Alexander M. Castellino, PhD

September 12, 2017

Madrid ― A new standard for treating melanoma patients with BRAF mutations in the adjuvant setting has ben established by the results from from the COMBI-AD phase 3 study, say experts. With these data, the combination of dabrafenib (Tafinlar, Novartis) and trametinib ( Mekinist, Novartis) moves up front from the metastatic to the adjuvant setting.

The results were presented here at a presidential session at the European Society for Medical Oncology (ESMO) 2017 Congress and were simultaneously published online in the New England of Medicine.

In patients with surgically resected BRAF-V300-positive melanoma, 1 year of oral adjuvant therapy with dabrafenib and trametinib was reported to provide a 53% lower risk for 3-year recurrence compared with placebo.

"The efficacy and tolerability of dabrafenib in combination with trametinib seen in this study represent an important step forward in the treatment of stage III BRAF-V600E/K mutation-positive melanoma," said lead investigator Axel Hauschild, MD, PhD, professor of dermatology, University Hospital Schleswig-Holstein, in Kiel, Germany, in a statement.

"These unprecedented results confirm a targeted therapy combination has the potential to transform the standard of care in the melanoma adjuvant setting," he added.

"It is a good day for melanoma patients," said ESMO expert Dummer Reinhard, MD, professor and vice-chairman of the Department of Dermatology at the University Hospital of Zürich, Switzerland. He noted that at the same session in which results with the combination of dabrafenib and trametinib were presented, results for adjuvant nivolumab were also presented. Medscape Medical News also reported on this study (CheckMate 238).

Dr Dummer Reinhard

"These studies will change guidelines for patients with melanoma in the adjuvant setting and provide two new treatment options for these patients," he said.

With these new options, clinicians will have to decide which option will best serve their patients with BRAF-V600-positive mutant melanoma. But it was universally agreed that high-dose and low-dose interferon should no longer be a treatment option and that textbooks need to reflect the paradigm shift.

New landscape. End of interferon. End of ipilimumab. Prof Alexander Eggermont

All melanoma experts agreed with this sentiment. Discussant of the COMBI-AD study, Alexander M. M. Eggermont, MD, PhD, professor of oncology surgery at the Gustave Roussy Cancer Campus, Paris, France, said it best: "New landscape. End of interferon. End of ipilimumab" in the setting of adjuvant therapy for melanoma.

COMBI-AD Study Details

COMBI-AD was a randomized, double-blind, placebo-controlled, phase 3 study in patients with high-risk, stage III, BRAF-V600E/K-mutant melanoma who had not received prior anticancer therapy. Participating patients had undergone surgical resection and had been disease free for ≤12 weeks. They were randomly selected to receive either the combination of dabrafenib 150 mg twice daily and trametinib 2 mg once daily (n = 438) or matching placebo (n = 432). Dabrafenib and trametinib were used at doses approved in the metastatic melanoma setting.

Patients were stratified on the basis of BRAF mutation and disease stage (IIIA vs IIIB vs IIIC) and received adjuvant therapy for 12 months. The median duration of follow-up was 2.8 years.

COMBI-AD Results

For patients who received placebo, relapse-free survival (RFS) was 16.6 months; median RFS was not reached for patients who received the BRAF-MEK inhibitor combination. Patients who received the BRAF-MEK inhibitor combination had a 53% reduced risk for disease recurrence (hazard ratio [HR], 0.47; P < .001). Median RFS was not reached for patients who received dabrafenib/trametinib; it was 16.6 months for those receiving placebo. The benefit in RFS was seen across all subgroups, including patients with stage IIIA, IIIB, and IIIC, disease.

"The results are spectacular, and the therapeutic effects kick in immediately and continue throughout the study period," Dr Eggermont said.

"This is the best Kaplan-Meier curve we have ever seen in the adjuvant setting," COMBI-AD presenter Axel Hauschild, MD, professor and head of the Interdisciplinary Skin Cancer Center in the Department of Dermatology, University Hospital Schleswig-Holstein in Kiel, Germany, said.

Dr Axel Hauschild

One-year RFS was 88% and 56% for dabrafenib/trametinib and placebo, respectively. Corresponding 2-year RFS rates were 67% and 44%, respectively; 3-year RFS rates were 58% and 39%, respectively. "Consistent benefit was seen across the entire study period," Dr Hauschild said.

Freedom from relapse also mirrored RFS. One-year, 2-year, and 3-year rates were 88%, 67%, and 55% for the combination and 56%, 44%, and 39% for placebo, respectively (HR, 0.47; P < .001).

Distant metastases-free survival also significantly favored dabrafenib/trametinib, with 1-year, 2-year, and 3-year rates of 91%, 77%, and 71%, respectively. Corresponding rates for the placebo-treated patients were 70%, 60%, and 57%, respectively (HR, 0.51; P < .001).

It was not surprising that these data translated into significant survival, Dr Hauschild said. At this first interim analysis (three are planned), overall survival (OS) was also significant (P =.0006); for patients who received dabrafenib/trametinib, there was a 43% reduced risk for death. One-year, 2-year, and 3-year OS rates were 97%, 91%, and 86%, respectively, for patients who received dabrafenib/trametinib and 94%, 83%, and 77% for patients who received placebo.

"OS is not going to change over time, since similar percentage of patients in both arms received salvage therapies on recurrence," Dr Hauschild predicted. He reported salvage therapy data, which showed that for patients with disease recurrence, any post-recurrence cancer therapy was provided for 91% of patients in the dabrafenib/trametinib arm and 88% in the placebo arm. Systemic therapy was reported in 74% of patients in each arm.

The frequency of adverse events was higher for the BRAF-MEK inhibitor combination (97% vs 88% for placebo), as were grade 3/4 adverse events (AEs): 41% vs 14% for placebo. AEs leading to discontinuation were reported for 26% of patients who received the BRAF-MEK combination and 3% of those who received placebo.

"The number of treatment discontinuations was a little higher than in trials on stage IV melanoma patients," Dr Hauschild said in a statement. This could be because 90% of patients did not experience disease progression and were treated for the scheduled full year. The longer patients receive treatment, the more likely they are to have AEs, he explained. "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," Dr Hauschild said.

"These are practice-changing results. The combination of dabrafenib and trametinib is a new and very effective adjuvant treatment option in high-risk melanoma patients," Dr Hauschild concluded.

Significantly Better Options for Patients

ESMO melanoma faculty coordinator Olivier Michielin, MD, head of personalized analytical oncology, Lausanne, Switzerland, said in a statement: "We have 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.

"Interferon and ipilimumab are both immunotherapies, but COMBI-AD is the first trial reporting on the use of targeted therapies in the adjuvant setting for melanoma," Dr Michielin noted.

"Both ipilimumab and the combination of dabrafenib plus trametinib have improved overall survival compared to placebo. We now need to determine which adjuvant strategy is best suited for which patient, factoring in also the upcoming results of PD-1 blockade in that setting," he further added.

Dabrafenib/trametinib or nivolumab for patients with BRAF- V300-positive stage III resected melanoma - that is the question that will be asked over and over in the clinic. It is not an easy question to answer for patients with BRAF-V300-positive mutant stage III melanoma, conceded many melanoma experts. Although the COMBI-AD and CheckMate 238 trials provided positive data, the studies cannot be compared. Patient characteristics were different in the two studies. COMBI-AD included patients with stage IIIA disease, not stage IV disease; CheckMate 238 did not include stage IIIA disease but did include patients with stage IV disease.

"There is a direct correlation of data from the metastatic to the adjuvant setting," Dr Eggermont noted. "The best performers in stage IV [metastatic] are the best performers in the adjuvant setting," he said.

Dr Eggermont indicated that stage III patients were a heterogeneous group, and therefore, risk information and risk/benefit discussion with patients were crucial. He signified that although it was an end of an era for interferon and ipilimumab, he also pointed out that for patients with ulcerated melanoma, interferon is an option when physicians have no access to the newer therapies.

Dr Eggermont did indicate that only "ipi-light" should be considered for the future development of ipilimumab in combination with other immune-oncology approaches. "Ipi-light" refers to a regimen in which ipilimumab 1 mg/kg is included in the dosing scheme.

Although immunotherapy may likely be a choice for some clinicians, Dr Hauschild indicated that patient perspective may become important and sway decision making. Patient convenience may factor into the equation, he suggested. He noted that nivolumab requires infusions twice weekly, whereas combination dabrafenib/trametinib is taken orally. For patients who have to travel long distances to get to the clinic, targeted therapy with dabrafenib/trametinib may be a better option than nivolumab.

Another point that merits consideration is treatment toxicity. "Since surgery is a curative option for most patients with stage III melanoma, drug toxicities will be more relevant in the adjuvant setting," Dr Reinhard said. Melanoma experts agreed that toxicity will play a critical role in patient choices in this disease setting, with dabrafenib/trametinib having more problems regarding safety than nivolmab.

Another factor that may affect decision making is whether patients can be rechallenged with the same drugs on recurrence. With the dabrafenib/trametinib combination, responses are seen when patients are rechallenged with the combination at recurrence, Dr Hauschild pointed out.

Medical oncologist Michael Postow, MD, of the Memorial Sloan Kettering Cancer Center, New York City, provided additional thoughts. "Since surgical resection is of curative intent, if all patients are being treated with adjuvant therapy, we may be overtreating patients," he suggested.

He agreed that if one is going to treat, then these two options are both good and viable options for patients with stage IIIB and IIIC BRAF-V300 positive mutated melanoma. However, should all patients be treated? he asked.

Although survival data for adjuvant nivolumab are not available, Dr Postow noted that in COMBI-AD, patients were not permitted to cross over to the combination arm on recurrence. If crossover had been allowed, the OS curve may have been different, he noted.

He also admitted that some patients might avoid treatment in the adjuvant setting and still obtain the same survival benefits of the therapies in the metastatic setting upon recurrence. It is not known which patients will benefit most, nor is it known in which patients treatment can be deferred, he pointed out. Dr Postow observed that the discussion on treatment choices has not factored in the costs of the therapies and the financial toxicities the patients and their families may have to bear.

COMBI-AD was funded by GlaxoSmithKline. Dr Hauschild has received clinical trial support or speaker´s honoraria or consultancy fees from Amgen, BMS, MerckSerono, MSD, Novartis, OncoSec, Philogen, Pierre Fabre,and from Provectus, Regeneron, and Roche during the conduct of the study. Dr. Eggermont has received honoraria from Bayer, Nektar, and Sanofi.

European Society for Medical Oncology (ESMO) 2017 Congress. Abstract LBA6. Presented September 11, 2017.

N Engl J Med. Published online September 10, 2017. Full text

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