Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.
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DOI：
10.1016/s1470-2045(20)30168-6
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发表时间：
2020-07
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通讯作者：
von Mehren M
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作者：
Blay JY;Serrano C;Heinrich MC;Zalcberg J;Bauer S;Gelderblom H;Schöffski P;Jones RL;Attia S;D'Amato G;Chi P;Reichardt P;Meade J;Shi K;Ruiz-Soto R;George S;von Mehren M
KIT原癌基因、受体酪氨酸激酶（KIT）和血小板衍生生长因子受体α (PDGFRA)抑制剂的耐药是晚期胃肠道间质肿瘤患者的临床挑战。我们比较了利普雷替尼（一种开关控制酪氨酸激酶抑制剂，对广谱KIT和PDGFRA突变有活性）与安慰剂在既往治疗的晚期胃肠道间质肿瘤患者中的疗效和安全性。在这项双盲、随机、安慰剂对照的三期研究中，我们招募了来自12个国家29家专科医院的成年患者。我们纳入了年龄在18岁或以上的患者，这些患者患有晚期胃肠道间质肿瘤，至少接受伊马替尼、舒尼替尼和瑞非尼治疗进展，或尽管剂量调整，但对这些治疗的任何不耐受，并且他们的东部肿瘤合作组（ECOG）表现状态为0-2。符合条件的患者被随机分配（2:1）接受每日一次口服150毫克的利普雷替尼（利普雷替尼组）或每日一次安慰剂（安慰剂组）。随机化是通过一个互动反应系统进行的，该系统使用随机排列的6个块大小，并根据先前治疗的数量和ECOG表现状态进行分层。患者、研究者、研究人员和赞助研究团队对患者的治疗分配保密，直到盲法独立中心评价（BICR）显示患者的疾病进展。主要终点是通过BICR评估的无进展生存期。初步分析是在意向治疗人群中进行的，并对接受至少一剂研究药物的患者进行了安全性评估。随机分配到安慰剂组的患者在疾病进展时被允许转为使用150 mg的利普雷替尼。INVICTUS研究已在ClinicalTrials.gov注册，注册号为NCT03353753，并在WHO国际临床试验注册平台注册，注册号为EUCTR2017-002446-76-ES；后续工作正在进行中。在2018年2月27日至11月16日期间，154名接受评估的患者中有129名被随机分配接受利普雷替尼（n=85）或安慰剂（n=44）。截至数据截止日期（2019年5月31日），利普雷替尼组的中位随访时间为6.3个月（IQR 3.2 - 8.2），安慰剂组的中位随访时间为1.6个月（IQR 1.1 - 1.7），利普雷替尼组和安慰剂组分别有51例和37例患者出现无进展生存事件。在双盲期间，利普雷替尼组的中位无进展生存期为6.3个月（95% CI 4.6 - 6.9），而安慰剂组的中位无进展生存期为1.0个月（0.9 - 1.7）（风险比0.15,95% CI 0.09 - 0.25; p< 0.0001）。在利普雷替尼组（n=85）中最常见的3级或4级治疗相关不良事件（> %）包括脂肪酶升高（4例[5%]）、高血压（3例[4%]）、疲劳（2例[2%]）和低磷血症（2例（2%））；在安慰剂组（n=43）中，最常见的3级或4级治疗相关不良事件是贫血（3例[7%]）、疲劳（1例[2%]）、腹泻（1例[2%]）、食欲下降（1例[2%]）、脱水（1例[2%]）、高钾血症（1例[2%]）、急性肾损伤（1例[2%]）和肺水肿（1例[2%]）。85名接受利普雷替尼的患者中有8名（9%）报告了治疗相关的严重不良事件，43名接受安慰剂的患者中有3名（7%）报告了治疗相关的严重不良事件。治疗相关死亡在安慰剂组中发生1例（感染性休克和肺水肿），在利普雷替尼组中发生1例（死亡原因未知；患者在睡眠中死亡）。与安慰剂相比，利普雷替尼显著提高了中位无进展生存期，并且在对批准的治疗有耐药性的晚期胃肠道间质肿瘤患者中具有可接受的安全性。Deciphera药品。
Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours. In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient’s treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing. Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2–8·2) in the ripretinib group and 1·6 months (1·1–2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6–6·9) with ripretinib compared with 1·0 months (0·9–1·7) with placebo (hazard ratio 0·15, 95% CI 0·09–0·25; p<0·0001).The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep). Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. Deciphera Pharmaceuticals.