PURPOSE: Metastatic 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 METHODS: We conducted a single-center, phase IB trial evaluating 
the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin 
G4 monoclonal antibody against PD-1 in combination with the VEGF receptor 
inhibitor axitinib in patients with advanced melanoma, including patients with 
chemotherapy-naïve 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.
RESULTS: Thirty-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-naïve 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.
CONCLUSION: The combination of toripalimab plus axitinib was tolerable and 
showed promising antitumor activity in patients with treatment-naïve 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.