By Mary Beth Nierengarten
Reviewed by Reinhard Dummer, MD, and Dirk Schadendorf, MD
Results from clinical trials published over the past several years are swiftly shaping what some are calling a new paradigm for the treatment of stage III melanoma.1,2
Evidence from surgical studies calls into question the role of complete lymph node dissection (CLND) in patients with positive sentinel lymph node biopsies, with studies showing that CLND may help refine staging and increase regional disease control but that it does not confer a survival advantage over observation.2-4
Within this evolving surgical approach to metastatic melanoma are important adjuvant therapies that have improved relapse-free survival for the many patients at risk of relapse after surgery. Preventing relapse is also a strong factor in maintaining patients’ quality of life.5 Two classes of drugs have emerged as the current standard of care for adjuvant therapies for patients with high-risk melanoma: immune checkpoint inhibitors (nivolumab and pembrolizumab) that target programmed cell death 1 (PD-1) protein, and targeted therapy (combination dabrafenib plus trametinib) that stops or slows the growth of cancer cells by blocking proteins that help cancer cells grow.6
Data from studies published in 2017 and 2018 established the role of these 2 classes of drugs as adjuvant therapies for patients with resected, high-risk melanoma7-10 (Table 1).
| TABLE 1. | ||
|---|---|---|
| Patients | Relapse-free survival | |
| PD-1 inhibitors | ||
| Pembrolizumab (compared to placebo)7 | Resected, stage III disease with or without BRAF V600 mutation | 1-year results: 75.4% vs 61.0%. P<0.001 |
| Nivolumab (compared to ipilimumab)8 | Resected, stage IIIB/IIIC/IV disease | 1-year results: 70.5% vs 60.8%, P<0.001 |
| Targeted therapy | ||
| Dabrafenib plus trametinib (compared to placebo)9,10 | Resected stage III melanoma with BRAF V600E or V600K mutations | 3-year results: 58% vs 39%, P<0.001 |
The results of these studies were based on 1-year follow up for the anti-PD-1 therapies7,8, and 3-year follow-up for combination dabrafenib plus trametinib.9,10
In September 2020, longer-term follow up data became available for combination dabrafenib plus trametinib. To date, this is the longest follow-up data on these new adjuvant treatments. Published in the New England Journal of Medicine by Dummer and colleagues, the study reports the results of 5-year follow-up of the Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD) trial showing a durable, long-term, relapse-free survival in patients treated with the combination therapy.6
The COMBI-AD trial
The COMBI-AD trial is a phase III, double-blind, controlled trial in which 870 patients with resected stage III melanoma with BRAFV600E or V600K mutations were randomized to 12 months of oral dabrafenib plus trametinib (n = 438) or placebo (n = 432) to assess the primary end point of relapse-free survival.
All patients had the BRAF mutation (a mutation that can lead to growth and spread of cancer cells) and were classified by stage based on the risk of recurrence (stage A is the lowest risk and stage C the highest risk). Patient characteristics were similar in the 2 groups.
Critical in the study was the inclusion of only patients with the BRAF mutations as the combination of dabrafenib plus trametinib is targeted to work only on patients with these mutations. “The BRAF V600E and V600K are so-called driver mutations, which are detectable in roughly 40% of cutaneous melanomas,” said senior author of the study, Dirk Schadendorf, MD, Director and Chair, Department of Dermatology, Director, Comprehensive Cancer Center, University Hospital Essen, Essen, Germany, adding that combination adjuvant dabrafenib plus trametinib will work only in patients carrying a BRAF V600 mutation and not in other mutations. “Detection of the mutation is of critical importance in order to be able to use a targeted treatment approach,” he emphasized.
All patients underwent melanoma resection within 12 weeks prior to the start of the study and were classified by stage based on the risk of recurrence (stage A is the lowest risk and stage C the highest risk). Patient characteristics were similar in the 2 groups.
As shown in Table 1, 3-year follow-up results showed a significant benefit of this combined targeted therapy compared to placebo.
Updated study at 5 years
In the updated study, investigators report on relapse-free survival in this cohort of patients after 5 years as well as survival without distant metastasis based on the intention-to-treat analysis.6
Table 2 shows the results of the 5-year analysis.
| TABLE 2. | Dabrafenib plus trametinib combination therapy | Placebo |
|---|---|---|
| Age <65 years | 81% | 83% |
| Male | 56% | 55% |
| White | 99% | 99% |
| Stage | ||
| IIIA | 19% | 16% |
| IIIB | 39% | 43% |
| IIIC | 41% | 38% |
The study results indicate a 49% reduction in the risk of melanoma coming back in patients treated with combination therapy. By stage, patients with stage IIIA had a 39% reduction, those with stage IIIB had a 50% reduction, and patients with stage IIIC had a 52% reduction. When looking at distant metastasis-free survival, 45% of patients treated with the combination therapy had a reduced risk of melanoma coming back at a distant site.
“This study represents the longest follow-up for a current standard of care adjuvant therapy for melanoma,” said lead author Reinhard Dummer, MD, Vice-Chairman, Department of Dermatology, Head of Skin Tumor Center, University Hospital Zurich, Switzerland.
“It demonstrates that there is a sustained benefit of adjuvant dabrafenib plus trametinib long after the treatment period is over, suggesting an increase in the fraction of patients who may never relapse, which is the ultimate goal of treatment.”
Long-term results provide clarification
Dr. Dummer noted 2 key questions concerning adjuvant therapy for melanoma: Can 1 year of adjuvant therapy increase the fraction of patients who may never relapse? and Which patients should be receiving adjuvant therapy?
The updated 5-year results of the COMBI-AD trial answer both. “These long-term follow-up data suggest that the combination of dabrafenib plus trametinib can achieve this outcome for some patients,” he said. “The results [also] show that a benefit with adjuvant dabrafenib plus trametinib is apparent across all stage III substages included in the study, so clinicians can feel confident in recommending adjuvant therapy to all of these subpopulations.”
Dr. Schadendorf underscored that the durability of relapse-free survival at 5 years suggests that a fraction of patients may be cured.
Noting evidence from previous studies of stage III melanoma patients in whom loco-regional involvement is controlled surgically, he said the studies show that about one-third of patients will not develop a relapse over the next 5 years and that relapses peak within the first 24-30 months.
The 5-year outcome on relapse-free survival from the COMBI-AD shows that 52% of the treatment group remain relapse-free at 5 years. “The long-lasting effects of treatment are clearly visible,” Dr. Schadendorf said.
Commenting on the study, Keith T. Flaherty, MD, Director of Clinical Research, Massachusetts General Hospital Cancer Center, Boston, said that the 5-year analysis reinforces the initial analysis that led to the April 2018 FDA approval of combination dabrafenib plus trametinib for stage III melanoma patients with BRAF V600 mutations.
“That [initial] study was monumental for the field as it showed for the first time that oncogene-targeted therapy could prevent recurrence in high-resected melanoma,” he said. “This publication confirms and extends the findings of the initial analysis, making it very clear that relapses can be prevented with dabrafenib/trametinib.”
Saying that the combination therapy remains a “pillar of our systemic therapy options for patients with resected stage III melanoma,” Dr. Flaherty said that this therapy, along with PD-1 antibody therapy, are both adjuvant treatment options that clinicians can offer their patients.
“Patients with BRAF mutation and resected stage III disease have dabrafenib/trametinib or a PD-1 antibody to choose from,” said Dr. Flaherty. The choice of treatment, he said, may depend on factors such as convenience (dabrafenib/trametinib is given orally, whereas a PD-1 antibody is administered intravenously), cost (patients may need to pay more out-of-pocket for oral medications), and side effects (fewer potentially life-threatening toxicities are associated with dabrafenib/trametinib). This last factor, he said, “causes some patients to prefer dabrafenib/trametinib.”
REFERENCES
- Rudchadkar RR, Michielin O, Van Akkooi ACJ. Practice-changing developments in stage III melanoma: surgery, adjuvant targeted therapy, and immunotherapy. 2018 ASCO Educational Book. American Society of Clinical Oncology. 2018.
- Ascierto PA, Borgognoni L, Botti G, et al. New paradigm for stage III melanoma: from surgery to adjuvant treatment. J Transl Med. 2019;17:266.
- Leiter U, Stadler R, Mauch C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT):a multi-centre, randomized, phase 3 trial. Lancet Oncol. 2016;17(6):757e67.
- Faries MB, Thompson JF, Cochran AJ, et al. Completion dissec-tion or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;377(19):1824-35.
- Schadendodrf D, Hauschild A, Santinami M, et al. Patient- reported outcomes in patients with resected high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomized, placebo- controlled, phase 3 trial. Lancet Oncol. 2019;20(5):701-710.
- Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Eng J Med. 2020;383:1139-1148.
- Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembroli-zumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789-1801.
- Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824-1835.
- Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Eng J Med. 2017;377:1813-1823.
- Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma. J Clin Oncol. 2018;36:3441-3449.
