EphrinB2 Emerges as Targetable Option in Urothelial Carcinoma

Sarmad Sadeghi, MD, PhD

Treatment with soluble EphB4-human serum albumin (sEphB4-HSA) plus pembrolizumab (Keytruda) elicited synergistic activity and an improved overall survival (OS) and objective response rate (ORR) compared with historical data for PD-1/PD-L1 monotherapy in patients with platinum-refractory metastatic urothelial carcinoma, according to findings from a phase 2 trial (NCT02717156) published in the Journal of Clinical Oncology.¹

At a median follow up of 22.9 months (range, 1.3-54.7) in the intention-totreat (ITT) analysis, the median OS was 14.6 months (95% CI, 9.2-21.5); the P value was .014 for rejecting the null hypothesis that the median survival would be 6.9 months or less. The median progression-free survival (PFS) was 4.1 months (95% CI, 1.5-5.7), and 26 patients (37%) had an objective response (95% CI, 26%-48%). The disease control rate (DCR) was 66% (95% CI, 55%-77%).

The regimen also had acceptable toxicity, and the tolerability monitoring boundary was not crossed, with a total of 11 events in 11 patients.

“The combination of sEphB4-HSA and pembrolizumab can be administered with acceptable toxicity and improves key efficacy end points especially in [the] sEphB4-HSA drug target (EphrinB2)–positive subgroup and forms the basis for further investigation in high-grade urothelial carcinoma,” lead study author Sarmad Sadeghi, MD, PhD, and coauthors wrote in the publication. Sadeghi is an associate professor of clinical medicine at Keck School of Medicine at the University of Southern California in Los Angeles.

Additional results indicated that at a median follow-up of 22.5 months (range, 3.5-54.7) among the patients with EphrinB2 expression (n = 46), the median OS was 21.5 months (95% CI, 12.4–not reached), and the median PFS was 5.7 months (95% CI, 2.7-27.9). The ORR was 52% (95% CI, 37%-67%), which included a complete response rate of 24% (95% CI, 12%-36%) and a partial response rate of 28% (95% CI, 15%-41%). The DCR was 80% (95% CI, 69%-92%).

Notably, response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of the patients, respectively. The median duration of response (DOR) was not reached in either the ITT population or the EphrinB2-positive cohort.

Poor outcomes are associated with metastatic urothelial carcinoma following failure on standard frontline chemotherapy, and approved PD-1 inhibitors have low response rates in the second-line setting.

EphB4 is highly expressed in urothelial cancer and leads to increased tumor cell invasion, proliferation, and survival. Interaction of high EphrinB2 in tumor vessels and EphB4 on tumor cells promotes angiogenesis and impedes immune cell traffic into the tumor. sEphB4-HSA binds EphrinB2 and inhibits bidirectional signaling and tumor growth and increases immune cell trafficking into the tumor.

In preclinical models, the combination of sEphB4 and PD-1 inhibition was more active than either agent alone, supporting further evaluation. In this phase 2 trial, 70 patients with metastatic urothelial carcinoma that recurred or progressed after platinum-based chemotherapy received sEphB4-HSA in combination with pembrolizumab.

When stratified by PD-L1 status and EphrinB2 status, those with PD-L1–positive disease (n = 18) had an ORR of 61%. In this population 13 patients had EphrinB2-positive disease and an ORR of 69%. Among the EphrinB2-negative disease, the ORR was 40%. In the PD-L1 or unknown group (n = 52), the ORR was 29%. Those with EphrinB2-positive disease (n = 33) had an ORR of 45%; and those with EphrinB2-negative disease had an ORR of 0%.¹

To be eligible for enrollment, patients had to be at least 18 years of age and have histologically confirmed urothelial carcinoma with disease progression after platinum-based chemotherapy for advanced disease or recurrence within 12 months of receiving platinum-based adjuvant or neoadjuvant therapy for localized muscle-invasive disease; at least 1 measurable lesion according to RECIST v1.114 criteria, and an ECOG performance status (PS) of 0 or 1.

Patients received 200 mg of intravenous (IV) pembrolizumab once on day 1 and 10 mg/m² of IV sEphB4-HSA once daily on days 1, 8, and 15 every 3 weeks. Treatment was continued until RECISTdefined disease progression, development of unacceptable toxicity, patient or investigator decision, or completion of 2 years of therapy.

The primary end points of the trial were tolerability and OS. The secondary end points were PFS, ORR, DOR, and toxicity. The median age of participants was 67 years. Sixty-four patients received only 1 prior line of therapy; 6 patients received more than one line of therapy. Baseline sites of disease included the lymph nodes (n = 45; 64%), lungs (n = 24; 34%), liver (n = 18; 26%), and bone (n =9; 13%).

Thirty-nine patients (56%) had an ECOG performance status of 0 and 31 (44%) patients had an ECOG performance status of 1. Stratification of Bellmunt risk demonstrated that 27% of patients had no risk factors, 37% had 1 risk factor, and 36% had 2 or more risk factors. Fourteen (20%) patients had upper-tract disease as their primary site of disease. Forty-six (66%) patients were EphrinB2 positive.

The median duration of therapy was 15 weeks (range, 3-120). Eight patients remain on treatment, and 37 patients (60%) discontinued treatment because of disease progression. Of the 25 patients who stopped treatment for reasons other than progressive disease, 15 remain without subsequent systemic treatment and 21 received subsequent systemic therapy.

Any-grade adverse effects (AEs) occurring in at least 10% of patients included hypertension (74%), fatigue (44%), anemia (17%), anorexia (13%), headache (13%), nausea (13%), proteinuria (11%), rash (11%), hyperuricemia (10%), increase in aspartate aminotransferase (AST; 10%), and pruritus (10%).

Six patients (8.6%) discontinued treatment because of grade 3 toxicity: arthralgia (n = 1), edema (n = 1), abdominal pain (n = 1), and supraventricular tachycardia (n = 1), increase in AST and alanine aminotransferase (n = 1), and endocrine disorder (n = 1).

Four (6%) patients died on treatment because of organ failure attributed to pembrolizumab (n = 1), aspiration pneumonia (n = 1), and overall decline in health and clinical progression of disease (n = 2). Five patients withdrew from the trial, and 6 patients discontinued therapy per the recommendation of the treating physician.

Hypertension was the most common toxicity attributed to sEphB4-HSA; 74% of patients experienced any-grade hypertension, and 46% had grade 3 or 4 hypertension.

Severe immune-related AEs included myositis in 1 patient, which resulted in death. Grade 2 pneumonitis occurred in 1 patient. Other immune-mediated AEs resolved with corticosteroids and without sequelae.

“A larger controlled phase 3 trial is required to confirm the efficacy signal observed in this study,” the study authors concluded. “A phase 2 study of this combination in metastatic urothelial carcinoma is under way, which includes a frontline cohort and an EphrinB2-positive biomarker-selected previously treated cohort (NCT04486781).”

References

1. Sadeghi S, Quinn D, Dorff T, et al. EphrinB2 inhibition and pembrolizumab in metastatic urothelial carcinoma. J Clin Oncol. Published online August 19, 2022. doi:10.1200/JCO.21.02923
2. Chrencik JE, Brooun A, Kraus ML, et al. Structural and biophysical characterization of the EphB4·EphrinB2 protein-protein interaction and receptor specificity. J Biol Chem. 2006;281(38):28185-28192. doi:10.1074/jbc.M605766200