Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial
Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial
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DOI：
10.1016/s1470-2045(18)30107-4
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发表时间：
2018-04-01
期刊：
影响因子：
51.1
通讯作者：
Rini, Brian I.
中科院分区：
文献类型：
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作者：
Choueiri, Toni K.;Larkin, James;Rini, Brian I.
免疫检查点抑制剂和VEGF途径抑制剂联合治疗晚期肾细胞癌患者可能比单独使用这些药物增加临床获益。在这里，我们报告了avelumab（一种针对程序性细胞死亡蛋白配体PD-L1的IgG1单克隆抗体）和axitinib（一种被批准用于晚期肾细胞癌二线治疗的VEGF受体抑制剂）联合治疗晚期肾细胞癌患者的初步结果。JAVELIN肾100研究是一项正在进行的开放标签、多中心、剂量发现和剂量扩展的1b期研究，在美国、英国和日本的14个中心进行。符合条件的患者年龄为18岁或以上（日本的>= 20岁），组织学或细胞学证实为透明细胞成分的晚期肾细胞癌，预期寿命至少为3个月，东部肿瘤合作组的表现状态为1或以下，既往未接受过晚期肾细胞癌的全身治疗，并切除了原发肿瘤。进入剂量寻找阶段的患者接受5mg阿西替尼口服，每天两次，持续7天，随后每2周静脉注射10mg /kg阿维单抗和5mg阿西替尼口服，每天两次的联合治疗。根据剂量寻找阶段的药代动力学数据，另外10名患者被纳入剂量扩展阶段并被分配到该方案。其他处于剂量扩张期的患者直接开始联合治疗。主要终点是阿维单抗加阿西替尼治疗前4周（2个周期）的剂量限制性毒性。对所有接受至少一剂avelumab或axitinib治疗的患者进行了安全性和抗肿瘤活性分析。该试验已在ClinicalTrials.gov注册，注册号NCT02493751。在2015年10月30日至2016年9月30日期间，我们招募了6名患者进入剂量寻找期，49名患者进入剂量扩展期。在剂量寻找阶段治疗的6例患者中报告了阿西替尼引起的3级蛋白尿的剂量限制性毒性。截止日期（2017年4月13日），6例剂量寻找期患者中有6例（100%,95% CI 54-100）， 49例剂量扩展期患者中有26例（53%,38-68）确认客观缓解（55例患者中有32例[58%，44-71]）。55例患者中32例（58%）出现3级或更严重的治疗相关不良事件，最常见的是16例（29%）患者出现高血压，4例（7%）患者出现谷丙转氨酶、淀粉酶和脂肪酶浓度升高和掌跖红肿综合征。55例患者中有6例（11%）在数据截止前死亡，5例（9%）死于疾病进展，1例（2%）死于治疗相关的自身免疫性心肌炎。在剂量寻找阶段结束时，联合用药的最大耐受剂量为avelumab 10 mg/kg / 2周，axitinib 5 mg/ 2天。阿维单抗联合阿西替尼治疗初治晚期肾细胞癌患者的安全性似乎是可控的，并且与每种药物单独使用的安全性一致，抗肿瘤活性的初步数据令人鼓舞。一项3期试验正在评估avelumab和axitinib与舒尼替尼单药治疗的比较。
Background The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma.Methods The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (>= 20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751.Findings Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily.Interpretation The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy.