Using an iterative approach coupling gene expression data with clinical outcomes, Ayers et al. identified an 18 member gene panel for prediction of response to pembrolizumab, which outperformed PD-L1 immunohistochemistry analysis. A highly T cell-infiltrated tumor is predicted, based on the genes induced, to correlate with positive outcomes.

Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-gamma is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-gamma-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.

Author Info: (1) Merck & Co. Inc., Kenilworth, New Jersey, USA. (2) Merck & Co. Inc., Kenilworth, New Jersey, USA. (3) Merck & Co. Inc., Kenilworth, New Jersey, USA. (4) Merck & Co. Inc., Kenil

Author Info: (1) Merck & Co. Inc., Kenilworth, New Jersey, USA. (2) Merck & Co. Inc., Kenilworth, New Jersey, USA. (3) Merck & Co. Inc., Kenilworth, New Jersey, USA. (4) Merck & Co. Inc., Kenilworth, New Jersey, USA. (5) Merck & Co. Inc., Kenilworth, New Jersey, USA. (6) Merck & Co. Inc., Kenilworth, New Jersey, USA. (7) Merck & Co. Inc., Kenilworth, New Jersey, USA. (8) Merck & Co. Inc., Kenilworth, New Jersey, USA. (9) Merck & Co. Inc., Kenilworth, New Jersey, USA. (10) University of Washington, Seattle, Washington, USA. (11) University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (12) Merck & Co. Inc., Kenilworth, New Jersey, USA. (13) University of Chicago, Chicago, Illinois, USA. (14) UCLA, Los Angeles, California, USA. (15) Merck & Co. Inc., Kenilworth, New Jersey, USA.