Abstract

<div>AbstractPurpose:<p>To investigate blood-based dynamic biomarkers that predict responses to anti–programmed cell death protein 1 (PD-1) therapy in solid tumors.</p>Experimental Design:<p>Preplanned biomarker analysis was performed as part of a phase II clinical trial (NCT02607631) in patients with metastatic or refractory thymic epithelial tumors (TETs; <i>n</i> = 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; <i>n</i> = 33) and validated in an independent cohort of patients with NSCLC (NSCLC cohort 2; <i>n</i> = 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.</p>Results:<p>A higher fold-change in the percentage of Ki-67<sup>+</sup> cells among PD-1<sup>+</sup>CD8<sup>+</sup> T cells 7 days after the first dose (Ki-67<sub>D7/D0</sub>) significantly predicted durable clinical benefit (DCB; <i>P</i> < 0.001) and prolonged progression-free survival (PFS; <i>P</i> = 0.027) in patients with TETs. Ki-67<sub>D7/D0</sub> ≥ 2.8 was also associated with better DCB, PFS, and overall survival (OS) in NSCLC cohort 1 (all <i>P</i> < 0.05). Ki-67<sub>D7/D0</sub> was subsequently validated in NSCLC cohort 2, and Ki-67<sub>D7/D0</sub> ≥ 2.8 significantly predicted better DCB (<i>P</i> = 0.001), PFS (<i>P</i> = 0.002), and OS (<i>P</i> = 0.037). Ki-67<sub>D7/D0</sub> had a low correlation with tumor PD-L1 expression and combining both factors did not improve the predictive power of Ki-67<sub>D7/D0</sub>.</p>Conclusions:<p>The proliferative response of peripheral blood PD-1<sup>+</sup>CD8<sup>+</sup> T cells, measured as the fold-change in the percentage of Ki-67<sup>+</sup> cells 7 days after treatment (Ki-67<sub>D7/D0</sub>), may be a useful surrogate biomarker for predicting the response and prognosis to anti-PD-1 therapy in solid tumors.</p></div>

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