Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial

Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can improve responses when combined with immune checkpoint therapy (ICT). We conducted a phase I trial to determine the optimal dose of triplet therapy with sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma (ccRCC). The primary endpoint was safety. The addition of even a low sitravatinib dose of 35 mg daily to nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events (irAEs). Subsequent dose reduction of ipilimumab to 0.7 mg/kg in combination with nivolumab 3 mg/kg allowed safe escalation of sitravatinib up to 100 mg daily. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Overall, the triplet combination in the dose-finding setting achieved an ORR of 45.5%, DCR of 86.4%, and a median PFS of 14.5 months with 72.7% of patients alive after a median follow-up of 15.7 months. Single-cell RNA-seq performed in longitudinally collected tumor biopsies from 12 patients treated with the triplet therapy identified a tumor cell-specific epithelial-mesenchymal transition (EMT)-like program associated with treatment resistance and poor outcomes in patients of this trial and in patients of the TCGA ccRCC cohort. Within the tumor microenvironment (TME), the emergence of treatment resistance was characterized by a transition from cytotoxic to exhausted T cell state and enrichment for M2-like myeloid cells. The observed changes in gene expression dynamics and cellular states in tumor cell and TME may help inform future strategies to optimize ICT efficacy. We performed single cell RNA sequencing (scRNA-seq) in 19 tissue samples collected from 12 patients enrolled in the trial. Baseline samples were collected from all 12 patients, while 4 patients also had samples collected prior to the second infusion of nivolumab plus ipilimumab (C2, Post timepoint) and 3 patients also had samples at the end of treatment (EOT timepoint) due to disease progression. Whenever possible, longitudinally collected samples were biopsied from the same organ site. contributor: Moon Shots Cancer Genomics Laboratory (CGL) contributor: MD Anderson institutional Advanced Genomics Technology Core (AGTC). *************************************************************** Raw data is not provided due to patient privacy concerns. *************************************************************** *************************************************************** Submitter states that missing raw files are due to patient privacy concerns. ***************************************************************

西他拉替尼（Sitravatinib）是一款免疫调节型酪氨酸激酶抑制剂（immunomodulatory tyrosine kinase inhibitor），与免疫检查点治疗（immune checkpoint therapy, ICT）联用时可增强抗肿瘤应答。本研究开展一项I期临床试验，旨在明确西他拉替尼联合纳武利尤单抗（nivolumab）、伊匹木单抗（ipilimumab）的三联疗法最优剂量，共纳入22例既往未接受治疗的晚期透明细胞肾细胞癌（clear cell renal cell carcinoma, ccRCC）患者。本试验的主要终点为安全性。
在纳武利尤单抗3mg/kg、伊匹木单抗1mg/kg的基础上联用每日35mg的低剂量西他拉替尼，即出现了高频率的免疫相关不良事件（immune-related adverse events, irAEs）。后续将伊匹木单抗剂量调整为0.7mg/kg并联合纳武利尤单抗3mg/kg后，可安全将西他拉替尼的剂量爬坡至每日100mg。
关键次要终点包括客观缓解率（objective response rate, ORR）、疾病控制率（disease control rate, DCR）、无进展生存期（progression-free survival, PFS）与总生存期（overall survival, OS）。在剂量探索阶段，该三联疗法整体实现了45.5%的ORR、86.4%的DCR，中位PFS为14.5个月；中位随访15.7个月时，72.7%的患者仍存活。
本研究对12例接受三联疗法患者的纵向采集肿瘤活检样本进行了单细胞RNA测序（single-cell RNA-seq），鉴定出一种肿瘤细胞特异性的上皮间质转化（epithelial-mesenchymal transition, EMT）样特征，该特征与本试验患者及TCGA ccRCC队列患者的治疗抵抗及不良预后相关。在肿瘤微环境（tumor microenvironment, TME）中，治疗抵抗的特征表现为细胞毒性T细胞向耗竭T细胞状态转变，以及M2样髓系细胞的富集。上述在肿瘤细胞与肿瘤微环境中观察到的基因表达动态及细胞状态变化，可为未来优化免疫检查点治疗疗效的策略提供参考依据。
本研究对入组12例患者的19份组织样本开展了单细胞RNA测序（single cell RNA sequencing, scRNA-seq）。所有12例患者均采集了基线样本；另有4例患者在第二次纳武利尤单抗联合伊匹木单抗输注前（C2, Post时间点）采集了样本，3例患者因疾病进展在治疗结束时（end of treatment, EOT）采集了样本。若条件允许，纵向采集的样本均取自同一器官部位。
贡献方为登月癌症基因组学实验室（Moon Shots Cancer Genomics Laboratory, CGL）及MD安德森癌症中心机构先进基因组技术核心实验室（MD Anderson institutional Advanced Genomics Technology Core, AGTC）。
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因患者隐私保护问题，本数据集未提供原始数据。
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提交者说明：原始文件缺失系受患者隐私保护政策限制。
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