Weber Highlights Adjuvant Melanoma Progress as Field Awaits Dabrafenib/Trametinib Approval

Jeffrey S. Weber, MD, PhD

Jeffrey S. Weber, MD, PhD

Experts in the field of melanoma are currently awaiting the pending FDA approval of dabrafenib (Tafinlar) and trametinib (Mekinist) as an adjuvant treatment for patients withBRAFV600E- or V600K-positive stage III melanoma, based on results of the phase III COMBI-AD study.

Findings of the study showed that the combination reduced the risk of relapse or death by 53% compared with placebo for these patients.After a median follow-up of 2.8 years, the 3-year relapse-free survival (RFS) rate with dabrafenib and trametinib was 58% compared with 39% for placebo (HR, 0.47; 95% CI, 0.39-0.58;P<.001).

Also in the adjuvant setting, nivolumab (Opdivo) was approved by the FDA this past December as a treatment for patients with completely resected melanoma with lymph node involvement or metastatic disease, based on findings from the phase III CheckMate-238 trial.

In the randomized trial, the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% (95% CI, 61.8%-70.6%) compared with 52.7% (95% CI, 47.8%-57.4%) for ipilimumab (Yervoy) in patients with stage IIIb/c or IV melanoma. There was a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor (HR, 0.65; 95% CI, 0.53-0.80;P<.0001).

Jeffrey S. Weber, MD, PhD, deputy director of the Perlmutter Cancer Center at NYU Langone Medical Center, recently discussed these 2 trials, as well as the most exciting ongoing research at his institution, in an interview withTargeted Oncologyduring the14th AnnualInternational Symposium on Melanoma and Other Cutaneous Malignancies hosted by Physicians&rsquo; Education Resource, LLC.

TARGETED ONCOLOGY:Can you discuss the most recent data in the adjuvant setting of melanoma?

Weber:We have had 2 outstanding, well-conducted, large phase III randomized trials [COMBI-AD and CheckMate-238] whose data were presented at the 2017 ESMO Annual Congress in Madrid, and were published simultaneously inThe New England Journal of Medicineonline. Both of them would suggest that we now have effective adjuvant therapies with very good hazard ratios for patients with resected stage III melanoma, and in the case of nivolumab, stage IV melanoma.

The impressive results of the CheckMate-238 trial led to a relatively rapid approval of nivolumab as adjuvant therapy for all patients with stage III and stage IV resected melanoma rendered free of disease. I'm pretty sure that soon enough we will see an FDA approval for the combination of dabrafenib and trametinib in patients with resected stage III melanoma.

TARGETED ONCOLOGY:As we await the FDA's decision on the approval of dabrafenib and trametinib, are there any adverse events that patients should be aware of?

Weber:The side effects of adjuvant dabrafenib and trametinib, in my view, have been very similar to the side effects that we see when we administer to patients with metastatic disease. It's really the fatigue and fevers, which can come on episodically and suddenly, and can be moderately debilitating. It may require the use of drug holds or drug holidays, and sometimes even steroids. That's a side effect that can be extremely annoying to patients.

In the COMBI-AD trial, I think it probably led to a significant number of treatment discontinuations. Sometimes you just can't control it. You can give someone high-dose steroids and it just keeps coming back. You're not going to put someone on 20 mg of prednisone every day for the next year.

That's the one thing I think occurs with patients that can be extremely annoying. Most of the other side effects are really one-offs, things that we have all seen—uveitis, hepatitis, nausea, vomiting, and diarrhea. The one reproducible side effect that I've noted, other than rash, which can occur with almost any of these drugs, is the fever and fatigue that comes on with BRAF/MEK drugs.

TARGETED ONCOLOGY: &nbsp;What areas of research are currently being explored at your institution?

Weber:One area is the use of HDAC inhibitors combined with immunotherapy to down modulate T regulatory cells and upregulate effector cells. I think that has a lot of potential. Another thing is the opportunity to suppress things like T regulatory cells and myeloid-derived suppressor cells with a TRAIL antibody. We have a trial where we combine those 2 together. Another area is the use of IDO inhibitors with PD-1 inhibition in patients with brain metastases. I think that has a lot of potential.

Applying all of these new ideas to the adjuvant mode is something I've been interested in for many years. I always think the best way to treat cancer is to not get it. Once you develop stage III disease, or high-risk stage II disease, the best way to deal with melanoma, like all other cancers, is to resect it, treat them, and avoid getting a recurrence. I think there will be a lot of excitement in the adjuvant mode with taking new ideas up there.

TARGETED ONCOLOGY:What are some other areas of research you think are particularly exciting?

Weber:The other exciting stuff that came out of this meeting are the extremely interesting data on the microbiome and how not only you are what you eat, but you are what you poop. In other words, the characterization of the bacterial species that inhabit our gut—of which we all have hundreds&mdash;can amazingly impact our response to immunotherapy and maybe even other therapies. That is a field that 5 years ago would have been scoffed at, but today it's now mainstream.

In January 2018, 3 really important articles inSciencedescribed how critical this field is. There will be any number of therapeutic trials happening in the next year, including 1 at my own institution, where will we not only try to understand how the microbiome influences outcomes with immunotherapy, but we are going to try to repopulate the gut or alter the microbiome to allow patients to have a better response to immunotherapy. That's the real manifestation of all this microbiome work.

TARGETED ONCOLOGY:In the midst of all these exciting developments, what kind of advice could you give to community oncologists in keeping up with these advancements?

Weber:I would tell them to come to the International Symposium on Melanoma and Other Cutaneous Malignancies every year. It sits in a great location in New York City. I would tell them to stay tuned for ASCO and ESMO and follow the latest developments. I think we are doing more clinically practice-focused kinds of meetings, such as this one, where we talk about how we can take the data that we learn from recent presentations and apply it to the actual treatment of patients, so I think that is critical. As the science advances, we now have to figure out how to translate it into practical clinical manifestations.

Reference:

Hauschild A, Santinami M, Long GV, et al. COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K—mutant melanoma. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA6_PR.