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Adjuvant Nivolumab Granted FDA Approval for Melanoma

Published Online:9:13 PM, Wed December 20, 2017

Jeffrey Weber, MD
Nivolumab (Opdivo) has received FDA approval for the adjuvant treatment of patients with completely resected melanoma with lymph node involvement or metastatic disease.

The approval is based on findings of the randomized phase III CheckMate-238 trial, in which 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 stage IV melanoma after surgery. 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 stage M1c, with the remainder being M1a/b.

In results presented at the 2017 ESMO Congress, patients with PD-L1 expression <5% had a 12-month RFS rate of 64.3% (95% CI, 58.3-69.7) in the nivolumab group and 53.7% (95% CI, 47.6-59.4) in the ipilimumab group. Among those with PD-L1 expression ≥5%, the 12-month RFS rate was 81.9% (95% CI, 74.7-87.2) in the nivolumab arm and 73.8% (95% CI, 65.9-80.1) in the ipilimumab arm.

Median RFS had not been reached in patients with stage III or stage IV disease in the nivolumab group. Among the patients with stage IIIB or IIIC disease, the 12-month RFS rate was 72.3% (95% CI, 67.4-76.7) for those assigned to nivolumab and 61.6% (95% CI, 56.3-66.5) in the ipilimumab group. The twelve-month RFS rate also favored nivolumab among those with stage IV disease, at 63.0% (95% CI, 51.6-72.5) versus 57.5% (95% CI, 46.0-67.4).

Nivolumab was associated with significantly longer RFS, with recurrence or death reported in 32.7% of the nivolumab group compared with 44.5% in the ipilimumab group among those with stage IIIB or IIIC disease (HR, 0.65; 95% CI, 0.51-0.82). Among those with stage IV disease, 33 of 82 patients (40.2%) in the nivolumab group experienced recurrence or death versus 43 of 87 patients (49.4%) in the ipilimumab group (HR, 0.70; 95% CI, 0.45-1.10).

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."
 

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