text: Axitinib in Combination with Toripalimab, a Humanized IgG4 mAb Against Programmed Death-1 (PD-1) in Patients with Metastatic Mucosal Melanoma: A Non-Randomized, Open-Label, Dose-Finding, and Cohort-Expansion Phase 1b Trial by Xinan Sheng, Xieqiao Yan, Zhihong Chi, Lu Si, Chuanliang Cui, Bixia Tang, Siming Li, Lili Mao, Bin Lian, Xuan Wang, Xue Bai, Li Zhou, Yan Kong, Jie Dai, Kai Wang, Xiongwen Tang, Huaning Zhou, Hai Wu, Hui Feng, Sheng Yao, Keith T. Flaherty, Jun Guo :: SSRN
  148 Pages Posted: 24 Jan 2019
  Harvard University - Harvard Medical School; Massachusetts General Hospital, Cancer Center
  Background: Metastatic mucosal melanoma responds poorly to anti-PD-1 monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. Combination therapy of VEGF inhibition with PD-1 blockade provides therapeutic opportunities for patients otherwise refractory to either monotherapy.
  Methods: We conducted a single center phase Ib trial evaluating the safety and preliminary clinical efficacy of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in combination with VEGFR inhibitor axitinib in chemotherapy naive advanced mucosal melanoma patients. Patients received toripalimab at 1 mg/kg or 3 mg/kg via IV infusion once every two weeks, in combination with 5 mg axitinib orally BID 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.
  Findings: Thirty-three patients were enrolled in the study. No dose-limiting toxicities (DLTs) were observed. 97% of patients experienced treatment-related adverse events (TRAE). The most common TRAE were mild (grade 1/2), including diarrhea, proteinuria, hand and foot syndrome, fatigue, AST/ALT elevation, hypertension, hypo- or hyper-thyroidism, bilirubin elevation, and rash. Grade 3 and above TRAE occurred in 39.4% subjects. By the data cutoff date, 20 (60.6%; 95% CI 42.1-77.1) patients achieved an objective response (complete or partial response) and median progression-free survival was 9.1 months (95% CI 3.9 to NE).
  Interpretation: The treatment combination of toripalimab plus axitinib was tolerable and showed promising anti-tumor activity in patients with treatment-naïve metastatic mucosal melanoma. A randomized phase III trial of toripalimab with axitinib versus standard of care is needed to validate the combination as a first-line treatment option for advanced mucosal melanoma.
  Trial Registration Number: Clinical trial (NCT03086174)
  Funding Statement: Study is sponsored by Shanghai Junshi Biosciences Co., LTD, Shanghai, China. This work was supported by grants from National Natural Science Foundation of China (81672696; 81772912), Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding support (ZYLX201603), and Beijing Municipal Science & Technology Commission (Z161100000516062).
  Declaration of Interests: Kai Wang is employed by OrigiMed. Xiongwen Tang, Huaning Zhou, Hai Wu, Hui Feng and Sheng Yao are employed by Shanghai Junshi Bioscience. The rest of authors
  have no disclosures of potential conflicts of interests.
  Ethics Approval Statement: The study was approved by Peking University Cancer Hospital institutional review board and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Each subject provided written informed consent.
  Keywords: Mucosal, Melanoma, anti-PD-1 antibody, Axitinib
  Sheng, Xinan and Yan, Xieqiao and Chi, Zhihong and Si, Lu and Cui, Chuanliang and Tang, Bixia and Li, Siming and Mao, Lili and Lian, Bin and Wang, Xuan and Bai, Xue and Zhou, Li and Kong, Yan and Dai, Jie and Wang, Kai and Tang, Xiongwen and Zhou, Huaning and Wu, Hai and Feng, Hui and Yao, Sheng and Flaherty, Keith T. and Guo, Jun, Axitinib in Combination with Toripalimab, a Humanized IgG4 mAb Against Programmed Death-1 (PD-1) in Patients with Metastatic Mucosal Melanoma: A Non-Randomized, Open-Label, Dose-Finding, and Cohort-Expansion Phase 1b Trial (January 17, 2019). Available at SSRN: https://ssrn.com/abstract=3320203 or http://dx.doi.org/10.2139/ssrn.3320203