A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.
A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.
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DOI：
10.1016/s0140-6736(21)00152-5
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发表时间：
2021-02-20
期刊：
影响因子：
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通讯作者：
Lara PN Jr
中科院分区：
文献类型：
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作者：
Pal SK;Tangen C;Thompson IM Jr;Balzer-Haas N;George DJ;Heng DYC;Shuch B;Stein M;Tretiakova M;Humphrey P;Adeniran A;Narayan V;Bjarnason GA;Vaishampayan U;Alva A;Zhang T;Cole S;Plets M;Wright J;Lara PN Jr
MET信号传导是乳头状肾细胞癌（PRCC）的关键驱动因素。鉴于转移性PRCC没有最佳治疗方法，我们试图将现有标准（舒尼替尼）与MET激酶抑制剂进行比较。我们进行了一项随机、开放标签、II期临床试验，患者患有转移性PRCC，既往接受过一种治疗（不包括血管内皮生长因子导向药物）。患者被分配接受舒尼替尼、卡博替尼、克唑替尼或savolitinib，并根据接受既往治疗和PRCC亚型进行分层。无进展生存期（PFS）是主要终点。每组有41例合格患者，与舒尼替尼相比，每个实验组有85%的把握度检测到中位PFS改善75%，每个测试采用单侧α = 0.10。共入组152例患者。savolitinib（N=29）和克唑替尼（N=28）组的入组在预先规定的无效性分析后停止;舒尼替尼（N=46）和卡博替尼（n=44）组的计划招募均已完成。卡博替尼的PFS长于舒尼替尼（9.0个月vs. 5.6个月;进展或死亡的风险比，0.60; 95% CI 0.37-0.97，P=0.019 [单侧]）。卡博替尼的应答率为23%，舒尼替尼为4%（双侧P=0.010）。与舒尼替尼相比，Savolitinib和克唑替尼未改善PFS。在接受舒尼替尼、卡博替尼、克唑替尼和savolitinib的患者中，分别有69%、74%、37%和39%的患者发生了3级或4级不良事件;在接受卡博替尼的患者中观察到了1例5级血栓栓塞事件。在转移性PRCC患者中，与舒尼替尼相比，卡博替尼导致PFS显著更长。
MET signaling is a key driver of papillary renal cell carcinoma (PRCC). Given that there is no optimal therapy for metastatic PRCC, we sought to compare an existing standard (sunitinib) to MET kinase inhibitors. We conducted a randomized, open-label, phase II trial involving patients with metastatic PRCC who had received up to one prior therapy (excluding vascular endothelial growth factor-directed agents). Patients were assigned to receive sunitinib, cabozantinib, crizotinib or savolitinib, with stratification by receipt of prior therapy and PRCC subtype. Progression-free survival (PFS) was the primary endpoint. With 41 eligible patients per arm, there was 85% power to detect a 75% improvement in median PFS in each experimental arm compared to sunitinib, employing a one-sided alpha of 0.10 for each test. Overall, 152 patients were enrolled. Enrollment to savolitinib (N=29) and crizotinib (N=28) arms was halted after a pre-specified futility analysis; planned accrual was completed for both sunitinib (N=46) and cabozantinib (n=44) arms. PFS was longer with cabozantinib versus sunitinib (9.0 months vs. 5.6 months; hazard ratio for progression or death, 0.60; 95% CI 0.37–0.97, P=0.019 [1-sided]). Response rate for cabozantinib was 23% versus 4% for sunitinib (2-sided P=0.010). Savolitinib and crizotinib did not improve PFS relative to sunitinib. Grade 3 or 4 adverse events occurred in 69%, 74%, 37% and 39% of patients receiving sunitinib, cabozantinib, crizotinib and savolitinib, respectively; one grade 5 thromboembolic event was seen with cabozantinib. Cabozantinib resulted in significantly longer PFS when compared to sunitinib in patients with metastatic PRCC.