The First-week Proliferative Response of Peripheral Blood PD-1CD8 T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors

Purpose: To investigate blood-based dynamic biomarkers that predict responses to anti-programmed cell death protein 1 (PD-1) therapy in solid tumors.

Experimental Design: Preplanned biomarker analysis was performed as part of a phase II clinical trial (NCT02607631) in patients with metastatic or refractory thymic epithelial tumors (TETs; = 31) who received pembrolizumab. The biomarker was further tested in an independent cohort of prospectively recruited patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab (NSCLC cohort 1; = 33) and validated in an independent cohort of patients with NSCLC (NSCLC cohort 2; = 46). Peripheral blood samples were obtained immediately before treatment (D0) and 7 days after the first dose (D7) and analyzed using multi-color flow cytometry.

Results: A higher fold-change in the percentage of Ki-67 cells among PD-1CD8 T cells 7 days after the first dose (Ki-67) significantly predicted durable clinical benefit (DCB; < 0.001) and prolonged progression-free survival (PFS; = 0.027) in patients with TETs. Ki-67 ≥ 2.8 was also associated with better DCB, PFS, and overall survival (OS) in NSCLC cohort 1 (all < 0.05). Ki-67 was subsequently validated in NSCLC cohort 2, and Ki-67 ≥ 2.8 significantly predicted better DCB ( = 0.001), PFS ( = 0.002), and OS ( = 0.037). Ki-67 had a low correlation with tumor PD-L1 expression and combining both factors did not improve the predictive power of Ki-67.

Conclusions: The proliferative response of peripheral blood PD-1CD8 T cells, measured as the fold-change in the percentage of Ki-67 cells 7 days after treatment (Ki-67), may be a useful surrogate biomarker for predicting the response and prognosis to anti-PD-1 therapy in solid tumors.