Nivolumab (Opdivo) may represent a new standard option for adjuvant therapy for patients with resected stage IIIB/C and IV melanoma, whether or not they have a BRAF mutation. In a comparison with current standard high-dose ipilimumab (Yervoy), nivolumab demonstrated a significant improvement in relapse-free survival.
Jeffrey Weber, MD
Nivolumab (Opdivo) may represent a new standard option for adjuvant therapy for patients with resected stage IIIB/C and IV melanoma, whether or not they have a BRAF mutation. In a comparison with current standard high-dose ipilimumab (Yervoy), nivolumab demonstrated a significant improvement in relapse-free survival (RFS), reported Jeffrey Weber, MD, at the 2017 ESMO Congress in Madrid.
In the randomized CheckMate-236 trial, the improvement in RFS with nivolumab compared with high-dose ipilimumab was 35%,1 said Weber, deputy director, Perlmutter Cancer Center, New York University Langone Health Center, New York City. The rate of side effects was also lower with nivolumab.
Ipilimumab was approved by the US Food and Drug Administration for adjuvant therapy of resected stage III melanoma based on an improvement in RFS versus placebo in a randomized phase III trial, but >50% of patients treated with ipilimumab experienced a grade 3/4 event.2,3 “There is a clear need to improve the risk-benefit ratio of adjuvant treatment given the toxicity observed with the approved ipilimumab adjuvant regimen of 10 mg/kg, particularly for patients with high-risk resected stage IIIB/C and IV melanoma,” said Weber.
The phase III CheckMate-238 trial included 906 patients with stages IIIB, IIIC, and IV completely resected melanoma who had ≥50% risk of relapse over 5 years. Patients were randomized 1:1 to nivolumab, 3 mg/kg (IV), given every 2 weeks, or to ipilimimab, 10 mg/kg (IV), every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks.
Most patients (85%) had cutaneous melanoma. Eighty-one percent in each arm had stage IIIB or IIIC disease, about 40% in each arm had a mutation in BRAF, and 34% in each arm had PD-L1 expression ≥5%. All 905 patients are off treatment; the median number of doses administered were 24 in the nivolumab group and 4 in the ipilimumab group.
The primary endpoint was RFS. The trial was halted early by the Data Safety Monitoring Committee due to clear evidence of benefit for nivolumab. In the planned interim analysis at a minimum follow-up of 18 months, the rate of RFS was significantly improved with nivolumab compared with ipilimumab (66.4% vs 52.7%), corresponding to a 35% reduction in risk (HR, 0.65, P <.0001). Weber, in his remarks, noted key milestones demonstrating superiority of nivolumab: “a 10% difference at 12 months, slightly widening to a 13% difference at 18 months, with 66% relapse-free [with nivolumab] at 18 months.”
When the primary endpoint was analyzed by PD-L1 status, 1-year RFS was superior with nivolumab versus ipilimumab in the subset with PD-L1 expression <5% (64% vs 54%, HR, 0.71) and in those with PD-L1 expression ≥5% (82% vs 74%, HR, 0.50). The median PFS was not reached in the nivolumab arm and was 15.9 months in the ipilimumab arm in the former subset, and was not reached in either arm in the latter subset. Nivolumab was also superior on 1-year RFS in patients with BRAF-mutant disease (68% vs 63%, HR, 0.72) and BRAF wild-type disease (72% vs 57%, HR, 0.58).
Results were similar across prespecified patient subgroups.
Distant metastases-free survival among stage III patients, an exploratory endpoint, was 80% at 1 year in the nivolumab arm and 73% in the ipilimumab arm (HR, 0.73, P = .0204).
Post-protocol treatment with immunotherapy was twice as frequent in the ipilimumab arm versus the nivolumab arm (23% vs 11%). “I was struck by the fact that a fair number of patients could have surgery, suggesting that some of these patients were rendered free of disease yet again,” he said. About 15% of patients in each arm had surgery as post-protocol treatment. Ipilimumab may retain a role in patients in whom nivolumab fails and in whom another resection is possible, said Weber.
There were significantly fewer treatment-related, clinically relevant side effects (grade 3/4) in the nivolumab arm compared with the ipilimumab arm 14% vs 46%. Treatment discontinuation due to adverse events was necessary in 10% of patients in the nivolumab group compared with 43% in the ipilimumab group. There were no treatment-related deaths in the nivolumab group and 2 in the ipilimuamb group (marrow aplasia and colitis). The percentage of patients with low-grade thyroid disorders, primarily hypothyroidism, was greater with nivolumab compared with ipilimumab (20.4% vs 12.6%).
“The results of CheckMate 238 are very exciting,” said John Haanen, MD, head, Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. “They show for the first time that an anti-PD-1 drug is superior in the adjuvant setting and, because of its lower toxicity, nivolumab is much easier to give than ipilimumab. The same occurs in the metastatic setting where anti-PD-1 treatment is more efficacious and has a much better safety profile and has replaced ipilimumab as first-line treatment.”
“Nivolumab looks like a superior adjuvant melanoma regimen compared to ipilimumab from every angle,” Weber said. “It leads to better RFS, has fewer side effects, and is well tolerated.”