Abstract
Combined sEphB4-HSA and pembrolizumab improves overall survival as compared to pembrolizumab alone.
Major Finding: Combined sEphB4-HSA and pembrolizumab improves overall survival as compared to pembrolizumab alone.
Concept: The regimen was well tolerated, with hypertension being the most commonly reported toxicity.
Impact: Further evaluation of sEphB4-HSA in high-grade urothelial carcinoma is warranted.
First-line platinum-based chemotherapy as well as antibodies targeting PD-1 or PD-L1 demonstrate low response rates in patients with metastatic urothelial carcinoma (UC); therefore, treatments for these patients remain an unmet clinical need. The EphB4 receptor tyrosine kinase and its ligand EphrinB2 are highly expressed in UC, and blocking their bidirectional signaling using soluble EphB4-human serum albumin (sEphB4-HSA) inhibits tumor growth in preclinical models. Moreover, combining sEphB4-HSA with an anti–PD-1 agent is more effective than each single agent alone. Sadeghi and colleagues therefore initiated a phase II clinical trial to assess the combination of sEphB4-HSA along with the PD-1 inhibitor pembrolizumab in 70 patients with platinum-refractory UC. The primary endpoints for this study were overall survival (OS) and tolerability, with additional endpoints of progression-free survival (PFS), objective response, duration of response (DOR), and toxicity. The study met its primary endpoints with an overall median OS of 14.6 months, with the median OS for patients who were EphrinB2-positive being 21.5 months. Among 63 evaluable patients, the objective response rate was 41%, with a complete response rate of 18% (11 patients). Among the 70 intent-to-treat patients, the median PFS was 4.1 months, while the median DOR was not yet reached. For EphrinB2-positive patients, the ORR was 52% and the complete response rate was 24%. This patient population also had a median PFS of 5.7 months, and the median DOR was not yet reached. Evaluation of toxicity showed that six patients (8.6%) discontinued treatment, with hypertension being the most common toxicity related to sEphB4-HSA. Severe immune-related adverse events were observed in one patient and resulted in death, but other immune-mediated adverse events were resolved with corticosteroids. In summary, this trial shows that the combination of sEphB4-HSA and pembrolizumab improves OS as compared to the historical data for pembrolizumab alone in UC, suggesting further phase III trials are warranted for this regimen in this setting.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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