Dr Long Highlights Long-Term Benefit of Dabrafenib/Trametinib in Melanoma
Georgina V. Long, MD, MSc, discussed the long-term follow-up data for the combination of adjuvant dabrafenib and trametinib in stage III BRAF-mutated melanoma.
Georgina V. Long, MD, MSc
The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) led to sustained survival benefits as an adjuvant treatment vs placebo when given for the treatment of patients with stage III melanoma, according to over 8 years of follow-up in the COMBI-AD trial (NCT01682083).1
Presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine, the final analysis revealed durable improvements in relapse-free survival (RFS) and distant metastasis-free survival, though the overall survival and melanoma-specific survival benefits did not reach statistical significance.
In an interview with Targeted OncologyTM, Georgina V. Long, MD, MSc, chair of melanoma medical oncology and translational research, at The University of Sydney in Australia, discussed these long-term follow-up data for the combination of adjuvant dabrafenib and trametinib in stage III BRAF-mutated melanoma.
Extreme close-up of a melanoma: © mavis - stock.adobe.com
Targeted Oncology: Can you discuss the COMBI-AD study in melanoma and the long-term results from the trial?
Long: At ASCO 2024, I presented the final analysis, the long-term data, and the overall survival from the clinical trial COMBI-AD. That is a randomized phase 3 clinical trial of adjuvant dabrafenib combined with trametinib vs placebo in resected stage III melanoma that is BRAF-mutated.
What we saw in this trial—patients were randomized 1:1—was a durable and sustained improvement in the relapse-free survival with dabrafenib and trametinib vs placebo. The hazard ratio was 0.52, and we had follow-up of nearly 10 years. So, this is a 48% reduction in the risk of relapse using adjuvant dabrafenib and trametinib. The 8-year landmark relapse-free survival was 50% for those that received dabrafenib and trametinib for 12 months vs placebo, which was 35%.
Similarly, we saw a nice, durable, and sustained improvement in the distant metastasis-free survival using adjuvant dabrafenib and trametinib versus placebo. And then we looked at the overall survival, and we saw a numerical improvement with adjuvant dabrafenib and trametinib vs placebo—a clear separation of the Kaplan-Meier curves and a hazard ratio of 0.80, favoring dabrafenib and trametinib. This is a 20% reduction in the risk of death from any cause. The issue was, though, the confidence interval just crossed 1, and the P-value was 0.063, so it was not statistically significant.
What were the safety findings?
Importantly, with safety, we saw that there were no new safety signals, and there were no irreversible toxicities with longer-term follow-up. So, this was very pleasing to see this durable and sustained improvement in the relapse-free survival and distant metastasis-free survival, and a good separation for Kaplan-Meier curves for overall survival and the melanoma-specific survival, which is an end point that is increasingly important when you are trying to cure patients.
What does this mean for the field?
We have 3 available adjuvant treatments in melanoma: 2 anti-PD-1 drugs, and this is our only BRAF-targeted combination available for adjuvant treatment. We have not seen any overall survival benefit in the nivolumab vs ipilimumab trial that was analyzed, and there was no overall survival benefit. And we were yet to see any analysis of overall survival in the KEYNOTE-054 trial [NCT02362594] of pembrolizumab vs placebo. I suspect we will not see an overall survival benefit, and why? Because when we treat in the stage IV or the advanced setting, we are curing patients then as well. So, it was pretty amazing to see a separation of the curves in the COMBI-AD trial and a hazard ratio of 0.80, although not statistically significant.
What unmet needs still remain for patients with BRAF-mutant melanoma?
Going forward, what do we need to do for our BRAF-mutated patients with melanoma? When we look at our long-term data, we can see that more than 50% recur if you give adjuvant dabrafenib and trametinib. Also, we know in the metastatic setting that just under 50% die of advanced melanoma. So, we have got a lot more work to do. That is our greatest unmet need: finding what treatments work for those patients who are still dying from melanoma.
At ASCO 2024, we also presented the results from the NADINA trial [NCT04949113]. This was a plenary session at this ASCO. My colleague, Christian Blank, MD, PhD, presented these results. He and I have been working on this trial for many, many years, and we are pleased to see a 68% reduction in the event-free survival. So, an event is a recurrence, progression before surgery, or recurrence after surgery, or death from melanoma, when we give neoadjuvant combination nivolumab and ipilimumab. And that trial was vs just adjuvant nivolumab. So, this is a huge benefit and improvement for patients. I think this is a strategy that we need to be looking at for all patients with melanoma, including those with BRAF-mutant melanoma.
About that NADINA trial, what were the findings for patients who did not have a pathological response?
Nearly 60% of patients had a major pathological response. They did not get any further treatment after their neoadjuvant two doses of combination immunotherapy. But those who did not have a good response—so, a major pathological response—about 40% of patients, if they were BRAF-mutant, we switched them to combination dabrafenib and trametinib. And so, we see this real improvement in the event-free survival overall in the trial, with a decrease in the risk of 68%.
What kind of conversations would you recommend that patients have with clinicians before starting this dabrafenib/trametinib combination?
Any patient who comes in with resectable stage III melanoma that’s clinically detectable needs to be talking to their physicians, their doctors, about neoadjuvant treatment, particularly neoadjuvant immunotherapy. Patients with lower-risk or not clinically detectable stage III melanoma, then they need to discuss with their physicians adjuvant treatment, and that is where the discussion of dabrafenib and trametinib vs the other available adjuvant treatments occurs. The great thing about dabrafenib and trametinib is the toxicities are reversible.
