FOR PATIENTS with malignant melanoma, the significant improvement in outcomes with targeted agents and antibodies against the programmed cell death protein 1 (PD-1) has now been observed in the adjuvant setting. Two landmark studies presented at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid1,2 have established these drugs as the new standard of care for patients with locally advanced, resectable disease considered at high risk for relapse.
The CheckMate 238 trial showed superiority for nivolumab (Opdivo) over ipilimumab (Yervoy) in reducing the risk of relapse,1 while the COMBI-AD trial revealed “robust” benefits for BRAF/MEK inhibition vs placebo in BRAF-mutated patients.2 The results of both trials were simultaneously published in The New England Journal of Medicine.3,4
Giuseppe Curigliano, MD, PhD
Melanoma experts enthusiastically embraced the findings. Giuseppe Curigliano, MD, PhD, ESMO spokesperson and Associate Professor of Medical Oncology at the University of Milan, opened a press briefing by calling the findings “unprecedented.” Invited discussant Reinhard Dummer, MD, Professor of Dermatology at the University of Zurich in Switzerland, predicted, “The breakthroughs we have heard about will really change the management of our patients.”
“This day, September 11, 2017, will mark a change in our textbooks and guidelines,” added Axel Hauschild, MD, who presented the results of COMBI-AD. “With the likely approval of the agents tested in these trials, high-dose and low-dose interferon will be completely replaced. We have at least two effective new treatment options. This is a good day for melanoma patients.”
COMBI-AD Meets Primary Endpoint
COMBI-AD EVALUATED the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist), vs placebo, in 870 patients with stage III BRAF V600E/K–mutant melanoma. Patients were treated for 1 year.
Axel Hauschild, MD
“The results of COMBI-AD actually exceeded my personal expectations,” said Dr. Hauschild, Professor of Dermatology at the University of Kiel in Germany. “The Kaplan-Meir survival curve is the best ever seen in the adjuvant treatment of melanoma.”
Combination treatment with dabrafenib and trametinib significantly improved relapse-free survival, the primary endpoint, and showed an “impressive” overall survival benefit as well, he said.
After a median follow-up of 2.8 years, median relapse-free survival time was not reached with the combination and was 16.6 months with placebo, representing a highly significant 53% risk reduction. Relapse-free survival rates were 67% vs 44% at 2 years and 58% vs 39% at 5 years, showing that “the benefit is maintained over years.”
The Kaplan-Meir survival curve is the best ever seen in the adjuvant treatment of melanoma.— Axel Hauschild, MD
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Referring to a slide of the data flashing an unusually long P value (hazard ratio [HR] = 0.47; P = .0000000000000153), Dr. Hauschild interpreted the figure: “That’s 13 zeros…. This is a remarkable hazard ratio, with a very narrow confidence interval [95% CI = 0.39–0.58], for this new treatment,” he commented.
Overall survival was also improved in the first interim analysis. At 2 years, 91% of patients were alive on the combination vs 83% with placebo. At 3 years, these figures were 86% and 77%, respectively (HR = 0.57; P = .0006). Median survival was not reached in either arm.
Approximately three-fourths of patients received other systemic treatment upon relapse, the same proportion per arm. Nevertheless, a survival benefit emerged with adjuvant BRAF/MEK inhibition.
Dr. Hauschild reported that a similar benefit was seen across all subgroups. “Not a single subgroup was an outlier,” he said. “All stages of stage III disease benefited the same.”
Grade 3/4 adverse events occurred in 41% of patients on the combination and in 14% of the placebo arm. Adverse events leading to treatment discontinuation were seen in 26% and 3%, respectively. “This was a bit more than we expected, but treatment in the adjuvant setting may not be the same as for stage IV patients,” he suggested.
CheckMate 238: Nivolumab Bests Ipilimumab
CHECKMATE 238 showed an anti–PD-1 antibody to be the superior checkpoint inhibitor in stage III/IV resected melanoma, demonstrating clear superiority over ipilimumab, which led to early termination of the trial. In a previous European Organisation for Research and Treatment of Cancer study, Eggermont et al showed a relapse-free and overall survival benefit for ipilimumab over placebo, leading to the drug’s approval in this setting.5
Jeffrey Weber, MD, PhD
In CheckMate 238, nivolumab led to a statistically significant and clinically meaningful improvement in relapse-free survival in surgically resected stage III/IV patients, vs ipilimumab, and was better tolerated, according to Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York.
“Nivolumab looks like a superior adjuvant melanoma regimen, from every angle,” he concluded.
The phase III CheckMate 238 trial enrolled 906 patients with stages IIIB, IIIC, and IV resected melanoma, a group considered to have a 50% or greater risk of relapse over 5 years. Patients were randomized to receive nivolumab at 3 mg/kg every 2 weeks or ipilimumab at 10 mg/kg every 3 weeks for 4 doses, then every 12 weeks, for up to 1 year of treatment.
At a median follow-up of 18.5 months, nivolumab significantly improved relapse-free survival, the primary endpoint, with a rate of 66.4% vs 52.7%; median relapse-free survival was not reached in either arm (HR = 0.65; P < .0001), he reported.
Benefit was observed across the majority of subgroups: by stage, programmed cell death ligand 1 (PD-L1) staining, BRAF mutation status, age, ulceration of the primary lesion, and other factors.
“Longer follow-up will be needed to determine if there is an overall survival benefit, though that will be complicated by de facto crossover,” he said.
Nivolumab’s superiority also extended to the safety profile, as treatment-related grade 3/4 adverse events occurred in only 14% of that arm, vs 46% of the ipilimumab arm; 8% vs 42% of patients, respectively, discontinued the drug because of a treatment-related adverse event.
He concluded, “Nivolumab provides an acceptable benefit-risk ratio as adjuvant therapy for high-risk resected melanoma and has the potential to be an effective treatment option for patients with resected stage III and IV melanoma.” ■
DISCLOSURE: Dr. Curigliano is an advisor for Roche, Pfizer, and Samsung. Dr. Dummer has been a consultant and/or advisor for Novartis, Merck Sharp & Dhome, BMS, Roche, Amgen, Takeda, and Pierre Fabre outside the submitted work. Dr. Hauschild has received clinical trial support from Amgen, BMS, MerckSerono, MSD, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, and Roche; consultant fees from Amgen, MBS, MerckSerono, MSD, Novartis, OncoSec, Philogen, Pierre Fabre, Provectus, Regeneron, and Roche; and he has been a speaker for Amgen, BMS, MSD, Novartis, Pierre Fabre, Provectus and Roche. Dr. Weber reported no conflict of interest.
REFERENCES
1. 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). 2017 ESMO Congress. Abstract LBA8_PR. Presented September 11, 2017.
2. Hauschild A, Santinami M, Long GV, et al: COMBI-AD: Adjuvant dabrafenib plus trametinib for resected stage III BRAF V600E/K-mutant melanoma. 2017 ESMO Congress. Abstract LBA6_PR. Presented September 11, 2017.
3. Weber J, Mandala M, Del Vecchio M, et al: Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. September 10, 2017 (early release online).
4. Long GV, Hauschild A, Santinami M, et al: Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. September 10, 2017 (early release online).
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.
