ESMO 2021: Phase II Trial of Pembrolizumab (P) in Combination with sEphB4-HSA (B4) in Previously Treated Metastatic Urothelial Carcinoma (mUC)

( In the Proffered Paper session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate cancer genitourinary tumors, Dr. Sadeghi presented a phase II trial of the combination of pembrolizumab (P) and sEphB4-HSA (B4) in patients previously treated for metastatic urothelial carcinoma (mUC).

He began by describing EphrinB2, a transmembrane protein expressed in capillary endothelial during development (during the embryonic period primarily) which ceases to be expressed in adults. However, it is re-expressed in tumors and their related blood vessels. EphB4 is a related, high-affinity cognate receptor with similar longitudinal expression patterns. The interaction of these two molecules activates bidirectional signaling which promotes tumor progression through effects on cell viability, angiogenesis, and immune cell response. These two molecules are highly expressed in urothelial tumors and are associated with a negative prognosis.

Mechanistically, a soluble receptor (sEphB4-HSA) may block the interaction of these two molecules by occupying EphrinB2. The authors hypothesized that the effect of this agent would be synergistic with anti-PD-1/PD-L1 antibodies to improve anti-tumor activity.


The authors sought to assess the feasibility of a combination of pembrolizumab and sEphB4-HSA including estimation of OS, PFS, ORR, and DOR. The authors further assessed correlative outcomes, including biomarker studies.

The authors enrolled patients with platinum-refractory mUC who had not received prior anti-PD-1/PD-L1 therapy. They targeted up to 70 patients to ensure 60 would be evaluable. Patients received pembrolizumab 200mg IV q3 weeks + B4 10mg/kg IV weekly in a 21 day cycle until progression (PD) or unacceptable toxicities. The authors assess response by CT chest/abdomen and pelvis every 6 weeks, interpreted per RECIST 1.1. The primary endpoint was tolerability and overall survival (OS) while secondary endpoints included progression-free survival (PFS), duration of response (DOR), and objective response rate (ORR) as well as correlative studies. Tumor tissue for all evaluable patients was tested for B2 by Immunohistochemical (IHC) staining.

The authors enrolled 69 patients 12/2016 - 09/2020. The median age of included patients was 67 years and 58 were men while 11 were female. 63 patients had received one prior line of therapy while 6 had received more than 1 line. At baseline, disease involvement was distributed as follows: nodes 43 (62%), lungs 24 (35%), liver 16 (23%), bone 9 (13%). ECOG 0 39 (57%) vs. 1 30 (43%). Nearly one-quarter of patients (23%) had upper tract disease. Forty-six patients were ephrinB2 positive based on IHC.

The overall ORR among all included patients (intention to treat cohort) was 37% and the median duration of response was not reached (complete response rate 15.7%). The ORR was higher in the subset of patients who were EphrinB2 positive (52%) and a complete response rate of 23.9%. Notably, all 12 complete responses were among patients who were EphrinB2 positive


As highlighted in the following swimmer’s plot, the majority of responders had a prolonged duration of response which continues at the time of data cut-off. Additionally, a proportion of patients maintained response after ceasing therapy.


Over a median follow-up of 25.4 months (range 1.3-48.3), the median PFS was 4.1 months (95% CI 2.3, 5.5) and the median OS was 14.6 months. Among those who are EphrinB2 positive, median PFS was 5.7 months and OS was 21.5 months.

In terms of toxicity, there were no additive effects. The most frequent effect was hypertension which could be medically managed.

Dr. Sadeghi concluded that this combination regime of pembrolizumab and sEphB4-HSA was well tolerated and demonstrated synergistic activity. Additionally, EphrinB2 has the potential to be a predictive biomarker of response. Based on these data, the FDA granted a breakthrough designation on September 1, 2021, for this regime in EphrinB2 positive patients. A phase III trial is in development.

Presented by: Sarmad Sadeghi MD, PhD, Keck School of Medicine of USC, Los Angeles, CA, United States of America

Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.