Based on findings from the phase III CheckMate-238 trial, nivolumab (Opdivo) has been recommended for approval by the European Medicines Agency’s Committee for Medicinal Products for Human Use as an adjuvant treatment for adult patients with completely resected melanoma with lymph node involvement or metastatic disease, according to Bristol-Myers Squibb, the developer of the PD-1 inhibitor.
Arvin Yang, MD, PhD
Based on findings from the phase III CheckMate-238 trial, nivolumab (Opdivo) has been recommended for approval by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) as an adjuvant treatment for adult patients with completely resected melanoma with lymph node involvement or metastatic disease, according to Bristol-Myers Squibb, the developer of the PD-1 inhibitor.
In results from the trial, the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% (95% CI, 61.8%-70.6%) compared with 52.7% (95% CI, 47.8%-57.4%) for ipilimumab (Yervoy) in patients with stage IIIB/C or IV melanoma. There was a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor (HR, 0.65; 95% CI, 0.53-0.80;P<.0001).
The European Commission (EC) will now review the CHMP recommendation and make a final decision on whether to approve nivolumab for this indication in the European Union.
“This positive opinion supports the potential of Opdivo in the adjuvant setting to prevent relapse and progression to an advanced stage,” Arvin Yang, MD, PhD, development lead, melanoma and genitourinary cancers, Bristol-Myers Squibb. “We look forward to the upcoming EC decision and the potential opportunity to bring Immuno-Oncology treatment options to more patients across the European Union.”
In the CheckMate-238 trial, patients with stage IIIB/C or IV melanoma were randomized to 1 year of treatment with nivolumab (n = 453) or ipilimumab (n = 453), which was approved by the FDA as an adjuvant therapy for melanoma in 2015. Nivolumab was administered at 3 mg/kg every 2 weeks and ipilimumab was given at 10 mg/kg every 3 weeks for 4 doses then every 12 weeks. The FDA-approved recommended dose for adjuvant nivolumab is 240 mg every 2 weeks.
Baseline characteristics were similar across groups, with patients stratified by stage and PD-L1 status. In the nivolumab arm, the median age of patients was 56 years (range, 19-83). Eighteen percent of patients had stage IV disease, with the remainder have stage IIIB (36%) and stage IIIC (45%). Lymph node involvement was primarily macroscopic (59.3%) and 41.5% of patients with stage III disease had tumor ulceration. Of those with stage IV disease, 24.4% had M1c disease, with the remainder being M1a/b. Overall, 33.6% of patients tested positive for PD-L1 (≥5% expression) and 41.3% of patients tested positive for aBRAFmutation.
In findings published in theNew England Journal of Medicine,median RFS had not yet been reached in either arm of the trial. The 12-month RFS rate with nivolumab was 70.5% (95% CI, 66.1%-74.5%) versus 60.8% (95% CI, 56.0%-65.2%) in the ipilimumab group. The median distant metastasis-free survival was not reached in either treatment group, with fewer events noted in the nivolumab arm (HR, 0.73; 95% CI, 0.55-0.95).
Improvements in RFS were seen regardless of tumor stage. In those with stage IIIB/C, the 12-month RFS rates were 72.3% versus 61.6%, for nivolumab and ipilimumab, respectively (HR, 0.65; 95% CI, 0.51-0.82). In those with stage IV disease, the 12-month RFS rate was 63.0% with nivolumab versus 57.5% with ipilimumab (HR, 0.70; 95% CI, 0.45-1.10).
In those with PD-L1negative tumors, the 12-month RFS rates were 64.3% versus 53.7%, for nivolumab versus ipilimumab, respectively. In those with PD-L1–positive tumors, the 12-month RFS rates were 81.9% with nivolumab versus 73.8% for ipilimumab. In those with aBRAFmutation, there was a 28% reduction in the risk of recurrence or death with nivolumab (HR, 0.72; 95% CI, 0.52-1.00). In those withBRAFwild-type tumors, there was a 42% reduction (HR, 0.58; 95% CI, 0.43-0.79). The FDA approval was granted regardless of PD-L1 or BRAF status.
Recurrence or death was reported for 34.0% of those in the nivolumab group and for 45.5% of those treated with ipilimumab. Overall, 28.5% of those in the nivolumab arm had received subsequent therapy versus 37.7% in the ipilimumab group. At the time of the analysis, data were not yet available for the secondary endpoint of overall survival (OS). In the EORTC 18071 trial, which led to the approval of adjuvant ipilimumab, improvements in RFS translated to later OS benefit. Follow-up of the CheckMate-238 remains ongoing.
Treatment-related grade 3/4 adverse events (AEs) were much more common in the ipilimumab group compared with the nivolumab arm (14.4% vs 45.9%). Additionally, there were fewer serious AEs (17.5% vs 40.4%) and grade 3/4 AEs (45.9% vs 14.4%) with nivolumab versus ipilimumab. Treatment-related AEs (TRAEs) leading to discontinuation occurred for 7.7% of those in the nivolumab arm compared with 41.7% of patients in the ipilimumab group.
There were 2 deaths (0.4%) in the ipilimumab group of marrow aplasia and colitis, both of which occurred more than 100 days after the last dose. There were no treatment-related deaths in the nivolumab group.
The most commonly reported TRAEs with nivolumab versus ipilimumab, respectively, were fatigue (34.5% vs 32.9%), diarrhea (24.3% vs 45.9%), pruritus (23.2% vs 33.6%), rash (19.9% vs 29.4%), and nausea (15% vs 20.1%). The most common grade 3/4 TRAEs with nivolumab were diarrhea (1.5%), rash (1.1%), and increased ALT (1.1%). With ipilimumab, the most frequent grade 3/4 TRAEs were diarrhea (9.5%), increased ALT (5.7%), increased AST (4.2%), rash (3.1%), hypophysitis (2.4%), and maculopapular rash (2.0%).
In the United States, the FDA approved nivolumab in December 2017 as an adjuvant treatment for patients with completely resected melanoma with lymph node involvement or metastatic disease, based on the same findings from the phase III CheckMate-238 trial.
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.