mi Zhou, Jin Seok Lee, Steven P Vensko, Mark G Woodcock, Hsing-Hui Wang, Sara E Wobker, Gatphan Atassi, Alec D Wilkinson, Kenneth Fowler, Leah M Flick, Jeffrey S Damrauer, Michael R Harrison, Karen P McKinnon, Tracy L Rose, Matthew I Milowsky, Jonathan S Serody, William Y Kim, Benjamin G Vincent
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, Durham, NC, USA., Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ., Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ., Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. .