Toripalimab plus axitinib in patients with metastatic mucosal melanoma: 3-year survival update and biomarker analysis

Abstract

Background: Mucosal melanoma is an aggressive melanoma subtype with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Axitinib in combination with toripalimab, a humanized IgG4 mAb against PD-1, showed a promising response rate in patients with metastatic mucosal melanoma (MM) in a phase Ib study. Here, we report the updated overall survival (OS), duration of response (DoR), and biomarker analysis results.

Methods: Patients with advanced MM received toripalimab 1 or 3 mg/kg intravenously every 2 weeks combined with axitinib 5 mg orally two times per day until disease progression or unacceptable toxicity. Tumor programmed cell death ligand-1 (PD-L1) expression, tumor mutational burden (TMB), and gene expression profile (GEP) by messenger RNA sequencing were evaluated for correlation with survival.

Results: As of April 2, 2021, the median follow-up was 42.5 months. Among 29 chemotherapy-naïve patients with metastatic MM, the median OS was 20.7 months (95% CI 9.7 to 32.7 months); the median progression-free survival (PFS) was 7.5 months (95% CI 3.8 to 14.8 months); and the median DoR was 13.4 months (95% CI 5.5 to 20.6 months). The OS rates of 1, 2, and 3 years were 62.1%, 44.8%, and 31.0%, respectively. Biomarker analysis found that PD-L1 expression and TMB level were not associated with survival benefits. In contrast, a 12-GEP signature correlated with improved PFS (17.7 vs 5.7 months, p=0.0083) and OS (35.6 vs 17.6 months, p=0.039).

Conclusions: The 3-year survival update confirmed the antitumor activity and long-term survival benefit of the toripalimab plus axitinib combination in patients with advanced MM. The 12-gene GEP is of value in predicting the outcomes of vascular endothelial growth factor receptor-tyrosine kinase inhibitor and PD-1 blockade combination therapy, but requires further validation.

Trial registration numbers: NCT03086174.

Keywords: biomarkers; combination; drug therapy; immunotherapy; melanoma; tumor.

Figure 1

(A) Waterfall plot. Maximal change of tumor size from baseline assessed by investigator per RECIST V.1.1 (n=33). The length of the bar represents maximal decrease or minimal increase in target lesion(s). (B) Spider plot. Change in individual tumor burden over time from baseline assessed by investigator per RECIST V.1.1 (n=33). PD, progressive disease; PD-L1, programmed cell death ligand-1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TMB, tumor mutational burden.

Figure 2

(A) DoR by RECIST V.1.1. (B) PFS by Response Evaluation Criteria in Solid Tumors V.1.1. (C) OS of 29 patients with chemotherapy-naïve mucosal melanoma. Probability of survival is shown at indicated time points. Censored patients are marked with a vertical line in the graph. Numbers of patients at risk at indicated time points are shown below the x-axis. DoR, duration of response; OS, overall survival; PFS, progression-free survival.

Figure 3

Forest plot. Subgroup analysis of overall survival of 29 patients with chemotherapy-naïve mucosal melanoma. The scale is months (0–50) in the forest plot. ECOG, Eastern Cooperative Oncology Group; GEP, gene expression profile; LDH, lactate dehydrogenase; NA, not applicable; OS, overall survival; PD-L1, programmed cell death ligand-1; TMB, Tumor mutational burden.

Figure 4

PFS and OS by biomarkers include (A, B) PD-L1, (C, D) TMB, and (E, F) GEP. GEP, gene expression profile; OS, overall survival; PFS, progression-free survival; PD-L1, programmed cell death ligand-1; TMB, tumor mutational burden