Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G4 Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial
Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G4 Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial
复制标题
DOI：
10.1200/jco.19.00210
复制
发表时间：
2019-11-10
影响因子：
45.3
通讯作者：
Guo, Jun
中科院分区：
文献类型：
--
作者：
Sheng, Xinan;Yan, Xieqiao;Guo, Jun
转移性黏膜黑色素瘤对抗程序性细胞死亡-1(PD-1)单一治疗的反应很差。血管内皮生长因子(VEGF)在肿瘤微环境中发挥着重要的免疫抑制作用。我们进行了一项单中心IB期试验，评估了抗PD-1的人源化免疫球蛋白G(4)单抗与血管内皮生长因子受体抑制剂Axitinib联合治疗晚期黑色素瘤的安全性和初步疗效，其中包括化疗后的粘膜黑色素瘤患者(88%)。在剂量递增和队列扩大研究中，患者每两周静脉滴注托里帕利单抗1或3 mg/kg，联合阿西替尼5 mg，每天两次，直到确认疾病进展、不可接受的毒性或自愿停药。首要目标是安全。次要目标包括疗效、药代动力学、药效学、免疫原性和肿瘤组织生物标志物。未观察到剂量限制毒性。97%的患者经历了与治疗相关的不良事件(TRAE)。最常见的TRAE是轻微的(1级或2级)，包括腹泻、蛋白尿、手足综合征、乏力、AST或ALT升高、高血压、甲状腺功能减退或甲亢和皮疹。39.4%的患者出现3级或以上的TRAE。截至截止日期，29例化疗后转移性粘膜黑色素瘤患者中，14例(48.3%，95%CI，29.4%~67.5%)获得客观缓解，按RECIST 1.1版疗效评价标准，中位无进展生存期为7.5个月(95%CI，3.7个月未达到)。结论托里帕利单抗联合阿昔替尼治疗转移性黏膜黑色素瘤患者可耐受，具有良好的抗肿瘤活性。参加这项研究的患者都是亚洲人，这种联合疗法必须在包括非亚洲人群的随机III期试验中得到验证，然后才能成为治疗的标准。
PURPOSEMetastatic mucosal melanoma responds poorly to anti?programmed cell death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. The combination of VEGF inhibition and PD-1 blockade provides therapeutic opportunities for patients refractory to either therapy alone.PATIENTS AND METHODSWe conducted a single-center, phase IB trial evaluating the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin G(4) monoclonal antibody against PD-1 in combination with the VEGF receptor inhibitor axitinib in patients with advanced melanoma, including patients with chemotherapy-na?ve mucosal melanomas (88%). Patients received toripalimab at 1 or 3 mg/kg via intravenous infusion every 2 weeks, in combination with axitinib 5 mg orally twice a day, in a dose-escalation and cohort-expansion study until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and tumor tissue biomarkers.RESULTSThirty-three patients were enrolled. No dose-limiting toxicities were observed. Ninety-seven percent of patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included diarrhea, proteinuria, hand and foot syndrome, fatigue, AST or ALT elevation, hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs occurred in 39.4% of patients. By the cutoff date, among 29 patients with chemotherapy-na?ve mucosal melanoma, 14 patients (48.3%; 95% CI, 29.4% to 67.5%) achieved objective response, and the median progression-free survival time was 7.5 months (95% CI, 3.7 months to not reached) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.CONCLUSIONThe combination of toripalimab plus axitinib was tolerable and showed promising antitumor activity in patients with treatment-na?ve metastatic mucosal melanoma. Patients enrolled in this study were all Asian, and this combination therapy must be validated in a randomized phase III trial that includes a non-Asian population before it can become a standard of care.