1997P - Novel biomarker, ephrinB2 (B2), predicts resistance to treatment and poor overall survival (OS) metastatic urothelial carcinoma (mUC)

Background

B2 is a ligand for EphB4 (B4) that enhances tumor invasion, proliferation, survival and promotes angiogenesis. TCGA analysis of 409 bladder cancer patients (pts) showed B2 high (Hi) expression (34%) had poor OS vs. low (Lo) expression (66%) (Hazard Ratio- HR- 0.7 p=0.02). Our phase II trial of sEphB4-HSA- a B2 inhibitor- plus pembrolizumab in pre-treated mUC (N=70) showed an objective response rate (ORR) of 37%. Pts with B2 Hi had 52% ORR with 24% complete response (CR) (JCO PMID 35984996). In this study we investigated the association of B2 expression with OS and ORR in mUC.

Methods

Pts with mUC treated with a PD1/L1 antibody (Ab) were eligible if they had radiographic response data and tumor tissue for B2 testing. Demographics, disease characteristics, RECIST 1.1 radiographic response, and survival data were collected. Tumor specimens were analyzed for intensity of B2 expression using in-situ hybridization (ISH). Scores of 2-4 were marked Hi and 0-1 Lo. Descriptive statistics summarized the results. Log-rank and Fisher’s exact test were used for the associations of B2 status with OS and ORR using SAS 9.4.

Results

159 pts from University (U) of Southern California (USC, n=49), Dana Farber (DFCI, n=55), and U of California, Irvine (UCI, n=39) and U of Colorado (UC, n=16) were included. 116 pts were male (73%). Median age was 73. PD1/L1 Ab included pembrolizumab (n=121, 76%), atezolizumab (n=30, 19%) and nivolumab, avelumab, and durvalumab, 3%, 1%, and 1%, respectively. ORR defined as CR + partial response (PR) was 20% (95% CI 13%, 27%) (N=152 evaluable). ORR was 12% vs 33% in B2 Hi vs Lo, p=0.004. The median OS and its 95% CI was 16.5 (12.8, 21.0) months (N=159). Median OS was 13.5 (8.3, 16.7) mo. vs 20.6 (13.7, 39.8) mo. for B2 Hi vs Lo (HR 1.64 95% CI: 1.10, 2.44, p=0.014). Table: 1997P

Conclusions

B2 Hi was associated with poor OS and ORR to PD1/L1 Ab monotherapy in mUC. These data propose B2-B4 pathway as a mechanism of resistance to PD1/L1 Ab, a biomarker of outcome, and a therapeutic target.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.