Evaluating clinical responses to BRAF inhibition in BRAF/TERT promoter mutated melanoma.
Authors: Ciccosanti Colleen , Hershey Alexander , Chen Chunxia , Moore Dirk F. , Stephenson Ryan D. , Weiner Joseph P. , Koshenkov Vadim P. , Silk Ann W. , Mehnert Janice M. , Berger Adam C. , Groisberg Roman 
Published: June 2021

e21551

Background: Combined BRAF/MEK inhibition results in improved progression free and overall survival in BRAF mutated melanoma, but significant response is not universally observed. TERT promoter activating mutations often co-occur with BRAF mutations and have been associated with aggressive features and poorer prognosis. The TERT promotor inhibits apoptosis via a mechanism dependent upon BRAF mutant MAPK activation. Preclinical data in mouse models suggests that BRAF/TERT genetic duet melanomas are associated with improved response to BRAF/MEK inhibition as compared with BRAF mutant/TERT-WT melanomas. Methods: We performed a single center retrospective analysis of adults with melanoma with confirmed BRAF mutations +/- TERT promoter mutations. Responses and progression free survival in response to BRAF/MEK inhibition was assessed. Differences in RR and PFS were compared using Kaplan-Meier and Log-Rank. Results: 52 cases of BRAF/TERT genetic duet and BRAF mutated/TERT-WT melanomas were assessed. A total of 24 patients received BRAF/MEK inhibitors over the course of treatment meeting criteria for study inclusion; 9 (37.5%) BRAF/TERT genetic duet and 15 (62.5%) BRAF mutated/TERT-WT. BRAF V600E was present in 19/24 (79.2%) and V600K in 5/24 (20.8%). In the genetic duets, TERT -146C > T was present in 4/9 (44.4%), -124C > T in 2/9 (22.2%), -139_-138CC > TT in 2/9 (22.2%), and a SNV in 1/9 (11.1%). Mean age at diagnosis was 56 ± 13.5 years and 62.5% were male. ECOG PFS was 0-1 in 15/24 (62.5%), 2-3 in 6/24 (25%), and unreported in 3/24 (12.5%). Mean LDH at start of therapy was 391 (range 81-1664). At initial diagnosis 20.8% were Stage I, 25% Stage II, 37.5% Stage III, and 16.7% Stage IV. Two or more sites of disease were present in 10/24 (41.7%) and 2/24 (8.3%) had CNS metastases. BRAF/MEK directed therapy was first line in 6/24 (25%) of patients, others received prior immunotherapy. No significant differences between groups were observed in baseline demographics, disease state at diagnosis, or treatment history. In BRAF/TERT genetic duet melanomas CR was observed in 1/9 (11.1%), PR in 7/9 (77.8%), and NR in 1/9 (11.1%). In BRAF mutated/TERT-WT CR was observed in 3/15 (20%), PR in 11/15 (73.3%), and NR in 1/15 (6.7%). BRAF/TERT genetic duets were observed to initially have somewhat better PFS on first exposure to BRAF/MEK directed therapy but the PFS curves crossed at about 5 months with no significant difference observed overall (p = 0.40). Conclusions: This study is the first to report on outcomes of BRAF/MEK directed therapy in BRAF/TERT genetic duet vs BRAF mutated/TERT-WT melanomas in humans. While preclinical data from mouse models observed an improved response to BRAF/MEK inhibition in genetic duet tumors, no significant difference was observed. Our study is limited by small sample size. A multicenter analysis may be of interest to better understand the effects of BRAF inhibition in patients with BRAF/TERT genetic duet melanoma.