Adjuvant dabrafenib-trametinib provides ‘real chance to cure’ BRAF-mutant melanoma
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Adjuvant dabrafenib and trametinib provided long-term benefit for patients with resected stage III BRAF V600-mutant melanoma, according to an analysis of the COMBI-AD trial presented during the ASCO20 Virtual Scientific Program.
More than half of patients assigned the combination remained recurrence free at 5 years.
“The 5-year data are simply excellent,” Axel Hauschild, MD, PhD, professor of dermatology at University Hospital Schleswig-Holstein Campus Kiel in Germany, told Healio. “When the first data were released 3 years ago, I was surprised by the benefit. Now that we have longstanding good results, I’m not surprised because I was expecting the curves to flatten. Even though it met my expectation, to have 50% of patients with high-risk melanoma still without relapse at 5 years is a very good result.”
Most patients with localized melanoma can be cured with surgery. However, those with stage III disease — characterized by regional nodal involvement — are at higher risk for relapse and death after resection.
The randomized phase 3 COMBI-AD trial assessed the combination of the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK1/2 inhibitor trametinib (Mekinist, Novartis) for this patient population.
The trial included 870 patients with high-risk stage III BRAF V600E- or BRAF V600K-positive melanoma who had undergone complete surgical resection.
Researchers assigned 438 patients to dabrafenib dosed at 150 mg twice daily and trametinib dosed at 2 mg daily. The other 432 patients received matched placebo.
Investigators stratified patients by BRAF status and disease stage.
RFS served as the primary endpoint. Secondary endpoints included OS and distant metastasis-free survival.
Previously reported results from the primary analysis showed a higher 3-year RFS rate with the dabrafenib-trametinib combination (58% vs. 39%; HR = 0.47; 95% CI, 0.39-0.58).
Three-year OS results also favored the dabrafenib- trametinib combination (86% vs. 77%; HR = 0.57; 95% CI, 0.42-0.79).
Based on those initial results, the FDA approved the combination for adjuvant treatment of patients with BRAF V600E- or BRAF V600K-positive melanoma that spread to lymph nodes.
At ASCO, Hauschild presented results of 5-year analyses, including long-term RFS results and findings from a Weibull mixture cure rate model that estimated the percentage of patients who will remain relapse free long-term.
Median follow-up was 60 months in the dabrafenib-trametinib group and 59 months in the placebo group. At data cutoff, 190 patients (43.3%) assigned dabrafenib-trametinib and 262 (60.6%) of those assigned placebo had experienced an RFS event.
Median RFS had not been reached in the combination group (95% CI, 47.9 months to not reached) and was 16.6 months (95% CI, 12.7-22.1) in the placebo group (HR = 0.51; 95% CI, 0.42-0.61).
A higher percentage of patients assigned dabrafenib-trametinib remained relapse free at 4 years (55% vs. 38%) and 5 years (52% vs. 36%). Those findings match the cure rate model estimates, Hauschild said.
Researchers observed the RFS benefit with dabrafenib-trametinib across all disease stage subgroups: stage IIIA (HR = 0.61; 95% CI, 0.35-1.07), stage IIIB (HR = 0.5; 95% CI, 0.37-0.67) and stage IIIC (HR = 0.48; 95% CI, 0.36-0.64).
“We don’t want to see a certain mean RFS. We want to see a meaningful difference at the tail of the curves,” Hauschild told Healio. “The difference at 5 years tells you the truth about the value of these drugs. The difference in RFS between 3 years and 5 years is not big, so I’m pretty sure we have a real chance to cure patients in the adjuvant setting. That is very meaningful.”
Median distant metastasis-free survival had not been reached in either group but results favored dabrafenib-trametinib (HR = 0.55; 95% CI, 0.44-0.7).
OS results were not updated because the prespecified number of events for the final survival analysis had not occurred at data cutoff.
Researchers did not perform updated safety analyses because all patients had completed treatment by the time of the primary analysis.
“Patients may have some transient toxicities but they are not permanent,” Hauschild said. “That is a key difference between this regimen and PD-1 antibodies, which can be associated with unexpected, rare adverse events that can persist for the rest of a patient’s life. We want to cure patients in the adjuvant setting, but we need to remember that the treatment we provide can affect quality of life for those patients.” – by Mark Leiser
Reference:
Hauschild A, et al. Abstract 10001. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Disclosures: Novartis funded this study. Hauschild reports research funding or honoraria from, consultant/advisory roles with, or travel, accommodations or expenses from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Oncosec, Philogen, Provectus, Regeneron, Roche and Sanofi. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Philip Friedlander, MD, PhD
Many patients with resected stage III melanoma have a high risk for subsequent recurrence as distantly metastatic stage IV melanoma. Advances in the treatment of stage IV melanoma using anti-PD-1 and anti-CTLA-4 checkpoint inhibitory immunotherapy — or, in the context of a BRAF V600 mutation, targeted therapy with BRAF and MEK inhibitors — have improved OS, leading to study in resected stage III melanoma. The combination of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib is FDA approved as adjuvant treatment following resection of melanoma metastatic to regional lymph nodes.
The presentation by Hauschild and colleagues provides very important longer-term follow-up of patients treated in the COMBI-AD trial that led to this approval. With median follow-up of 5 years, patients treated with dabrafenib plus trametinib derived a significant RFS benefit compared with patients who received placebo (52% vs. 35%). This demonstrates durable benefit despite the adjuvant treatment only being administered for 1 year.
These data support the use of dabrafenib and trametinib for patients with resected stage III melanoma expressing a BRAF V600E or V600K mutation. Updates on OS benefits will be important to review once data mature to help with treatment decisions.
When oncologists talk to their patients about treatment options, they should discuss these data relative to adjuvant data that led to FDA approval of anti-PD-1 immune checkpoint inhibitor therapy. Unfortunately, adjuvant therapy with a year of dabrafenib treatment has not been compared in a randomized fashion with a year of anti-PD-1 immunotherapy treatment, which would provide prospective randomized data to support more definitively relative benefit.
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Hauschild A, et al. Abstract 10001. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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