Alexander Eggermont, MD, PhD
BASED ON THE RESULTS of COMBI-AD1 and CheckMate 238,2 invited discussant Alexander Eggermont, MD, PhD, Professor of Oncology at Gustave Roussy in Paris, commented: “It’s a good day for melanoma!”
In COMBI-AD, treatment with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) significantly improved both relapse-free and overall survival, vs placebo. Median relapse-free survival was not reached with the combination and was 16.6 months with placebo (hazard ratio [HR] = 0.47; P < .001). Overall survival was improved by 43% (P = .0006).
In CheckMate 238, nivolumab (Opdivo) was superior to ipilimumab (Yervoy), improving relapse-free survival at 18 months from 52.7% to 66.4% (HR = 0.65; P < .0001). Nivolumab was also better tolerated.
“For the first time, you see a total linear correlation for what we know to be success stories in advanced melanoma,3 now directly translated as success stories in the adjuvant setting in stage III and resected stage IV disease,” he said. “The best performers in stage IV (BRAF/MEK and checkpoint inhibitors) are the best performers in the adjuvant setting.”
However, Dr. Eggermont cautioned against overextrapolation, pointing to the “extremely heterogeneous prognosis” in stage III melanoma. Based on the number and size of positive lymph nodes, relapse rates in trials have varied from 12% to more than 90%. Even within the sentinel node–positive population, 5-year overall survival rates vary from 25% to 88%, he indicated.
“The risk-benefit discussion, therefore, will be crucial in your discussions with patients as to their choice of adjuvant therapeutic options,” he said.
Interferon, Single-Agent Ipilimumab: No Longer Relevant
ALTHOUGH THE BEST CHOICE between the two new adjuvant strategies remains unclear, what has been established is the need to strike interferon from the algorithm. “It’s goodbye to interferon, except for ulcerated melanoma,” remarked Dr. Eggermont, co-investigator of a recent meta-analysis of interferon trials.4 Patients with nonulcerated primary lesions derived no benefit, but those with ulcerated primaries experienced a 10.5% absolute survival improvement at 10 years.
“The best performers in stage IV (BRAF/MEK and checkpoint inhibitors) are the best performers in the adjuvant setting.”— Alexander Eggermont, MD, PhD
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“For those still prescribing interferon, I have a simple message: stop!” he said, adding that clinicians in low-resource areas should use interferon only in patients with ulcerated melanomas “and wait for the new drugs to be approved and reimbursed in your countries.”
The striking results with nivolumab in CheckMate 238 also render single-agent ipilimumab moot, he said. Based on an 11% absolute survival improvement vs placebo in stage III disease, which Dr. Eggermont reported at the ESMO Congress this past year,5 U.S. regulators approved ipilimumab for stage III melanoma, but European regulators opted to wait for more data. “There’s no need to submit this file anymore,” he said. “There will be another file submitted!”
The next high-impact trial in this setting will be European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054, which is evaluating pembrolizumab (Keytruda; a flat 200-mg dose every 3 weeks) vs placebo in stage IIIA (> 1.0 mm)/B/C disease. This study also allows crossover, which will help answer a second important question: Must a whole population of patients be exposed to adjuvant therapy, or is it sufficient to treat at relapse, since the same population will be salvaged?
A Place for Single-Agent Vemurafenib?
AT A PRESS BRIEFING, other experts discussed the negative results of BRIM8 for single-agent vemurafenib (Zelboraf).6 Axel Hauschild, MD, of the University of Kiel in Germany, said the study’s conclusion mirrored what has been shown in stage IV disease: “Vemurafenib plus a MEK inhibitor would have led to better results, I’m convinced.”
Jeffrey Weber, MD, Deputy Director of the Perlmutter Cancer Center, NYU Langone Health, New York, commented: “The results of BRIM8 will be a historical anecdote. For mutated patients, clinicians will use dabrafenib plus trametinib or nivolumab. There will be no real place for a single-agent BRAF inhibitor as adjuvant therapy, the way there’s no real place in metastatic disease, with a few exceptions.”
Future Changes in Treatment
THE EMERGING ADJUVANT options could be joined by several other shifts in adjuvant therapy predicted by Dr. Eggermont. One is a gradual abandonment of completion lymph node dissection for sentinel node–positive patients based on the MSLT-II results, showing this failed to improve melanoma-specific survival.7 The downside to this is the loss of prognostic information for the risk-benefit discussion. “You need multiple lymph nodes to assess this,” Dr. Eggermont pointed out.
“If this survival curve in stage IV disease holds up, do we even need adjuvant therapy? That’s how good our treatments are in stage IV melanoma.”— Alexander Eggermont, MD, PhD
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Another potential shift would be the addition of neoadjuvant treatment to the adjuvant strategy, which would offer the opportunity to improve locoregional tumor control and avoid therapeutic nodal dissection. Studies have shown pathologic complete response rates of 50% with dabrafenib/trametinib and 40% with nivolumab/ipilimumab, and overall response rates of 100% and 80%, respectively. Neoadjuvant treatment also enhances diversity among T-cell clones, which could boost immune responses.
“This would completely change the paradigm that we always have to have surgery first,” Dr. Eggermont said.
Reduced dosing of ipilimumab (1 mg/kg given in four doses over 12 weeks)—ie, “ipi light”—will become the standard way to give this drug in combination. Lower doses will significantly reduce toxicity. “It’s the way to keep ipilimumab on board,” Dr. Eggermont said.
Questions Remain
IN THE PHASE IB KEYNOTE-029 trial, estimated 1-year survival in the metastatic setting was 89% with “ipi light” plus pembrolizumab.8 Such excellent results, he added, also beg the question: “If this survival curve in stage IV disease holds up, do we even need adjuvant therapy? That’s how good our treatments are in stage IV melanoma.”
“We should always re-ask the question,” he continued, “of whether we have enough proof to expose populations of patients to adjuvant therapy when we know there are already populations of advanced-stage patients who are cured?”9
As for the choice between checkpoint blockade and BRAF/MEK inhibition as adjuvant therapy, the answer awaits. “We will have to see how the tail of the curves will evolve,” Dr. Eggermont said, “for BRAF/MEK combinations vs immunotherapeutic approaches.” ■
DISCLOSURE: Dr. Eggermont has received honoraria from Actelion, BMS, GSK, HalioDX, Incyte, ISA Pharmaceuticals, MSD, Nektar, Novartis, Pfizer, and Sanofi. Dr. Weber hasa received honoraria and travel compensation from BMS, is named on a patent for a PD-1 biomarker by Biodesix and a ipilimumab biomarker by Moffitt Cancer Center.
REFERENCES
1. Hauschild A, Santinami M, Long GV, et al: COMBI-AD: Adjuvant dabrafenib plus trametinib for resected stage III BRAF V600E/K-mutant melanoma. ESMO 2017 Congress. Abstract LBA6_PR. Presented September 11, 2017.
2. Weber J, Mandala M, Del Vecchio M, et al: Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). ESMO 2017 Congress. Abstract LBA8_PR. Presented September 11, 2017.
3. Ugurel S, Röhmel J, Ascierto PA, et al: Survival of patients with advanced metastatic melanoma: The impact of novel therapies-update 2017. Eur J Cancer 83:247-257, 2017.
4. Ives NJ, Suciu S, Eggermont AMM, et al: Adjuvant interferon-alpha for the treatment of high-risk melanoma: An individual patient-data meta-analysis. Eur J Cancer 82:171-183, 2017.
5. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 375:1845-1855, 2016.
6. Lewis K, Maio M, Demidov L, et al: BRIM8: A randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients with completely resected BRAF V600+ melanoma at high risk for recurrence. ESMO 2017 Congress. Abstract LBA7_PR. Presented September 11, 2017.
7. Faries MB, Thompson JF, Cochran AJ, et al: Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 376:2211- 2222, 2017.
8. Long GV, Atkinson V, Cebon JS, et al: Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): An open-label, phase 1b trial. Lancet Oncol 18:1202-1210, 2017.
9. Eggermont AMM, Dummer R: The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients. Eur J Cancer 86:101-105, 2017.
