Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2019 Dec 15;25(24):7287-7293. doi: 10.1158/1078-0432.CCR-19-2150. Epub 2019 Aug 30.
Polyclonal emergence of KIT secondary mutations is a main mechanism of imatinib progression in gastrointestinal stromal tumor (GIST). Approved KIT inhibitors sunitinib and regorafenib have complementary activity against KIT resistance mutations. Preclinical evidence suggests that rapid alternation of sunitinib and regorafenib broadens the spectrum of imatinib-resistant subclones targeted.
Phase Ib study investigating continuous treatment with cycles of sunitinib (3 days) followed by regorafenib (4 days) in patients with tyrosine kinase inhibitor (TKI)-refractory GIST. A 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Plasma samples were analyzed for pharmacokinetics and circulating tumor DNA (ctDNA) studies using targeted error correction sequencing (TEC-seq) and droplet digital PCR (ddPCR).
Of the 14 patients enrolled, 2 experienced dose-limiting toxicities at dose level 2 (asymptomatic grade 3 hypophosphatemia). Sunitinib 37.5 mg/day and regorafenib 120 mg/day was the RP2D. Treatment was well-tolerated and no unexpected toxicities resulted from the combination. Stable disease was the best response in 4 patients, and median progression-free survival was 1.9 months. Combined assessment of ctDNA with TEC-seq and ddPCR detected plasma mutations in 11 of 12 patients (92%). ctDNA studies showed that KIT secondary mutations remain the main mechanism of resistance in TKI-refractory GIST, revealing effective suppression of KIT-mutant subpopulations in patients benefiting from the combination.
Sunitinib and regorafenib combination is feasible and tolerable. Rapid alternation of TKIs with complementary activity might be effective when combining drugs with favorable pharmacokinetics, potentially allowing active doses while minimizing adverse events. Serial monitoring with ctDNA may guide treatment in patients with GIST.
KIT 继发突变的多克隆出现是胃肠道间质瘤（GIST）伊马替尼进展的主要机制。已批准的 KIT 抑制剂舒尼替尼和瑞戈非尼对 KIT 耐药突变具有互补活性。临床前证据表明，舒尼替尼和瑞戈非尼的快速交替拓宽了靶向伊马替尼耐药亚克隆的谱。
一项 Ib 期研究，在对酪氨酸激酶抑制剂（TKI）耐药的 GIST 患者中，连续使用舒尼替尼（3 天）序贯瑞戈非尼（4 天）的治疗。采用 3+3 剂量方案确定推荐的 II 期剂量（RP2D）。使用靶向纠错测序（TEC-seq）和液滴数字 PCR（ddPCR）分析血浆样本进行药代动力学和循环肿瘤 DNA（ctDNA）研究。
在 14 名入组患者中，2 名患者在剂量水平 2 时出现剂量限制毒性（无症状的 3 级低磷血症）。舒尼替尼 37.5mg/天和瑞戈非尼 120mg/天是 RP2D。治疗耐受性良好，组合治疗未产生意外毒性。4 名患者的最佳反应为疾病稳定，中位无进展生存期为 1.9 个月。TEC-seq 和 ddPCR 联合评估 ctDNA 在 12 名患者中的 11 名（92%）中检测到血浆突变。ctDNA 研究表明，KIT 继发突变仍然是 TKI 耐药 GIST 耐药的主要机制，显示出在受益于组合的患者中有效抑制 KIT 突变亚群。
舒尼替尼和瑞戈非尼联合是可行和可耐受的。当将具有良好药代动力学的药物联合使用时，具有互补活性的 TKI 快速交替可能是有效的，这可能允许使用有效剂量，同时最大限度地减少不良反应。ctDNA 的连续监测可能指导 GIST 患者的治疗。
