Correlation of circulating PD-L2 levels with outcomes of therapy with the anti-PD-1 antibody pembrolizumab (P) in patients (pts) with advanced soft tissue sarcomas (STS): Biomarker analysis of SARC028.

Abstract

60 Background: The activity of the anti-PD-1 antibody P in pts with advanced STS was evaluated in a prospective multicenter Phase II study conducted by the Sarcoma Alliance for Research through Collaboration (SARC). SARC028 enrolled 40 patients with advanced soft tissue sarcoma. Pembro had an ORR of 19% and PFS rate at 12 weeks of 55%, suggesting clinical activity. We investigated biomarkers of response to P. Methods: The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, and biomarkers of response in blood and tumor. Pre- and on-treatment biopsies were required and obtained from over 90% and 72% of pts respectively. Serum was obtained from all pts at baseline and at multiple time points on therapy (pre-, week 8, and every 12 weeks). Sera were examined for candidate circulating biomarkers by Affymetrix Luminex platform array, including PD-L2. To determine whether there is a statistically significant difference between different conditions, we used Mann-Whitney and two-tailed t tests. Log-rank p-values in Kaplan-Meier survival analyses were calculated using the "survival" R package. Results: Forty pts with STS were enrolled into 4 cohorts (10 each) based on histological subtype including undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (LPS), synovial sarcoma (SS), and leiomyosarcoma (LMS). 4 pts with UPS, 2 pts with LPS, and one pt with SS achieved a response. Six of seven responses were durable at the time of this analysis. Circulating levels at baseline or after therapy of PD-1, PD-L1, 4-1BB, IDO, BTLA, CTLA-4, LAG-3, and TIM-3 did not correlate with outcome. However, pre-treatment and week 8 PD-L2 levels correlated best with clinical outcome: high PD-L2 levels were associated with better PFS (p=0.019) in STS. Conclusions: P has clinical activity in specific histologic subtypes of STS, namely UPS and LPS. Pre-treatment circulating PD-L2 levels correlated with progression-free survival and is a novel and promising predictor of improved clinical outcome of PD-1 therapy in STS.