Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: The COMBI-AD investigators believe that tumour mutational burden (TMB) and interferon-gamma (IFNγ) gene expression may be useful biomarkers when choosing treatments for patients with stage III melanoma.
The prespecified exploratory biomarker analysis was performed for the phase III trial which compared adjuvant dabrafenib plus trametinib versus placebo for stage IIIA–C cutaneous melanoma with a BRAF V600E or V600K mutation, explain Reinhard Dummer, from University Hospital Zürich in Switzerland, and co-workers.
The team was able to perform DNA sequencing on baseline samples from 368 patients and gene expression profiling for tumour microenvironment features for 507 patients, after a median of 44 months of follow-up for the patients given the combination regimen and 42 months for controls.
Median relapse-free survival (RFS) did not significantly differ within the treatment arms for patients with or without baseline BRAF amplification or MAP2K1/MEK1 mutation, the researchers report in The Lancet Oncology.
TMB was significantly associated with RFS in the placebo arm, with a hazard ratio (HR) for relapse of 0.56 for patients in the upper third quantile for this biomarker. But a significant correlation between RFS and TMB was not found among the patients with high TMB who were given dabrafenib plus trametinib.
By contrast, the investigators report that patients in the lower two-third quantiles for TMB achieved a “substantial” RFS benefit from receipt of the targeted therapy regimen, with a significant HR of 0.49 compared with placebo.
They also found that patients who had an IFNγ gene expression signature above the median had better RFS than those with a below median value regardless of treatment received.
Nevertheless, the researchers observe that patients with a high TMB showed a trend towards being less likely to benefit from targeted therapy than those with a lower TMB, especially if they also had an IFNγ signature below the median, although neither HR for relapse reached statistical significance.
“Tumour mutational burden alone or in combination with interferon-γ gene expression signatures, or other markers for an adaptive immune response, might be of relevance for identification of patients who could derive clinical benefit from targeted therapy”, summarise Reinhard Dummer et al.
Giorgos Karakousis, from the Hospital of the University of Pennsylvania in Philadelphia, USA, notes in an accompanying comment that the current findings “contrast with a study of adjuvant PD-1 therapy, which showed more favourable clinical outcomes in patients with high tumour mutational burden and concomitant IFNγ expression.”
He continues: “Ultimately, prognostic models that not only predict risk of relapse, but also treatment efficacy and toxicity will allow clinicians and patients to jointly make the best overall informed decisions about treatment strategy.
“This personalised approach will no doubt result in cost savings by safely offering the optimal treatment to the appropriate patient”, adds Giorgos Karakousis.
“After decades of inadequate treatment options for patients with resected melanoma, we now have many choices—now we must learn how to choose best.”
Dummer R, Brase JC, Garrett J, et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol; Advance online publication 30 January 2020. https://doi.org/10.1016/S1470-2045(20)30062-0
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