Adjuvant nivolumab bests ipilimumab in surgically resected melanoma
Adjuvant nivolumab treatment significantly improved outcomes vs ipilimumab in patients with surgically resected stage III/IV melanoma, according to interim results of the CheckMate 238 trial.
In the trial, nivolumab significantly improved the rate of relapse-free survival (RFS) vs ipilimumab (hazard ratio [HR], 0.65; p<0.0001) and was associated with substantially fewer adverse events. [N Engl J Med 2017, doi: 10.1056/NEJMoa1709030]
The results suggest that the PD-1 inhibitor nivolumab may be a new standard treatment option for patients with resected stage III/IV melanoma. CheckMate 238 was stopped early due to a clear benefit in the nivolumab arm.
“Nivolumab clearly showed a very clinically and statistically significant improvement in RFS vs high-dose ipilimumab for these patients,” said investigator Dr Jeffrey Weber of the New York University Langone Medical Center in New York City, US, who presented the results at the European Society for Medical Oncology (ESMO) 2017 Congress. “The benefit of nivolumab was observed in virtually all of the prespecified subgroups, whether you look at disease stage, PD-L1 staining, BRAF mutation status, age, or ulceration of the primary tumour.”
Both nivolumab and the CTLA-4 inhibitor ipilimumab are approved for the treatment of patients with advanced melanoma. Ipilimumab was approved for adjuvant treatment of patients with stage III resected melanoma in the US in 2015. However, its use is still debated due to concerns over its high level of toxicity.
CheckMate 238 was a phase III, randomized, double-blind clinical trial that included 906 patients with completely resected stage IIIB, IIIC or IV melanoma with a >50 percent risk of relapse over 5 years. Patients were randomized to receive either nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then once every 12 weeks.
At the 18-month interim follow-up, the rate of RFS was 66.4 percent in the nivolumab arm vs 52.7 percent in the ipilimumab arm. In subgroup analyses, the 12-month RFS rate in patients with PD-L1 expression level ≥5 percent was 81.9 percent in the nivolumab arm vs 73.8 percent in the ipilimumab arm, while the RFS rate in patients with PD-L1 expression level <5 percent was 64.3 vs 53.7 percent. The exploratory endpoint of distant metastasis-free survival was also significantly improved in the nivolumab vs ipilimumab arm (HR, 0.73; p=0.02).
Importantly, rates of grade 3/4 adverse events were substantially lower with nivolumab vs ipilimumab. Treatment-related grade 3/4 adverse events occurred in 14.4 percent of patients receiving nivolumab vs 45.9 percent of patients receiving ipilimumab. Moreover, fewer patients receiving nivolumab had to discontinue treatment due to any adverse events compared with those receiving ipilimumab (9.7 vs 42.6 percent).
“In my opinion, nivolumab provides a very acceptable risk-benefit ratio as adjuvant therapy for high-risk resected melanoma. It has the potential to be an effective treatment option for patients with resected stage III and IV disease,” Weber said.