Transcriptomic Determinants of Response to Pembrolizumab Monotherapy across Solid Tumor Types

PURPOSE: To explore relationships between biological gene expression signatures and pembrolizumab response. EXPERIMENTAL DESIGN: RNA-sequencing data on baseline tumor tissue from 1,188 patients across seven tumor types treated with pembrolizumab monotherapy in nine clinical trials were used. A total of 11 prespecified gene expression signatures [18-gene T-cell–inflamed gene expression profile (Tcell(inf)GEP), angiogenesis, hypoxia, glycolysis, proliferation, MYC, RAS, granulocytic myeloid-derived suppressor cell (gMDSC), monocytic myeloid-derived suppressor cell (mMDSC), stroma/epithelial-to-mesenchymal transition (EMT)/TGFβ, and WNT] were evaluated for their relationship to objective response rate (per RECIST, version 1.1). Logistic regression analysis of response for consensus signatures was adjusted for tumor type, Eastern Cooperative Oncology Group performance status, and Tcell(inf)GEP, an approach equivalent to evaluating the association between response and the residuals of consensus signatures after detrending them for their relationship with the Tcell(inf)GEP (previously identified as a determinant of pembrolizumab response) and tumor type. Testing of the 10 prespecified non-Tcell(inf)GEP consensus signatures for negative association [except proliferation (hypothesized positive association)] with response was adjusted for multiplicity. RESULTS: Covariance patterns of the 11 signatures (including Tcell(inf)GEP) identified in Merck–Moffitt and The Cancer Genome Atlas datasets showed highly concordant coexpression patterns in the RNA-sequencing data from pembrolizumab trials. Tcell(inf)GEP was positively associated with response; signatures for angiogenesis, mMDSC, and stroma/EMT/TGFβ were negatively associated with response to pembrolizumab monotherapy. CONCLUSIONS: These findings suggest that features beyond IFNγ-related T-cell inflammation may be relevant to anti–programmed death 1 monotherapy response and may define other axes of tumor biology as candidates for pembrolizumab combinations. See related commentary by Cho et al., p. 1479