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EphrinB2 Inhibition and Pembrolizumab in Metastatic Urothelial Carcinoma
Sarmad Sadeghi1, David Quinn1, Tanya Dorff2
1USC Norris Comprehensive Cancer Center, Los Angeles, CA.
Purpose:
Patients with metastatic urothelial carcinoma have poor prognosis after failure of standard first-line chemotherapy. Immune check point programmed death 1-programmed death ligand 1 antibodies have low response rates and thus there exists a major unmet need.
Materials And Methods:
In this phase II trial, patients with metastatic urothelial carcinoma that recurred or progressed after platinum-based chemotherapy received soluble EphB4-human serum albumin (sEphB4-HSA) in combination with pembrolizumab. The primary end points were tolerability and overall survival (OS). The secondary end points were progression-free survival (PFS), objective response rate (ORR), duration of response, and toxicity. The expression of sEphB4-HSA target EphrinB2 was correlated with outcomes.
Results:
Seventy patients were enrolled. The median follow up was 22.9 months (range, 1.3-54.7). The regimen had acceptable toxicity. In the intent-to-treat analysis (N = 70), the median OS was 14.6 months (95% CI, 9.2 to 21.5). Twenty-six (37%) patients had an objective response (95% CI, 26 to 48). The median PFS was 4.1 (95% CI, 1.5 to 5.7) months. Forty-six (66%) patients expressed EphrinB2, and among them, the median OS was 21.5 months (95% CI, 12.4 to not reached), the ORR was 52% (95% CI, 37 to 67), including a complete response rate of 24% (11 of 46; 95% CI, 12 to 36). The median PFS was 5.7 (95% CI, 2.7 to 27.9) months. Response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of the patients, respectively.
Conclusion:
The combination of sEphB4-HSA and pembrolizumab appears synergistic with improved OS and ORR compared with historical data for programmed death 1/programmed death ligand 1 monotherapy.
Insights
This study shows that combining soluble EphB4-human serum albumin (sEphB4-HSA) with pembrolizumab improves outcomes for metastatic urothelial carcinoma patients. This combination therapy offers a promising new treatment option for patients with advanced disease.
Area of Science:
- Oncology
- Immunotherapy
- Urothelial Carcinoma Research
Background:
- Metastatic urothelial carcinoma (mUC) carries a poor prognosis following standard chemotherapy.
- Current immune checkpoint inhibitor therapies (programmed death 1/programmed death ligand 1 antibodies) demonstrate limited efficacy in this patient population.
- A significant unmet need exists for more effective treatments in advanced mUC.
Purpose of the Study:
- To evaluate the safety and efficacy of combining soluble EphB4-human serum albumin (sEphB4-HSA) with pembrolizumab in patients with metastatic urothelial carcinoma.
- To assess overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) as primary and secondary endpoints.
- To explore the correlation between EphrinB2 expression and treatment outcomes.
Main Methods:
- A Phase II clinical trial was conducted involving 70 patients with metastatic urothelial carcinoma who progressed on platinum-based chemotherapy.
- Patients received a combination of sEphB4-HSA and pembrolizumab.
- Outcomes including OS, PFS, ORR, and toxicity were meticulously recorded and analyzed. EphrinB2 expression was assessed and correlated with clinical results.
Main Results:
- The combination regimen exhibited acceptable toxicity.
- The median overall survival (OS) was 14.6 months, with an objective response rate (ORR) of 37%.
- Patients expressing EphrinB2 (66%) showed significantly improved outcomes: median OS of 21.5 months, ORR of 52%, and median PFS of 5.7 months, with durable responses observed.
Conclusions:
- The combination of sEphB4-HSA and pembrolizumab demonstrates synergistic activity in metastatic urothelial carcinoma.
- This combination therapy shows improved OS and ORR compared to historical data of single-agent programmed death 1/programmed death ligand 1 inhibitors.
- Targeting EphrinB2 in combination with immunotherapy presents a promising therapeutic strategy for advanced urothelial carcinoma.
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