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

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-naive 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.