Department of Medicine and the Dartmouth Cancer Center at Dartmouth-Hitchcock Medical Center, Section of Clinical Pharmacology, Lebanon, New Hampshire, USA.
Division of Hematology/Oncology, University of Vermont Cancer Center, Burlington, Vermont, USA.
Cancer Med. 2023 Jun;12(12):13100-13110. doi: 10.1002/cam4.5990. Epub 2023 May 6.
Sunitinib is a multi-target tyrosine kinase inhibitor (TKI) that inhibits VEGF receptor 1, 2, 3 (VEGFRs), platelet-derived growth factor receptor (PDGFR), colony-stimulating factor receptor (CSFR), and the stem cell factor receptor c-KIT. Temsirolimus inhibits mammalian target of rapamycin (mTOR) through binding to intracellular protein FKBP-12. Both agents are approved for the treatment of metastatic renal cell carcinoma (mRCC), have different anticancer mechanisms, and non-overlapping toxicities. These attributes form the scientific rationale for sequential combination of these agents. The primary objective of the study was to investigate the efficacy of alternating sunitinib and temsirolimus therapy on progression-free survival (PFS) in mRCC.
We undertook a phase II, multi-center, single cohort, open-label study in patients with mRCC. Patients were treated with alternating dosing of 4 weeks of sunitinib 50 mg PO daily, followed by 2 weeks rest, then 4 weeks of temsirolimus 25 mg IV weekly, followed by 2 weeks rest (12 weeks total per cycle). The primary endpoint was PFS. Secondary endpoints included clinical response rate and characterization of the toxicity profile of this combination therapy.
Nineteen patients were enrolled into the study. The median observed PFS (n = 13 evaluable for PFS) was 8.8 months (95% CI 6.8-25.2 months). Best responses achieved were five partial response, nine stable disease, and three disease progression according to RECIST 1.1 guidelines (two non-evaluable). The most commonly observed toxicities were fatigue, platelet count decrease, creatinine increased, diarrhea, oral mucositis, edema, anemia, rash, hypophosphatemia, dysgeusia, and palmar-plantar erythrodysesthesia syndrome.
Alternating sunitinib and temsirolimus did not improve the PFS in patients with mRCC.
舒尼替尼是一种多靶点酪氨酸激酶抑制剂（TKI），可抑制血管内皮生长因子受体 1、2、3（VEGFRs）、血小板衍生生长因子受体（PDGFR）、集落刺激因子受体（CSFR）和干细胞因子受体 c-KIT。替西罗莫司通过与细胞内蛋白 FKBP-12 结合来抑制哺乳动物雷帕霉素靶蛋白（mTOR）。这两种药物均被批准用于治疗转移性肾细胞癌（mRCC），具有不同的抗癌机制，且毒性不重叠。这些特性构成了这两种药物序贯联合应用的科学依据。该研究的主要目的是探讨交替使用舒尼替尼和替西罗莫司治疗 mRCC 患者的无进展生存期（PFS）的疗效。
我们开展了一项 II 期、多中心、单队列、开放性研究，纳入 mRCC 患者。患者接受舒尼替尼 50mg PO 每日 1 次，持续 4 周（用药周期），然后休息 2 周，接着给予替西罗莫司 25mg IV 每周 1 次，持续 4 周（用药周期），然后休息 2 周（每个周期共 12 周）。主要终点是 PFS。次要终点包括该联合治疗方案的临床缓解率和毒性特征。
共有 19 例患者入组该研究。中位观察到的 PFS（n=13 例可评估 PFS）为 8.8 个月（95%CI 6.8-25.2 个月）。根据 RECIST 1.1 标准，最佳缓解疗效为 5 例部分缓解、9 例疾病稳定和 3 例疾病进展（2 例不可评估）。最常见的毒性反应为乏力、血小板计数下降、血肌酐升高、腹泻、口腔黏膜炎、水肿、贫血、皮疹、低磷血症、味觉障碍和掌跖红斑感觉迟钝综合征。
交替使用舒尼替尼和替西罗莫司并未改善 mRCC 患者的 PFS。
