■这项Ib/II期试验评估了卡马替尼联合司他珠单抗或单独司他珠单抗在晚期肝细胞癌(HCC)患者中的安全性和有效性。
■对索拉非尼有进展或不耐受的合格患者接受了递增剂量的卡马替尼200mg,300毫克,在Ib期研究中,每天两次400mg(bid)加司他珠单抗每3周300mg(q3w)。一旦确定了推荐的II期剂量(RP2D),II期研究开始时采用卡马替尼+司帕珠单抗(n=32)或单用司帕珠单抗(n=30)进行随机1:1治疗.主要终点是安全性和耐受性(Ib期),并且根据RECISTv1.1对组合与使用贝叶斯逻辑回归模型(第二阶段)的单剂武器。
■在Ib阶段,卡马替尼联合司他珠单抗的RP2D确定为400mgbid.据报道,在一名患者中,卡马替尼400mgbid+司帕珠单抗300mgq3w剂量水平的剂量限制性毒性包括3级腹泻。未达到II期研究的主要终点。卡马替尼+司他珠单抗组观察到的总体反应率为9.4%,与10%的司他珠单抗组。最常见的任何级别治疗相关的不良事件(TRAEs,≥20%)为恶心(37.5%),虚弱及呕吐(各28.1%),腹泻,发热,合并组的食欲下降(各25.0%);TRAEs≥10%为瘙痒(23.3%),和皮疹(10.0%)在单用司帕珠单抗组。
■400mgbid加司帕珠单抗300mgq3w的卡马替尼被确定为RP2D,具有可控的毒性,没有明显的安全信号,但在先前接受过索拉非尼治疗的晚期HCC患者中,与司他珠单抗单药治疗相比,该联合用药未显示出更好的临床活性.
■同时靶向MET和程序性细胞死亡蛋白1可能在晚期HCC患者中提供协同临床益处。这是首次报道卡马替尼(MET抑制剂)和司帕珠单抗(程序性细胞死亡蛋白1抑制剂)联合作为索拉非尼治疗晚期HCC的二线治疗。在先前接受过索拉非尼治疗的晚期HCC患者中,与司他珠单抗单药治疗相比,该组合未显示出优异的临床活性。结果表明,显然需要确定HCC反应的可靠预测标志物,并确定将受益于检查点抑制剂+/-靶向治疗组合的HCC患者。
■NCT02795429。
UNASSIGNED: This phase Ib/II trial evaluated the safety and efficacy of capmatinib in combination with
spartalizumab or
spartalizumab alone in patients with advanced hepatocellular carcinoma (HCC).
UNASSIGNED: Eligible patients who had progressed or were intolerant to sorafenib received escalating doses of capmatinib 200 mg, 300 mg, and 400 mg twice a day (bid) plus spartalizumab 300 mg every 3 weeks (q3w) in the phase Ib study. Once the recommended phase II dose (RP2D) was determined, the phase II study commenced with randomised 1:1 treatment with either capmatinib + spartalizumab (n = 32) or
spartalizumab alone (n = 30). Primary endpoints were safety and tolerability (phase Ib) and investigator-assessed overall response rate per RECIST v1.1 for combination vs. single-agent arms using a Bayesian logistic regression model (phase II).
UNASSIGNED: In phase Ib, the RP2D for capmatinib in combination with spartalizumab was determined to be 400 mg bid. Dose-limiting toxicity consisting of grade 3 diarrhoea was reported in one patient at the capmatinib 400 mg bid + spartalizumab 300 mg q3w dose level. The primary endpoint in the phase II study was not met. The observed overall response rate in the capmatinib +
spartalizumab arm was 9.4% vs. 10% in the
spartalizumab arm. The most common any-grade treatment-related adverse events (TRAEs, ≥20%) were nausea (37.5%), asthenia and vomiting (28.1% each), diarrhoea, pyrexia, and decreased appetite (25.0% each) in the combination arm; TRAEs ≥10% were pruritus (23.3%), and rash (10.0%) in the spartalizumab-alone arm.
UNASSIGNED: Capmatinib at 400 mg bid plus
spartalizumab 300 mg q3w was established as the RP2D, with manageable toxicities and no significant safety signals, but the combination did not show superior clinical activity compared with spartalizumab single-agent treatment in patients with advanced HCC who had previously been treated with sorafenib.
UNASSIGNED: Simultaneous targeting of MET and programmed cell death protein 1 may provide synergistic clinical benefit in patients with advanced HCC. This is the first trial to report a combination of capmatinib (MET inhibitor) and spartalizumab (programmed cell death protein 1 inhibitor) as second-line treatment after sorafenib for advanced HCC. The combination did not show superior clinical activity compared with spartalizumab single-agent treatment in patients with advanced HCC who had previously been treated with sorafenib. The results indicate that there is a clear need to identify a reliable predictive marker of response for HCC and to identify patients with HCC that would benefit from the combination of checkpoint inhibitor +/- targeted therapy.
UNASSIGNED: NCT02795429.