EphrinB2 (B2) expression predicts poor response to PD1/L1 antibodies (Ab) in metastatic urothelial carcinoma (mUC).

Abstract

4575 Background: B2 is a ligand for EphB4 which enhances tumor invasion, proliferation, survival and promotes angiogenesis. A prior analysis of TCGA data from 409 muscle invasive bladder cancer (MIBC) patients (pts) demonstrated that high (34%) B2 gene expression had poor survival vs. low (66%) expression (Hazard Ratio 0.7 p = 0.02). Our phase II trial of sEphB4-HSA (JCO PMID 35984996) which targets B2, in combination with pembrolizumab in previously treated mUC (N=70) demonstrated an objective response rate (ORR) of 37%. Among pts with high expression of B2, ORR was 52% with 24% complete response (CR). This retrospective study examined the ORR to PD1/L1 Ab in pts with mUC and its correlation with B2 mRNA expression. Methods: Pts with mUC who had received anti PD1/L1 Ab were eligible if they had radiographic response data and tumor tissue for B2 testing. Pts’ demographics and disease characteristics were abstracted. Radiographic images were reviewed using RECIST 1.1. Tumor specimens were analyzed for intensity of B2 expression using in-situ hybridization (ISH). Scores of 2-4 were considered High (Hi) and 0-1 were considered Low (Lo) expression. Standard descriptive statistics were used to summarize study results. Fisher’s exact test was used to test the association of ORR with B2 expression using SAS 9.4. Results: 120 (N) pts from University of Southern California (USC, n=49), Dana Farber (DFCI, n=55), and University of Colorado (UC, n=16) met were included. 88 pts were male (73%). Median age was 72. PD1/L1 Ab were administered in the post-platinum progressive disease (n=95, 79%) and first-line setting (n=25, 21%) and included pembrolizumab (n=88, 73%), atezolizumab (n=26, 22%) and nivolumab, avelumab, and durvalumab, 3%, 1%, and 1%, respectively. Objective response rate (ORR) defined as radiographic CR plus partial response (PR) were calculated and summarized. Among all pts (N=120), ORR was 20% (95% CI 13-28). 62% had B2 Hi expression with a response rate of 12%, and 38% had B2 Lo expression with a response rate of 33%, p=0.009). These proportions were similar for each institution. Conclusions: In addition to conferring poor prognosis in MIBC, B2 expression is associated with poor ORR to PD1/L1 Ab monotherapy in mUC. Given that the combination of B2 inhibition & pembrolizumab was more active in B2 expressing mUC, these data provide further rationale for investigating B2 as a mechanism of resistance to PD1/L1 ab, biomarker of response and a therapeutic target. [Table: see text]