pTERT mutational status is associated with survival in stage IV melanoma patients receiving first-line immune therapy.

Background: TERT promoter mutations are the most prevalent mutations in melanoma. In this study, we investigated clinical characteristics and survival after first line therapies in a cohort of melanoma patients with known TERT promoter (pTERT) mutation status.

Methods: Sequencing data from 2013 to 2021 covering 29 genes and the pTERT status was assessed and 774 melanomas patients with known pTERT status and clinical data were analyzed. Progression free survival (PFS) and overall survival (OS) of 374 melanoma patients in AJCC-stage IV who received first-line immune checkpoint inhibitors (ICI, anti-CTLA4 /anti-PD1 combination therapy or anti-PD1 monotherapy) or targeted therapy (TT) were assessed applying Cox uni-/ multivariable analyses and Kaplan-Meier curves.

Results: The cohort included 573 cutaneous, 69 mucosal, 37 acral and 95 MUP (melanomas of unknown primary) melanoma patients with a median observational time from first diagnosis to patient death or censoring of 38.5 months. TERT promoter mutations were identified in 476 melanomas (61.5 %). Survival analysis of 374 patients with stage IV disease undergoing first-line systemic therapy (ICI or TT) suggested prolonged PFS and OS for patients with pTERT mutation positive tumors (pTERT(+)). Particularly, pTERT(+) patients receiving anti-CTLA4/anti-PD1 therapy showed mPFS of 14.8 months (95 % CI: 7.1-40.3) and mOS of 105.2 months (95 % CI: 27.6-not reached) compared to pTERT(-) patients with mPFS of 5.5 months (95 % CI: 2.7-10.0) and mOS of 14.7 months (95 % CI: 11.7-24.1).

Conclusions: Our findings suggest that presence of a pTERT mutation in melanomas might favor PFS and OS after first line ICI with the greatest improvement after receiving anti-CTLA4 / anti-PD1. If validated in larger prospective studies, pTERT mutation status may be a valuable prognostic marker for stage IV melanoma patients.