Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100

• Published in: Gynecologic oncology 2023-11, Vol.178, p.119-129
• Main Authors: Ledermann, Jonathan A., Shapira-Frommer, Ronnie, Santin, Alessandro D., Lisyanskaya, Alla S., Pignata, Sandro, Vergote, Ignace, Raspagliesi, Francesco, Sonke, Gabe S., Birrer, Michael, Provencher, Diane M., Sehouli, Jalid, Colombo, Nicoletta, González-Martín, Antonio, Oaknin, Ana, Ottevanger, P.B., Rudaitis, Vilius, Kobie, Julie, Nebozhyn, Michael, Edmondson, Mackenzie, Sun, Yuan, Cristescu, Razvan, Jelinic, Petar, Keefe, Stephen M., Matulonis, Ursula A.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents, Immunological - therapeutic use; Biomarkers, Tumor - genetics; Carcinoma, Ovarian Epithelial - drug therapy; Female; Gene expression signatures; Humans; Ovarian cancer; Ovarian Neoplasms - chemically induced; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Pembrolizumab; Progression-Free Survival; Tumor Microenvironment; Tumor microenvironment cell phenotypes; Tumor mutational burden
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2023.09.012

This prespecified exploratory analysis evaluated the association of gene expression signatures, tumor mutational burden (TMB), and multiplex immunohistochemistry (mIHC) tumor microenvironment–associated cell phenotypes with clinical outcomes of pembrolizumab in advanced recurrent ovarian cancer (ROC) from the phase II KEYNOTE-100 study. Pembrolizumab-treated patients with evaluable RNA-sequencing (n = 317), whole exome sequencing (n = 293), or select mIHC (n = 125) data were evaluated. The association between outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and gene expression signatures (T-cell–inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures), TMB, and prespecified mIHC cell phenotype densities as continuous variables was evaluated using logistic (ORR) and Cox proportional hazards regression (PFS; OS). One-sided p-values were calculated at prespecified α = 0.05 for TcellinfGEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-TcellinfGEP signatures; all but TcellinfGEP and TMB were adjusted for multiplicity. No evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and TcellinfGEP-adjusted glycolysis (PFS, adjusted-p = 0.019; OS, adjusted-p = 0.085) and hypoxia (PFS, adjusted-p = 0.064) signatures. TMB as a continuous variable was not associated with outcomes (p > 0.05). Positive associations were observed between densities of myeloid cell phenotypes CD11c+ and CD11c+/MHCII−/CD163−/CD68− in the tumor compartment and ORR (adjusted-p = 0.025 and 0.013, respectively). This exploratory analysis in advanced ROC did not find evidence for associations between gene expression signatures and outcomes of pembrolizumab. mIHC analysis suggests CD11c+ and CD11c+/MHCII−/CD163−/CD68− phenotypes representing myeloid cell populations may be associated with improved outcomes with pembrolizumab in advanced ROC. Clinical trial registration: ClinicalTrials.gov, NCT02674061. [Display omitted] •Association of molecular determinants with outcomes of pembrolizumab in advanced recurrent ovarian cancer was evaluated.•No evidence of associations between ORR and key axes of gene expression was observed with pembrolizumab monotherapy.•T-cell–inflamed GEP-adjusted glycolysis and hypoxia signatures were negatively associated with clinical outcomes.•Continuous TMB was not associated with efficacy, but TMB ≥175 mut/exome