Comparing Nivolumab Plus Ipilimumab vs Nivolumab Alone in Resected Stage III to IV Melanoma

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The addition of ipilimumab to nivolumab failed to improve outcomes compared with nivolumab alone as adjuvant therapy for resected melanoma, according to the results of the CheckMate 915 trial, presented at the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021.1

In an intent-to-treat population of more than 1,800 patients with stage IIIB to IIID or IV melanoma enrolled in the trial, 2-year relapse-free survival was similar with dual nivolumab/ipilimumab vs nivolumab alone: 64.6% and 63.2%, respectively. In the subset of patients whose tumors had low PD-L1 expression (< 1%), 2-year relapse-free survival was 53.6% with nivolumab/ipilimumab compared with 52.4% with nivolumab alone.

“These results reaffirm nivolumab as an adjuvant standard of care,” said Georgina V. Long, MD, PhD, of the University of Sydney.

Georgina V. Long, MD, PhD

Georgina V. Long, MD, PhD

Previously, the CheckMate 067 trial showed a numerical advantage in 5-year overall survival with nivolumab plus ipilimumab vs nivolumab alone in patients with advanced melanoma.2 A subgroup analysis of that trial suggested that patients with low PD-L1 expression might have a preferential benefit from the dual checkpoint inhibitor combination. Other randomized trials also showed an advantage for the combination in advanced melanoma.

Dr. Long said that the failed results for dual checkpoint inhibition in the present trial (vs other randomized trials) may be related to differences in dose and drug exposure. In CheckMate 915, the median treatment duration and cumulative nivolumab dose were much lower in the combination arm (7.6 months and 3,840 mg) than in the monotherapy arm (11.1 months and 6,240 mg); these findings appear to be related to higher discontinuation rates for toxicity with the combination vs nivolumab alone (32% vs 10%).

Fewer than half of patients treated with nivolumab plus ipilimumab remained on therapy for more than 9 months, compared with two-thirds of those on the nivolumab-alone arm. A post hoc analysis showed that patients who were able to remain on the combination treatment for 6 months or more had a better outcome than those who discontinued therapy before 6 months: the rate of 2-year relapse-free survival was 79.6% and 74.9%, respectively.

Study Details

The phase III CheckMate 915 trial was conducted at 122 sites across 19 countries. The study randomly assigned 1,844 patients with completely resected stage IIIB to IIID or IV melanoma in a 1:1 ratio to 1 year of treatment with either nivolumab (240 mg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks, n = 920 patients) or nivolumab alone (480 mg every 4 weeks, n = 924 patients). Stratification factors were tumor PD-L1 expression and disease stage. Minimum follow-up was 2 years.

Baseline characteristics were comparable in both arms. The median age of patients was 55 years; 57% were men; 38% had low PD-L1 expression (< 1%); and about one-third had BRAF mutations. The largest percentage of patients (53%) had stage IIIC melanoma; 31% had stage IIIB disease; 3% had stage IIID disease; and 13% had stage IV disease.

Subgroup analyses failed to show any group that significantly benefited from the combination vs monotherapy, including by stage. The 2-year relapse-free survival rates were 64.7% and 63.6%, respectively, for patients with stage III disease and 63.6% and 61.1%, respectively, for stage IV disease.

In an exploratory analysis of distant metastasis–free survival in patients with stage III disease, the 2-year rates were 75.4% with the combination and 77.4% with nivolumab monotherapy. In the PD-L1 < 1% group, distant metastasis–free survival was not improved with combination therapy. The 2-year distant metastasis–free survival rates in the low PD-L1 group were 68.4% with the combination vs 67.9% with nivolumab monotherapy.

Dr. Long delved more deeply into potential explanations for the poor showing for the combination-therapy arm. “Patients who got the combination therapy received much less therapy and had a shorter duration of therapy,” she noted.


As would be expected, the combination of nivolumab/ipilimumab was associated with more toxicity than nivolumab alone. The rates of grade 3 or 4 treatment-related adverse events were almost triple for dual checkpoint inhibition: 33% with the combination vs 13% with ipilimumab.

Treatment-related adverse events were consistent with previous studies of these agents. The rates of discontinuations of therapy due to treatment-related adverse events were 19% in the combination-therapy arm and 6% in the nivolumab-monotherapy arm. Four treatment-related deaths were reported with nivolu­mab/ipilimumab vs none with nivolumab alone.

Quality of life remained stable across both arms for the duration of the study, with no deterioration or improvement from baseline reported. 

DISCLOSURE: The study was funded by Bristol Myers Squibb. Dr. Long has served as a consultant or advisor to Aduro Biotech, Amgen, Array BioPharma, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Hexel AG, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals, SkylineDx BV, and Specialised Therapeutics Australia Pty Limited.


1. Long GV, Schadendorf D, Del Vecchio M, et al: Adjuvant therapy with nivolumab combined with ipilimumab vs nivolumab alone in patients with resected stage IIIB-D/IV melanoma (CheckMate 915). AACR Annual Meeting 2021. Abstract CT004. Presented April 11, 2021.

2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381:1535-1546, 2019.


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