FDA Approves Nivolumab as Adjuvant Treatment for Melanoma

Nivolumab (Opdivo) is now approved by the Food and Drug Administration (FDA) as an adjuvant treatment for patients with completely resected melanoma with lymph node involvement or metastatic disease. The FDA based this approval on findings from the phase III CheckMate-238 trial.

In the randomized 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).

“Immuno-Oncology has transformed the treatment of metastatic melanoma and many other cancers over the last decade, and we are now extending the use of novel agents to help prevent the recurrence of melanoma,” lead investigator Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, and Professor of Medicine at NYU School of Medicine, said in a statement. “With its impressive efficacy and broad applicability within stage III and IV melanoma, nivolumab has the potential to become the next standard of care in preventing recurrence of melanoma following surgical resection.”

In the CheckMate-238 trials, 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.

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 a BRAF mutation.

In findings published in the New 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 was 63.0% with nivolumab versus 57.5% with ipilimumab (HR, 0.70; 95% CI, 0.45-1.10).

In those with PD-L1—negative 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 a BRAF mutation, 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 with BRAF wild-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.

Nearly 97% of the nivolumab group and 98.5% of the ipilimumab group reported adverse events (AEs) of any cause. Patients in the ipilimumab were more likely to experience grade 3/4 treatment-related AEs, at 45.9% vs 14.4%. The rate of serious AEs of any grade was 17.5% in the nivolumab group and 40.4% in the ipilimumab group.

Fewer than 10% of patients assigned to nivolumab (9.7%) discontinued the trial due to AEs compared with 42.6% of those in the ipilimumab group. Grade 3/4 AEs led to such discontinuations in 4.6% of nivolumab patients and 30.9% ipilimumab patients. Investigators determined that AEs related to a trial drug that led to discontinuation were less frequent in the nivolumab group than in the ipilimumab group (7.7% vs 41.7%).

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, and no treatment-related deaths in the nivolumab group.

"When melanoma has been removed surgically, physicians and patients alike sometimes struggle with the idea of further adjuvant treatment because the disease is no longer detectable, even though it may be likely to return," said Weber. "We recognized a need to develop new adjuvant treatments with lower toxicity compared to ipilimumab to help address this challenge."

The approval followed a breakthrough therapy designation that was granted in September 2017 for adjuvant nivolumab. Nivolumab is approved across several indications for patients with cancer, with several applications still pending with the FDA. The recent approval represents the first granted to an adjuvant melanoma therapy, based on comparison to an active control arm.

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.