The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study

Abstract

Introduction: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types.

Methods: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system).

Results: The study subjects comprised patients with head and neck cancer (n = 50), urothelial cancer (n = 42), renal cell cancer (n = 37), gastric cancer (n = 20), esophageal cancer (n = 10), malignant pleural mesothelioma (n = 6), or microsatellite instability-high tumors (n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients.

Conclusion: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy.

Keywords: immune checkpoint inhibitor; nivolumab; pembrolizumab; soluble PD-1; soluble PD-L1.

Figure 1

Levels of sPD-1 (A) and sPD-L1 (B) in patients with head and neck cancer (HNC, n = 50), urothelial cancer (UC, n = 42), renal cell cancer (RCC, n = 37) gastric cancer (GC, n = 20), esophageal cancer (EC, n = 10), malignant pleural mesothelioma (MPM, n = 6), or microsatellite instability (MSI)–high cancer (n = 6).

Figure 2

Kaplan-Meier curves of PFS (A, C) and OS (B, D) for patients with sPD-1^high or sPD-1^low levels (A, B) or with sPD-L1^high or sPD-L1^low levels (C, D).

Figure 3

Kaplan-Meier curves of PFS (A) and OS (B) for patients with sPD-1^low/sPD-L1^high levels and all other patients. The curves for sPD-1^low/sPD-L1^high are the same as those in Figure S2 .

Figure 4

Kaplan-Meier curves of PFS (A–C) and OS (D–F) for patients with sPD-1^low/sPD-L1^high levels and the other patients among individuals with head and neck cancer (A, D), urothelial cancer (B, E), or renal cell cancer (C, F).