IN THE TREATMENT of malignant melanoma, immune checkpoint inhibitors are no longer just for metastatic disease, and the best type may be agents targeting the programmed cell death protein 1 (PD-1), according to results of CheckMate 238, presented at the European Society for Medical Oncology (ESMO) 2017 Congress by Jeffrey Weber, MD, Deputy Director of the Perlmutter Cancer Center at NYU Langone Health in New York.1
“We couldn’t have dreamed these studies would be so positive.”— Olivier Michielin, MD
Two studies presented at the ESMO Congress concluded that adjuvant therapy for resectable melanoma prevents relapse. CheckMate 238 demonstrated a benefit for nivolumab (Opdivo), and in BRAF-mutated patients, dabrafenib (Tafinlar) plus trametinib (Mekinist) proved effective in COMBI-AD.2 The findings led to excitement among melanoma specialists at the Congress, such as ESMO spokesperson Olivier Michielin, MD, Head of Personalized Analytical Oncology and the Melanoma Clinic at Lausanne University Hospital in Switzerland. “We couldn’t have dreamed these studies would be so positive,” Dr. Michielin told journalists.
CHECKMATE 238 COMPARED OUTCOMES for nivolumab (3 mg/kg every 2 weeks) vs ipilimumab (Yervoy; 10 mg/kg every 3 weeks for 4 doses, then every 12 weeks), given for up to 1 year, in 906 surgically resected patients with stages IIIB, IIIC, and IV melanoma. This subset is considered to have a 50% or greater risk of relapse over 5 years. Nivolumab led to a 13% absolute increase in relapse-free survival, vs the active comparator ipilimumab.
“Nivolumab looks like a superior adjuvant melanoma regimen from every angle,” Dr. Weber observed. The positive findings triggered an early halt to the study. The results of the trial were simultaneously published in The New England Journal of Medicine.3
Nivolumab appears to answer an unmet medical need, he said: “There’s a need to improve the risk-benefit ratio of adjuvant treatment, given the toxicity observed with the approved ipilimumab adjuvant regimen of 10 mg/kg.”
“Unlike the benefit seen with dabrafenib/trametinib in COMBI-AD, patients with any BRAF status are candidates for nivolumab.”— Jeffrey Weber, MD
In the previous EORTC 18071 trial, Eggermont et al showed a relapse-free and overall survival benefit for ipilimumab over placebo, leading to the drug’s approval in this setting. However, more than half the patients on the drug experienced a grade 3/4 adverse event.4
Benefit in All Subgroups
NIVOLUMAB LED to a statistically significant and clinically meaningful improvement in the study’s primary endpoint, relapse-free survival (local, regional or distant metastasis, new primary melanoma, or death from any cause) and was better tolerated. At a median follow-up of 18.5 months, relapse-free survival was 66.4% with nivolumab vs 52.7% with placebo; median relapse-free survival was not reached in either arm (HR = 0.65; P < .0001), Dr. Weber reported. Median distant metastasis–free survival was not reached in either treatment group, but the time to distant metastasis was longer with nivolumab (HR = 0.73).
A treatment benefit was observed across the majority of subgroups: by stage, programmed cell death ligand 1 (PD-L1) staining, BRAF-mutation status, age, sex, ulceration of the primary lesion, and other factors. Among patients with PD-L1 expression < 5%, the 12-month recurrence-free survival rate was 64.3% with nivolumab and 53.7% with ipilimumab (HR = 0.71). Among those with PD-L1 expression ≥ 5%, these rates were 81.9% and 73.8%, respectively (HR = 0.50). “We saw a clear benefit, with good hazard ratios, in both PD-L1 groups,” he said.
By disease stage, median recurrence-free survival was not reached in stage III or IV patients in the nivolumab group, whereas the same-stage patients derived less benefit from ipilimumab. For stage IIIB/C patients, the recurrence-free rates at 12 months were 72.3% and 61.6%, respectively (HR = 0.65). For stage IV patients, these rates were 63.0% and 57.5%, respectively (HR = 0.70).
“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 adverse events grade 3/4 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. There were two deaths (0.4%) from toxic effects with ipilimumab, and none with nivolumab.
Dr. Weber 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.” He added that, unlike the benefit seen with dabrafenib/trametinib in COMBI-AD, “patients with any BRAF status are candidates for nivolumab.” ■
DISCLOSURE: Dr. Weber has received honoraria and travel compensation from BMS and is named on a patent for a PD-1 biomarker by Biodesix and an ipilimumab biomarker by Moffitt Cancer Center. Dr. Michielin reported no conflicts of interest.
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). ESMO 2017 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. ESMO 2017 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. 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.
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...!-->!-->