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Expert Discusses Emergence of New Agents in Adjuvant Melanoma

Shannon Connelly
Published Online:6:03 PM, Thu November 15, 2018

Hussein A. Tawbi, MD, PhD

The adjuvant treatment paradigm for melanoma has undergone a rapid expansion, with 2 new effective therapies approved in the past several years. Now, the field is aiming to develop combination regimens that are more effective and can provide improved long-term quality of life for patients.

The PD-1 inhibitor nivolumab (Opdivo) gained approval in December 2017, followed by the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) this May.

Nivolumab gained approval based on data from the CheckMate-238 trial, which compared nivolumab with ipilimumab in resected stage III or IV melanoma. Findings showed the 12-month RFS rate was 70.5% for nivolumab versus 60.8% for ipilimumab (HR, 0.65; 97.56% CI, 0.51-0.83; P <.001). In addition, grade 3/4 AEs were significantly lower for nivolumab: 14.4% versus 45.9%.

Dabrafenib and trametinib gained FDA approval as a result of findings from the COMBI-AD study, which tested the combination in high-risk BRAF V600 mutation-positive melanoma. The RFS rate was 59% versus 40% at 3 years for dabrafenib plus trametinib versus placebo and 54% versus 38% at 4 years, respectively (HR, 0.49; 95% CI, 0.40-0.59).

Ongoing trials are looking at combination treatments, including triplet regimens of immunotherapies with targeted therapies, with the goal of identifying even more effective treatment options for this population.

In an interview with Targeted Oncology during the 36th Annual CFS, Hussein A. Tawbi, MD, PhD, director of Melanoma Clinical Research and Early Drug Development in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the expansion of the treatment armamentarium for adjuvant melanoma and the next steps with research in this patient population.

TARGETED ONCOLOGY: Can you provide an overview of your presentation on adjuvant therapy in melanoma?

Tawbi: For patients with resectable melanoma, patients that start with skin primaries, and then sometimes may have nodal disease, surgery is very effective, and many patients get cured with surgery; however there is still a very high risk of relapse and death from melanoma. The new The American Joint Committee on Cancer (AJCC) has showed us that patients with stage III melanoma may have as high of a risk, for some categories as [much as a] 75% [risk] of dying of their melanoma. We are trying to develop therapies in that space to try to prevent recurrence and possibly death from melanoma.

In the last year, there has been a couple of really important clinical trials that came out that showed that treatment with anti-PD-1 antibodies like nivolumab was actually safe. It had about a 15% grade 3/4 toxicity rate. It was very effective, and more effective than the standard of care at the time, ipilimumab, in decreasing the risk of relapse, and also seems to be overall survival. 

That was really important. That became the standard of care FDA-approved regimen for those patients. At the same time, a trial that had been done several years earlier and finally read out was a targeted therapy, so taking pills dabrafenib and trametinib for patients that have a BRAF mutation. It actually did decrease the risk of relapse and death, also by almost 50%. There are really great changes in that area. We now have 2 approved therapies, 1 is targeted and 1 is immunotherapy. They seem to be comparable in terms of efficacy and our patients are now benefitting from that a lot. We actually put a lot of patients on standard of care treatment.

What I also discussed today is how we think about the next steps in the field. We're thinking about bringing more effective therapy, so combination treatments for this population. There's a trial with combination immunotherapy that has already been done. We're proposing and working on a trial of combination triplet therapies with immunotherapies and targeted therapy in that population. The last thing I discussed was that even stage II patients which are typically thought of as primaries without nodal disease that they have a great prognosis, but actually a subpopulation of them still has a high risk of relapse and death of melanoma. We are already doing clinical trials in that patient category as well.

TARGETED ONCOLOGY: What is it about melanoma that makes it respond so well to immunotherapy?

Tawbi: Melanoma that starts on the skin has a really high rate of mutations. The causative agent to a lot of extent is sun exposure and UV radiation, so that leads to a lot of mutations. Melanoma has more mutations almost 8-fold than the next highest cancer, essentially. From my perspective, I tell the patients it kind of tickles the immune system a little more and all that we need it to do is figure out why the immune system wasn't capable of eradicating it. A big part of it has been immune checkpoints. By developing immune checkpoint inhibitors, we managed to gain a lot of responses in that disease. 

TARGETED ONCOLOGY: What is the biggest unmet need in the treatment of melanoma?

Tawbi: I have a whole list of things we need to learn for our patients, but I think we need to focus on how we can cure the greatest number of patients we can with the least toxicity. I really think we are at a time where we have various combination options. We do need to develop combinations that are more effective and think about decreasing the risk of toxicity because we're getting patients that are cured even in the metastatic setting and we need to start thinking about their long-term outcome and quality of life as well. 

TARGETED ONCOLOGY: Is there anything you would like to add?

Tawbi: We have made a lot of progress, but there is still a lot to be done. We have a lot of patients with brain metastases that we need to focus on and try to help. It's about 40% of our population. We have some leeway there and some progress, but not nearly enough. I really think the participation in clinical trials is still the way to do that. Despite the fact that we have effective therapies, I think we need to continue to prioritize clinical trials.

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