In a phase II trial reported in the Journal of Clinical Oncology, Sadeghi et al found that EphrinB2 inhibition with soluble EphB4-human serum albumin (sEphB4-HSA) plus pembrolizumab appeared to exert substantial activity in patients with metastatic urothelial carcinoma, particularly among patients with tumors expressing EphrinB2.

As related by the investigators, the EphB4 receptor tyrosine kinase is highly expressed in urothelial cancer. In tumor vessels, EphrinB, its high-affinity ligand, interacts with EphB4 on tumor cells, promoting angiogenesis and blocking immune cell trafficking into tumors. sEphB4-HSA binds EphrinB2 and blocks bidirectional signaling, resulting in inhibition of tumor growth and promotion of immune cell trafficking into tumors.

Study Details

In the U.S. multicenter trial, 70 patients with disease that recurred or progressed after platinum-based chemotherapy were enrolled between December 2018 and January 2021. Patients received pembrolizumab at 200 mg on day 1 and sEphB4-HSA at 10 mg/m² intravenously once daily on days 1, 8, and 15 every 3 weeks; treatment continued until disease progression, unacceptable toxicity, or until a maximum of 2 years. 

The primary endpoints were tolerability and overall survival. For the endpoint of tolerability, failure was defined as either any toxicity at least possibly related to treatment that led to treatment discontinuation before the start of the third course, or immune-related toxicities that did not resolve within 42 days during the first two cycles.

Overall Survival and Other Efficacy Outcomes

Median follow-up was 22.9 months (range = 1.3–54.7 months). Median overall survival was 14.6 months (95% confidence interval [CI] = 9.2–21.5 months). Median progression-free survival was 4.1 months (95% CI = 1.5–5.7 months). Objective response was observed in 26 patients (37%, 95% CI = 26%–48%), including complete response in 11 (16%). Median duration of response was not reached (95% CI = 13.3 months–not reached), with 18 responses ongoing at time of analysis. Response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of responders. 

Among 46 patients with tumors expressing EphrinB2, median overall survival was 21.5 months (95% CI = 12.4 months–not reached). Median progression-free survival was 5.7 months (95% CI = 2.7–27.9 months). Objective response was observed in 24 patients (52%, 95% CI = 37%–67%), including complete response in 11 (24%).

Tolerability and Adverse Events

The protocol-defined tolerability boundary was not crossed. Events occurred in 11 patients, with 5 not starting the third course of treatment due to treatment-related toxicity and 6 having immune-related toxicities did not resolve within 42 days during the first two courses.

Hypertension was the most common toxicity attributed to sEphB4-HAS; any-grade hypertension occurred in 74% of patients and was grade 3 or 4 in 46%. After hypertension, the most common grade ≥ 3 adverse events were fatigue (9%) and abdominal pain (4%). Adverse events led to discontinuation of treatment in 9% of patients, with causes consisting of arthralgia, edema, abdominal pain, supraventricular tachycardia, increased aspartate aminotransferase and alanine aminotransferase, and endocrine disorder. Adverse events led to death in three patients, with causes consisting of organ failure, aspiration pneumonia, and myositis.

The investigators concluded, “The combination of sEphB4-HSA and pembrolizumab appears synergistic with improved overall survival and objective response rate compared with historical data for PD-1/PD-L1 monotherapy.”

Sarmad Sadeghi, MD, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The investigator-initiated study was supported by Merck and VasGene. For full disclosures of the study authors, visit ascopubs.org.