High-low.

Top Line: Outside of the specific therapeutic target for BRAF-mutated melanoma, there are few prognostic or predictive biomarkers of treatment outcome.

The Study: Remember the landmark COMBI-AD trial? It randomized patients with V600E or V600K BRAF-mutated stage III melanoma to placebo or D/T, combo dabrafenib (a BRAF-inhibitor) and trametinib (a MEK-inhibitor). D/T improved 3-year relapse free survival (RFS) by almost 20% and survival by almost 10%. This secondary analysis of the the COMBI-AD trial explored the prognostic and predictive value of tumor mutation burden (TMB) and a T-cell inflamed gene expression profile (specifically the interferon-Ɣ pathway)—both associated with immunotherapy response. Roughly one-third of patients had high TMB, which was strongly associated with the V600K mutation. A high TMB was also prognostic of better RFS among patients treated with placebo, but interestingly not among those treated with D/T. In contrast, high IFN-Ɣ signature was prognostic of better outcome regardless of treatment. While TMB-high / IFN-high melanoma had the best outcomes overall, TMB-low / IFN-high derived the greatest benefit from targeted therapy.

TBL: Tumor mutation burden and T-cell inflamed gene signature predict response to BRAF-targeted therapy, in addition to immunotherapy, and can thus help guide treatment sequencing for stage III melanoma. | Dummer, Lancet Oncol 2020