Scientific publications

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

Oct 18, 2023 | Magazine: Gynecologic Oncology

Jonathan A Ledermann  1 , Ronnie Shapira-Frommer  2 , Alessandro D Santin  3 , Alla S Lisyanskaya  4 , Sandro Pignata  5 , Ignace Vergote  6 , Francesco Raspagliesi  7 , Gabe S Sonke  8 , Michael Birrer  9 , Diane M Provencher  10 , Jalid Sehouli  11 , Nicoletta Colombo  12 , Antonio González-Martín  13 , Ana Oaknin  14 , P B Ottevanger  15 , Vilius Rudaitis  16 , Julie Kobie  17 , Michael Nebozhyn  17 , Mackenzie Edmondson  17 , Yuan Sun  17 , Razvan Cristescu  17 , Petar Jelinic  17 , Stephen M Keefe  17 , Ursula A Matulonis  18

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 [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.

Results: 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).

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.

CITATION  Gynecol Oncol. 2023 Nov:178:119-129.  doi: 10.1016/j.ygyno.2023.09.012.  Epub 2023 Oct 18