Sadeghi Sarmad, Quinn David, Dorff Tanya, Pal Sumanta, Groshen Susan, Tsao-Wei Denice, Parikh Rahul, Devitt Michael, Parikh Mamta, Jackovich Alexandra, Ruel Nora, Vogelzang Nicholas, Burgess Earle, Siddiqi Imran, Gill Inderbir S, Lara Primo N, Dreicer Robert, Gill Parkash S
USC Norris Comprehensive Cancer Center, Los Angeles, CA.
City of Hope Comprehensive Cancer Center, Duarte, CA.
J Clin Oncol. 2023 Jan 20;41(3):640-650. doi: 10.1200/JCO.21.02923. Epub 2022 Aug 19.
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.
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.
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.
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.
转移性尿路上皮癌患者在标准一线化疗失败后的预后较差。免疫检查点程序性死亡蛋白1-程序性死亡配体1抗体的反应率较低，因此存在重大的未满足需求。
在这项II期试验中，铂类化疗后复发或进展的转移性尿路上皮癌患者接受可溶性EphB4-人血清白蛋白（sEphB4-HSA）联合帕博利珠单抗治疗。主要终点是耐受性和总生存期（OS）。次要终点是无进展生存期（PFS）、客观缓解率（ORR）、缓解持续时间和毒性。sEphB4-HSA的靶标EphrinB2的表达与预后相关。
70例患者入组。中位随访时间为22.9个月（范围1.3 - 54.7个月）。该方案具有可接受的毒性。在意向性分析（N = 70）中，中位OS为14.6个月（95%置信区间，9.2至21.5个月）。26例（37%）患者有客观缓解（95%置信区间，26%至48%）。中位PFS为4.1（95%置信区间，1.5至5.7）个月。46例（66%）患者表达EphrinB2，其中位OS为21.5个月（95%置信区间，12.4个月至未达到），ORR为52%（95%置信区间，37%至67%），包括24%（46例中的11例；95%置信区间，12%至36%）的完全缓解率。中位PFS为5.7（95%置信区间，2.7至27.9）个月。分别有88%、74%和69%的患者在6个月、12个月和24个月时维持缓解。
与程序性死亡蛋白1/程序性死亡配体1单药治疗的历史数据相比，sEphB4-HSA与帕博利珠单抗联合使用似乎具有协同作用，可改善OS和ORR。
