Pant Shubham, Cho Byoung Chul, Kyriakopoulos Christos E, Spira Alexander, Tannir Nizar, Werner Theresa L, Yan Xiaohong, Neuteboom Saskia, Chao Richard, Goel Sanjay
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Invest New Drugs. 2024 Oct;42(5):547-558. doi: 10.1007/s10637-024-01465-9. Epub 2024 Aug 21.
Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n = 38, CRPC n = 10) received ≥ 1 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, P = 0.015 (null hypothesis [ORR ≤ 10%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. Clinical trial registration:ClinicalTrials.gov NCT02219711.
西曲替尼（MGCD516）是几种密切相关的致癌性酪氨酸激酶受体的口服抑制剂，这些受体包括血管内皮生长因子受体2（VEGFR-2）、AXL和间充质上皮转化因子（MET）。在参与1/1b期研究的两个组织学队列（抗血管生成难治性透明细胞肾细胞癌[RCC]和伴有骨转移的去势抵抗性前列腺癌[CRPC]）患者中报告了西曲替尼的安全性和抗肿瘤活性。患者采用基于观察到的客观缓解情况的三阶段设计入组。客观缓解率（ORR）是主要终点。还评估了缓解持续时间、无进展生存期（PFS）、总生存期（OS）和安全性。总体而言，48例患者（RCC 38例，CRPC 10例）接受了≥1剂西曲替尼。两个队列均经过大量预处理（既往全身治疗的中位数：RCC队列3次，CRPC队列6次）。在RCC队列中，ORR为25.9%，P = 0.015（原假设[ORR≤10%]被拒绝）。缓解持续存在（中位持续时间13.2个月）。中位PFS为9.5个月，中位OS为30.0个月。在CRPC队列中未观察到客观缓解；中位PFS和OS分别为5.8个月和10.1个月。在两个队列中，腹泻（72.9%）、疲劳（54.2%）和高血压（52.1%）是最常见的全因治疗中出现的不良事件（TEAE）。腹泻和呕吐（均为6.3%）是最常见的被认为与研究治疗相关的严重TEAE。西曲替尼在既往抗血管生成抑制剂治疗难治的透明细胞RCC患者中显示出可接受的安全性和有前景的临床活性。在CRPC和骨转移患者中未观察到临床活性的强指标。临床试验注册：ClinicalTrials.gov NCT02219711。
