The first-week proliferative response of peripheral blood PD-1+CD8+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-PD-1 therapy in solid tumors. Experimental Design: Pre-planned biomarker analysis was performed as part of a phase II clinical trial (NCT02607631)in patients with metastatic or refractory thymic epithelial tumors (TETs; n= 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; n= 33) and validated in an independent cohort of patients with NSCLC (NSCLC cohort 2; n= 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-1⁺CD8⁺T cells 7 days after the first dose (Ki-67_D7/D0) significantly predicted durable clinical benefit (DCB;P < 0.001) and prolonged progression-free survival (PFS; P=0.027) in patients with TET. Ki-67_D7/D0≥ 2.8 was also associated with better DCB, PFS, and overall survival (OS) in NSCLC cohort 1 (all P< 0.05). Ki-67_D7/D0was subsequently validated in NSCLC cohort 2, and Ki-67_D7/D0≥ 2.8 significantly predicted better DCB (P=0.001), PFS (P=0.002), and OS (P=0.037). Ki-67_D7/D0had a low correlation with tumor PD-L1 expression and combining both factors did not improve the predictive power of Ki-67_D7/D0. Conclusions: The proliferative response of peripheral blood PD-1⁺CD8⁺T cells, measured as the fold-change in the percentage of Ki-67⁺cells 7 days after treatment (Ki-67_D7/D0), may be a useful surrogate biomarker for predicting the response and prognosis to anti-PD-1 therapy in solid tumors.

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