Toripalimab plus axitinib effective in metastatic mucosal melanoma

A single-arm, open-label phase 1B study showed that toripalimab plus axitinib was well tolerated, as no dose-limiting toxicities were observed in 6 patients with metastatic mucosal melanoma. Further validation of the efficacy and safety of toripalimab plus axitinib in a phase 3 trial is required.

Compared with cutaneous melanoma, mucosal melanoma is a more aggressive malignancy with a high rate of distant metastases. Median overall survival (OS) is less than 12 months and mucosal melanoma appears to be largely resistant to traditional therapies, including immunotherapy. Expression of vascular endothelial growth factor (VEGF) has been shown to be associated with poor outcomes in patients with mucosal melanoma [1].

In the reported phase 1B study, the safety and efficacy of first-line treatment with the VEGFR inhibitor axitinib in combination with the anti-PD1 antibody toripalimab (approved in China for second-line treatment of metastatic melanoma) were evaluated [2]. Primary endpoint of the study was the dose-limiting toxicity; secondary endpoints included adverse events, objective response rate, duration of response, progression-free survival (PFS), and OS. In the dose-escalation part of the study 6 patients were enrolled; in the dose-expansion part of the study 33 patients were enrolled (60% female, >90% had no prior systemic chemotherapy). Patients were treated with axitinib (5 mg twice daily) plus toripalimab (3 mg/kg every 2 weeks).

The objective response rate was 48.5%: 1 patient had a complete response, 15 had a partial response, and 10 patients had stable disease. The median duration of response was 13.7 months, median PFS was 7.5 months (95% CI 3.9-14.8), median OS was 20.7 months (95% CI 10.2-not yet reached); 1-year OS rate was 65.5% and 2-year OS rate was 44.8%. Positive PD-L1 status (>1%) as well as tumour mutation burden ≥1 mut/Mbp were associated with a higher objective response rate, longer PFS, and a longer OS (not statistically significant due to the low numbers of patients). A combined gene expression profile of 12 genes – including genes related to inflammation and angiogenesis – was positively associated with response to axitinib plus toripalimab.

The combination therapy was well tolerated and no dose-limiting toxicities were observed in the initial 6 patients. Almost all patients in the dose-expansion part (32/33) experienced treatment-related adverse events, 13 patients (39%) experienced grade ≥3 treatment-related adverse events. Most prominent treatment-related adverse events grade ≥3 were proteinuria (n=3), hypertension (n=3), and neutropenia (n=3).

1. Simonetti O, et al. Anticancer Res. 2015; 35: 2113-2120.
2. Sheng X, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract 10007