1. Goodwin, Peter M.

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MADRID-Relapse-free survival was doubled in patients with fully-resected stage III melanoma who were at high risk of relapse and tested positive for the V600E or V600K mutation of the BRAF gene in the COMBI-AD study comparing therapy with a combination of the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib with placebo. Overall survival (OS) was nearly doubled by the same combination of targeted drugs (Abstract LBA6_PR).


After announcing these findings at the ESMO 2017 Congress, Axel Hauschild, MD, PhD, Professor and Head of the Interdisciplinary Skin Cancer Center at the Department of Dermatology, University Hospital Schleswig-Holstein in Kiel, Germany, noted it was necessary to rewrite the textbooks, current guidelines, and treatment recommendations. "For these patients, we can offer an oral treatment given at home with known and manageable toxicity. It's a new treatment option which is highly effective."


Dabrafenib, which targets the BRAF gene, and trametinib targeting MEK (another molecule in the same pathway towards tumorigenesis) were already approved in combination for patients with stage IV melanoma after phase III trials had shown an OS improvement over BRAF inhibition alone. "BRAF plus MEK inhibition is not only working in stage IV disease. It has its impact in the adjuvant setting. And I believe it is a new standard of care for mutated patients," Hauschild explained.

Axel Hauschild, MD, ... - Click to enlarge in new windowAxel Hauschild, MD, PhD. Axel Hauschild, MD, PhD

He noted there was no standard of care for the adjuvant treatment of stage III melanoma. "Interferon is approved for this situation but improves relative relapse-free survival by just 20 percent compared to placebo."


BRAF Mutation

Ninety-one percent of patients in COMBI-AD had the V600E mutation and 9 percent had the V600K mutation-a typical distribution in clinical practice. Patients had lymph node and skin metastases that had been fully resected.


This double-blind trial randomized 870 patients 1:1 to combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib for 12 months or placebo.


The primary endpoint was met-significantly prolonged relapse-free survival. At a median follow-up of 2.8 years, the combination therapy had reduced the risk of disease recurrence or death by 53 percent compared to placebo (a hazard ratio [HR] of 0.47) and this benefit was observed across all patient subgroups.


The combination also made big improvements to secondary endpoints. Overall survival (HR: 0.57), distant metastases-free survival (HR: 0.51), and freedom from relapse (HR: 0.47).


"These are the best results ever shown for an adjuvant treatment in stage III melanomas," said Hauschild. "Combination treatment with dabrafenib and trametinib more than doubled the relapse-free survival time compared to placebo and the improvement in overall survival was impressive, too."


Reviewing Toxicity

Nearly all patients on the combination (97%) had an adverse event (AE) of any grade and 41 percent had grade 3 or 4 AEs. Nearly as many patients (88%) in the placebo also had AEs of any grade and 14 percent of them had serious AEs. A quarter of patients on the combination had to stop treatment because of AEs. But in the placebo group, only 3 percent had to discontinue.


"The number of treatment discontinuations was a little higher than in trials on stage IV melanoma patients," stated Hauschild. "This could be because 90 percent of patients had no progressive disease and were treated for the scheduled full year. The longer patients receive treatment, the more likely they are to have adverse events. But there were no new toxicities compared to those already seen in stage IV disease. And overall, we can say the treatment was well-tolerated."


He regarded the COMBI-AD findings as practice-changing results. "The combination of dabrafenib and trametinib is a new and very effective adjuvant treatment option in high-risk melanoma patients."


Olivier Michielin, MD, PhD, Medical Oncologist at Lausanne University Hospital and Head of Personalized Analytical Oncology in the Melanoma Clinic in Lausanne, Switzerland, as well as ESMO's Melanoma Faculty Coordinator, said they had been trying to develop adjuvant therapies for melanoma for many years. "Interferon led to minimal benefit and high toxicity and has not been widely adopted. The first revolution was ipilimumab, which improved progression-free survival and overall survival compared to placebo. This was the first big breakthrough in the adjuvant setting. The ipilimumab regimen used in the [original] study is, however, fairly toxic," he noted.


COMBI-AD was the first trial reporting on the use of targeted therapies in the adjuvant setting for melanoma, Michielin said. "The improvements in relapse-free survival and overall survival are both very significant, making this new treatment an attractive option for patients with BRAF mutations, who constitute around half of the melanoma population."

Olivier Michielin, M... - Click to enlarge in new windowOlivier Michielin, MD, PhD. Olivier Michielin, MD, PhD

Patients who did not have mutated BRAF had been candidates for ipilimumab therapy, but results from studies using the PD-1 targeted therapy nivolumab (also reporting positive results at the ESMO Congress) could soon change the landscape, said Michielin. "We now need to determine which adjuvant strategy is best suited for which patient factoring in the upcoming results of PD-1 blockade in that setting," he said.


"With the data that we have today, BRAF and MEK inhibition with dabrafenib and trametinib is an absolute option for patients with the BRAF mutation, and we'll have to make decisions on an individual basis whether to go for immunotherapy or targeted therapy in patients. But clearly we now have two good options-which is a very good situation to be in."


Reinhard Dummer, MD, Professor and Clinic Director of the Skin Cancer Center at the University Hospital in Zurich, Switzerland, said the COMBI-AD data show there is a new opportunity for patients at high risk. "These treatments reduce the risk for progression and for death."


Peter M. Goodwin is a contributing writer.

Reinhard Dummer, MD.... - Click to enlarge in new windowReinhard Dummer, MD. Reinhard Dummer, MD