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

Abstract

Objective: 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.

Methods: 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 [Tcell_infGEP] and 10 non-Tcell_infGEP 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 Tcell_infGEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-Tcell_infGEP signatures; all but Tcell_infGEP and TMB were adjusted for multiplicity.

Results: No evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and Tcell_infGEP-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).

Conclusions: 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.

Keywords: Gene expression signatures; Ovarian cancer; Pembrolizumab; Tumor microenvironment cell phenotypes; Tumor mutational burden.