Association of ephrinB2 (B2) expression on overall survival (OS) and resistance to PD1/L1 inhibitors (inh) in metastatic urothelial carcinoma (mUC).

Sarmad Sadeghi Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA info_outline Sarmad Sadeghi, Nataliya Mar, Denice Tsao-Wei, Karam Ashouri, Imran Siddiqi, Jon P Cogan, Alexandra Jackovich, Dory Freeman, Jillian O'Toole, Thomas W. Flaig, parkash S. gill, Arash Rezazadeh, Guru P. Sonpavde, Joaquim Bellmunt

Authors Sarmad Sadeghi Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA info_outline Sarmad Sadeghi, Nataliya Mar, Denice Tsao-Wei, Karam Ashouri, Imran Siddiqi, Jon P Cogan, Alexandra Jackovich, Dory Freeman, Jillian O'Toole, Thomas W. Flaig, parkash S. gill, Arash Rezazadeh, Guru P. Sonpavde, Joaquim Bellmunt Organizations Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, University of California, Irvine Medical Center, Orange, CA, University of Southern California, Los Angeles, CA, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, Vasgene Therapeutics, Inc, Los Angeles, CA, Rutgers New Jersey Medical School, Newark, NJ, Dana-Farber Cancer Institute, Boston, MA, University of Colorado Anschutz Medical Campus, Aurora, CO, AdventHealth Cancer Institute, Orlando, FL Abstract Disclosures Research Funding No funding sources reported Background: B2 is a ligand for EphB4 (B4) which enhances tumor invasion, proliferation, survival and promotes angiogenesis. TCGA data (N= 409) bladder cancer patients (pts) showed B2 high expression (34%) had poor OS vs. low expression (66%) (Hazard Ratio- HR- 0.7 p=0.02). Our phase II trial of sEphB4-HSA, a B2 inhibitor, combined with pembrolizumab in pre-treated mUC (N=70) showed an objective response rate (ORR) of 37%. Pts with high B2 had 52% ORR with 24% complete response (CR) (JCO PMID 35984996). This retrospective study examined the OS and ORR to PD1/L1 inh in pts with mUC and its correlation with B2 expression. Methods: Pts with mUC who received PD1/L1 inh were eligible if they had radiographic response data and tumor tissue for B2 testing. Demographics and disease characteristics were abstracted. Radiographic was assessed using RECIST 1.1. Tumor specimens were analyzed for B2 expression using in-situ hybridization (ISH). Scores of 2-4 were marked High (Hi) and 0-1 Low (Lo). Descriptive statistics summarized the results. Cox Model, logrank and Fisher’s exact test were used for the association of B2 status with OS and ORR, respectively, using SAS 9.4. Results: 143 (N) pts from University of Southern California (USC, n = 49), Dana Farber (DFCI, n = 55), and University of California, Irvine (UCI, n = 39) were included. 101 pts were male (71%). Median age was 73. PD1/L1 inh included pembrolizumab (n = 111, 78%), atezolizumab (n = 25, 17%), nivolumab, avelumab, and durvalumab in 3%, 1%, and 1%, respectively. ORR defined as CR + partial response (PR) was 21% (95% CI 14%, 29%) (N = 136 evaluable). ORR was 12% vs 33% in B2 Hi vs Lo, p = 0.005. The median OS was 17.2 months (mo) (95% CI 13.5, 23.8) (N = 143). Median OS was 14.5 (95% CI 9.4, 21.0) mo vs 24.0 (95% CI 13.7, 60.8) mo for B2 Hi vs Lo, logrank p = 0.022 (HR 1.65 95% CI:1.07, 2.55 Wald p = 0.023). Conclusions: B2 Hi is associated with poor OS and poor ORR in PD1/L1 inh monotherapy treated mUC acting as a biomarker of disease outcome. These data suggest B2-B4 pathway to be a mechanism of resistance to PD1/L1 inh and a therapeutic target. Subgroups P B2 Any All, N=143 100% USC, n=49 100% DFCI, n=55 100% UCI, n=39 100% Median Age (range) 73 (48-91) 72 (48-87) 73 (48-91) 74 (48-90) 0.82 Male (%) 101 (71%) 37 (76%) 36 (65%) 28 (72%) 0.53 ECOG 0, 1, >1 (%) 42, 35, 23 51, 22, 27 40, 40, 21 33, 44, 23 0.23 Visceral Metastases (%) 79 (55%) 26 (53%) 36 (65%) 17 (44%) 0.11 ORR* 28 (21%) 10 (20%) 11 (20%) 7 (22%) 1.00 B2 Lo 55 (40%) 21 (43%) 19 (35%) 15 (47%) 0.005 ORR 18 (33%) 6 (29%) 7 (37%) 5 (33%) B2 Hi 81 (60%) 28 (57%) 36 (65%) 17 (53%) ORR 10 (12%) 4 (14%) 4 (11%) 2 (12%) OS (mo.) Median (95% CI) 17.2 (13.5, 23.8) 16.0 (8.1, 30.1) 14.5 (9.0, 18.0) 32.0 (13.3, 60.8) 0.32 B2 Lo 60 (42%) 21 (43%) 19 (35%) 20 (51%) 0.022 OS 24.0 (13.7, 60.8) 24.0 (9.2, NA) 17.5 (7.3, 27.6) 45.1 (10.8, 60.8) B2 Hi 83 (58%) 28 (57%) 36 (65%) 19 (49%) OS 14.5 (9.4, 21.0) 8.8 (3.8, 30.1) 13.8 (8.2, 16.7) 21.0 (9.4, 32.8) *7 pts inevaluable