Msaouel Pavlos, Yu Kai, Yuan Ying, Chen Jianfeng, Yan Xinmiao, Karki Menuka, Duan Fei, Sheth Rahul A, Rao Priya, Sircar Kanishka, Shah Amishi Y, Zurita Amado J, Genovese Giannicola, Li Min, Yeh Chih-Chen, Dang Minghao, Han Guangchun, Chu Yanshuo, Hallin Max, Olson Peter, Yang Rui, Slavin Daniela, Der-Torossian Hirak, Chin Curtis D, Tannir Nizar M, Wang Linghua, Gao Jianjun
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Commun. 2025 Jan 10;16(1):578. doi: 10.1038/s41467-024-55642-8.
We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics. Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7 mg/kg allowed safe escalation of sitravatinib up to 100 mg daily. Overall, the triplet combination achieved ORR 45.5%, DCR 86.4%, median PFS 14.5 months, and 1-year survival 80.8%. Median OS and DOR were not reached. Sitravatinib exposure increased dose-dependently. Single-cell RNA-seq of longitudinally collected tumor biopsies from 12 patients identified a tumor cell-specific epithelial-mesenchymal transition-like program associated with treatment resistance and poor outcomes. Treatment resistance was characterized by a transition from cytotoxic to exhausted T cell state and enrichment for M2-like myeloid cells. The observed hypothesis-generating changes in gene expression dynamics and cellular states may help inform future strategies to optimize immunotherapy efficacy. Clinical Trials.gov identifier: NCT04518046.
我们开展了一项I期试验，以确定酪氨酸激酶抑制剂西曲替尼联合纳武利尤单抗和伊匹木单抗三联疗法在22例先前未接受过治疗的晚期透明细胞肾细胞癌患者中的最佳剂量。主要终点是安全性。次要终点包括客观缓解率（ORR）、疾病控制率（DCR）、缓解持续时间（DOR）、无进展生存期（PFS）、总生存期（OS）、1年生存概率以及西曲替尼的药代动力学。西曲替尼每日剂量35mg联合纳武利尤单抗3mg/kg和伊匹木单抗1mg/kg导致免疫相关不良事件的发生率较高。随后将伊匹木单抗剂量降至0.7mg/kg，使得西曲替尼能够安全地增至每日100mg。总体而言，三联疗法的ORR为45.5%，DCR为86.4%，中位PFS为14.5个月，1年生存率为80.8%。中位OS和DOR未达到。西曲替尼的暴露量呈剂量依赖性增加。对12例患者纵向采集的肿瘤活检组织进行单细胞RNA测序，确定了一种与治疗耐药性和不良预后相关的肿瘤细胞特异性上皮-间质转化样程序。治疗耐药性的特征是从细胞毒性T细胞状态转变为耗竭T细胞状态，并富集M2样髓样细胞。观察到的基因表达动态和细胞状态的假设生成变化可能有助于为未来优化免疫治疗疗效的策略提供信息。临床试验注册号：NCT04518046。
