Thirasastr Prapassorn, Somaiah Neeta
Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Clin Exp Gastroenterol. 2023 Feb 10;16:11-19. doi: 10.2147/CEG.S351839. eCollection 2023.
In patients with gastrointestinal stromal tumors (GIST), systemic treatment after disease progression on imatinib is challenging. Sunitinib and regorafenib are approved in the second- and third-line setting, respectively, with activity against certain secondary mutations with comparatively much lower response rates and survival increment compared to imatinib. All three of these drugs were serendipitously found to have activity in GIST, starting with imatinib, which was formulated for its ability to inhibit in chronic myelogenous leukemia. Ripretinib is a drug that was specifically developed as a more potent KIT tyrosine kinase inhibitor (TKI), with broad-spectrum activity against the mutations encountered in GIST. Encouraging responses in early and later lines of treatment in the Phase 1 trial of ripretinib in GIST led to the rapid development of this novel drug. In a Phase 3 randomized clinical trial with cross-over, ripretinib demonstrated superior PFS and overall survival (OS) in 4th-line treatment and beyond compared to placebo. This established 150 mg once daily ripretinib as the standard of care in this setting. Ripretinib is generally well tolerated, with common adverse effects of hair loss, diarrhea, cramps, fatigue and nausea. The favorable safety profile and efficacy of ripretinib prompted its evaluation in a randomized phase 3 trial in the 2nd-line treatment setting. However, it did not result in a longer PFS duration than sunitinib. Although the efficacy of ripretinib in this unselected patient population was not significantly different from that of sunitinib, the tolerability profile was better. This review article aims to review the efficacy and tolerability profile of ripretinib, together with its role in the setting of unresectable or metastatic GIST.
在胃肠道间质瘤（GIST）患者中，伊马替尼治疗疾病进展后的全身治疗具有挑战性。舒尼替尼和瑞戈非尼分别被批准用于二线和三线治疗，它们对某些继发突变具有活性，但与伊马替尼相比，缓解率和生存期增加相对较低。这三种药物都是偶然发现对GIST有活性的，首先是伊马替尼，它最初是因其抑制慢性粒细胞白血病的能力而研发的。瑞派替尼是一种专门开发的更有效的KIT酪氨酸激酶抑制剂（TKI），对GIST中遇到的突变具有广谱活性。瑞派替尼在GIST的1期试验中，早期和晚期治疗均显示出令人鼓舞的反应，促使这种新药迅速得到开发。在一项3期交叉随机临床试验中，与安慰剂相比，瑞派替尼在四线及后续治疗中显示出更好的无进展生存期（PFS）和总生存期（OS）。这确立了每日一次150 mg瑞派替尼作为该情况下的治疗标准。瑞派替尼总体耐受性良好，常见不良反应包括脱发、腹泻、痉挛、疲劳和恶心。瑞派替尼良好的安全性和疗效促使其在二线治疗环境中进行随机3期试验评估。然而，它并未导致PFS持续时间长于舒尼替尼。尽管瑞派替尼在这个未选择的患者群体中的疗效与舒尼替尼没有显著差异，但其耐受性更好。这篇综述文章旨在回顾瑞派替尼的疗效和耐受性概况，以及它在不可切除或转移性GIST中的作用。
