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Updated: Aug 8, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- ("Triple")
Philipp Jansen1, Wolfgang Galetzka2, Georg C Lodde3
1Department of Dermatology, University Hospital Essen, Essen, Germany & German Cancer Consortium (DKTK), partner site Essen, Düsseldorf, Germany; Department of Dermatology, University Hospital Bonn, Bonn.
Background:
Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date.
Methods:
Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV.
Results:
184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2).
Conclusions:
While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.
Insights
Triple wild-type (tWT) melanomas, lacking common mutations, show limited response to immunotherapy. Survival outcomes for tWT melanomas treated with anti-CTLA-4/anti-PD-1 or anti-PD-1 were shorter than for melanomas with known mutations.
Area of Science:
- Oncology
- Dermatology
- Genetics
Background:
- Triple wild-type (tWT) melanomas lack BRAF, NRAS, and NF1 mutations, representing 5-10% of melanomas.
- These melanomas are poorly understood regarding clinical features and treatment response.
- This study presents the largest multicenter analysis of tWT melanomas.
Purpose of the Study:
- To characterize the clinical features and mutational landscape of tWT melanomas.
- To evaluate the efficacy of first-line immunotherapy in advanced (AJCC stage IV) tWT melanomas.
- To compare outcomes between anti-CTLA-4 plus anti-PD-1 combination therapy and anti-PD-1 monotherapy.
Main Methods:
- Targeted next-generation sequencing of 30 genes and the TERT promoter was performed on 3109 melanoma samples.
- 292 patients with tWT melanomas were identified.
- A subgroup of 141 stage IV tWT melanoma patients received either anti-CTLA-4 plus anti-PD-1 or anti-PD-1 monotherapy.
Main Results:
- The cohort included cutaneous, mucosal, acral, and unknown origin melanomas.
- TERT promoter mutations were found in 33.2% of all melanomas; 70.5% of tWT melanomas had fewer than three mutations.
- For stage IV patients, median progression-free survival (mPFS) was 6.2 months and median overall survival (mOS) was 24.8 months with combination therapy; mPFS was 4 months and mOS was 29.18 months with monotherapy.
Conclusions:
- Prognostic factors like TERT promoter mutations and tumor mutational burden (TMB) were similar between immunotherapy groups.
- Neither combination nor monotherapy demonstrated prolonged mPFS or mOS.
- Outcomes for tWT melanomas treated with these immunotherapies were notably shorter than those reported for melanomas with known oncogene mutations.
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