In an exploratory biomarker analysis from the COMBI-AD trial, reported in The Lancet Oncology, Dummer et al found that tumor mutational burden (TMB) and interferon-gamma gene-signature profiles might be associated with an augmented benefit of adjuvant dabrafenib plus trametinib in resected BRAF V600–mutant stage III melanoma.
The phase III COMBI-AD trial showed that the combination reduced the risk of relapse vs placebo in this setting. In the current analysis, intrinsic tumor genomic features were assessed in 368 patients, and tumor microenvironment characteristics were assessed in 507 patients.
Key Findings
Baseline MAPK pathway genomic alterations did not affect combination treatment benefit or outcomes in either the combination group or placebo group. An interferon-gamma gene-expression signature higher than the median was associated with prolonged relapse-free survival in both groups, with hazard ratios (HRs) of 0.54 (P = .0002) in the placebo group and 0.41 (P < .0001) in the dabrafenib plus trametinib group.
TMB was independently associated with better relapse-free survival in the placebo group (HR for top third vs bottom third of TMB values = 0.56, P = .0056) but not in the dabrafenib-plus-trametinib group (HR = 0.83, P = .44). However, patients with TMB in the lower two tertiles who received dabrafenib plus trametinib had improved relapse-free survival vs those who received placebo (HR = 0.49, P < .0001). Those with higher TMB had a nonsignificant benefit vs placebo patients with higher TMB (HR = 0.75, P = .27), with a smaller difference in outcome observed among those with an interferon-gamma signature lower than the median (HR = 0.88, P = .74).
KEY POINTS
- Tumor mutational burden (TMB) was independently associated with better relapse-free survival in the placebo group but not in the dabrafenib-plus-trametinib group.
- Patients with TMB in the lower two tertiles who received dabrafenib plus trametinib had improved relapse-free survival vs those who received placebo.
- Those with higher TMB had a nonsignificant benefit vs placebo patients with higher TMB, with a smaller difference in outcome observed among those with an interferon-gamma signature lower than the median.
The investigators concluded: “Tumour mutational burden alone or in combination with [interferon-gamma] gene-expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted.”
Reinhard Dummer, MD, University Hospital Zurich Skin Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.
