Searching for Biomarkers to Better Guide Melanoma Therapy

Jeffrey S. Weber, MD, PhD


June 03, 2020

This transcript has been edited for clarity.

Hello. I'm Dr Jeffrey Weber. I'm a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center in New York City.

I apologize for not having the usual bow tie. As many of you know, we're in the midst of the COVID-19 pandemic and we've been asked not to wear ties when we're seeing patients.

I would like to talk to you about a recent article in Lancet Oncology by Dummer and colleagues, which is a very interesting biomarker study from the COMBI-AD trial. This was a well-performed trial of adjuvant therapy with dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) in patients with resected stage IIIA, IIIB, and IIIC melanoma by the American Joint Committee on Cancer (AJCC) 7th edition criteria. This trial began in 2015 and now has approximately 44 months of follow-up in the dabrafenib/trametinib arm and 42 months in the placebo arm. This was a nice phase 3 study where the clinical results for the primary endpoint of relapse-free survival have already been described.

We all would like to see biomarkers for the use of our targeted therapies and immunotherapies. This is one of the first publications that describes a relatively rigorous assessment of biomarkers where, of the 870 patients randomized on this trial (roughly 430 per arm), about 250 per arm had NanoString RNA data where an interferon gamma expression signature was assessed, and about 180 patients per arm had genetic sequencing done.

The first piece of information, which was a little surprising, was that there was no significant impact of any of the mutations on outcome, including the BRAF amplifications, mutations in the MAP kinase pathway, or MEK1/2 mutations.

The patients with BRAF amplification actually did a little bit better, but not statistically significantly so, than those without BRAF amplification when they received dabrafenib/trametinib (BRAF/MEK inhibitors) adjuvant therapy. There was one clear difference: The patients who received dabrafenib/trametinib obviously did better in the amplification group than those who received placebo. The same was observed for the MEK1/2 mutations. As you would expect, there was an impact of dabrafenib/trametinib, but there really wasn't a difference within each arm of having or not having the mutations or the amplifications. There was no evidence that genetic abnormalities would have an impact on the outcome of this adjuvant trial.

The very interesting data, however, related to the measurement of the tumor mutational burden (TMB) and the interferon gamma gene signature. TMB is probably a prognostic factor because patients with lower TMB seemed like they did a little bit better with dabrafenib and trametinib, suggesting that, unlike with immunotherapy, high TMB really doesn't yield benefit with dabrafenib and trametinib.

When both of the variables were put together, however, patients with high TMB and high interferon gamma signature did well; patients with low TMB and low interferon gamma signature did poorly. Of those in between, patients with low TMB and high interferon gamma signature did particularly well with dabrafenib/trametinib therapy versus placebo, which really makes you wonder whether patients with high TMB simply had other mutations that could potentially harm the impact of dabrafenib/trametinib adjuvant therapy. These were independent variables, and patients did better when both were added together without question.

Do they show that we've come up with the definitive biomarker by which to choose our patients? No. But what we do see is that in patients with low TMB and low interferon gamma, there were mutations in the Wnt signaling pathway and beta-catenin, which we know bodes a poor outcome. This gives more support to the idea that you can combine these different gene expression profiles and mutations.

This is Dr Jeffrey Weber. Thank you very much for your attention.

Jeffrey S. Weber, MD, PhD, is deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center and co-director of its Melanoma Research Program.

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