Adjuvant Nivolumab Plus Ipilimumab vs Nivolumab Alone in Resected Stage IV Melanoma With No Evidence of Disease

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In an interim analysis of the German phase II IMMUNED trial reported in The Lancet, Lisa Zimmer, MD, of University Hospital Essen, and colleagues found that adjuvant nivolumab plus ipilimumab and nivolumab alone significantly prolonged recurrence-free survival vs placebo in patients with resected stage IV melanoma and no evidence of disease.1 Severe treatment-related toxicity and treatment discontinuations were substantially more common with combination vs nivolumab treatment.

Lisa Zimmer, MD

Lisa Zimmer, MD

Study Details

In the multicenter, double-blind trial, 167 patients with no evidence of disease after surgery or radiotherapy were randomly assigned 1:1:1 between September 2015 and November 2018 to receive nivolumab at 1 mg/kg every 3 weeks plus ipilimumab at 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks (n = 56), nivolumab at 3 mg/kg every 2 weeks plus placebo (n = 59), or double placebo (n = 52). Treatment continued for up to 1 year or until disease recurrence or unacceptable toxicity. Patients with uveal or mucosal melanoma and those who had received prior immune checkpoint inhibitors or any previous immunosuppressive therapy within 30 days before study drug administration were not eligible for the trial. The primary endpoint was recurrence-free survival in the intention-to-treat population. The results in the current report are from a prespecified interim analysis of recurrence-free survival after 90 events had been reported.

Among all patients, the median age was 55 years (26% ≥ 65 years); 57% were male; metastasis status was M1a in 40%, M1b in 29%, and M1c (including a history of brain metastasis) in 31%; all had an Eastern Cooperative Oncology Group performance status of 0 (93%) or 1; 76% had undergone surgery, 13% had had radiotherapy, and 11% had both; 98% had fewer than three organ sites with disease; 32% had received prior adjuvant systemic therapy, and 2% had received systemic therapy in the metastatic setting; 45% had BRAF-mutant disease; and programmed cell death ligand 1 (PD-L1) expression was at least 5% in 49%.

Recurrence-Free Survival

The median follow-up was 28.4 months at the time of analysis. The median number of doses received was eight in the nivolumab-plus-ipilimumab group, 18 in the nivolumab group, and 19 in the placebo group; the median time on treatment was 6.5 weeks, 21.9 weeks, and 24.1 weeks, respectively.

Median recurrence-free survival was not reached in the nivolumab-plus-ipilimumab group (hazard ratio [HR] vs placebo = 0.23, 97.5% confidence interval [CI] = 0.12–0.45, P < .0001), 12.4 months (95% CI = 5.3–33.3 months) in the nivolumab group (HR vs placebo = 0.56, 97.5% CI = 0.33–0.94, P = .011), and 6.4 months (95% CI = 3.3–9.6 months) in the placebo group. Recurrence-free survival was 75% and 52% vs 32% at 1 year and 70% and 42% vs 14% at 2 years. Exploratory analysis indicated a hazard ratio of 0.40 (97.5% CI = 0.20–0.79) for the combination vs nivolumab alone.

Benefits of nivolumab plus ipilimumab and nivolumab vs placebo were consistent across the subgroups examined. Hazard ratios vs placebo were 0.07 (95% CI = 0.02–0.23) for the combination and 0.39 (95% CI = 0.19–0.78) for nivolumab among patients with BRAF-mutant disease and 0.44 (95% CI = 0.22–0.88) and 0.71 (95% CI = 0.39–1.28), respectively, among patients with wild-type BRAF. Hazard ratios vs placebo were 0.21 (95% CI = 0.10–0.48) for the combination and 0.55 (95% CI = 0.30–1.02) for nivolumab for PD-L1 expression up to 5% and 0.24 (95% CI = 0.10–0.57) and 0.57 (95% CI = 0.29–1.11, respectively, for PD-L1 expression of at least 5%. For M1a, M1b, and M1c disease, hazard ratios vs placebo were 0.13, 0.46, and 0.19 for the combination and 0.39, 0.65, and 0.77 for nivolumab alone.

Relapse occurred in 26.8% of the combination group, 55.9% of the nivolumab group, and 80.8% of the placebo group. Relapse rates were 9%, 11.9%, and 25.0% for local relapse; 1.8%, 3.4%, and 7.6% for local and distant relapses; 14.3%, 39.0%, and 44.2% for distant relapse; and 0%, 1.7%, and 1.9% for new primary melanoma.

Overall survival outcomes are to be assessed when the last patient off treatment has been followed for 2 years.

Adverse Events

Treatment-related grade 3 or 4 adverse events were reported in 71% of the nivolumab-plus-ipilimumab group, 27% of the nivolumab group, and 6% of the placebo group. The most common adverse events in the combination group were increased alanine transaminase (24% vs 11% in the nivolumab group), autoimmune disorder (22% vs 2%), increased aspartate transaminase (15% vs 5%), increased lipase (15% vs 5%), and autoimmune hepatitis (11% vs 4%). Treatment-related serious adverse events occurred in 58%, 20%, and 4% of patients. Treatment-related adverse events of any grade led to treatment discontinuation in 62%, 13%, and 2% of patients.

Three deaths due to adverse events were reported, consisting of one in the nivolumab/ipilimumab group due to pneumonia and two in the nivolumab group due to pneumonia and liver abscess. None of the deaths were considered related to treatment.

The investigators noted: “High toxicity but substantial efficacy of combined nivolumab plus ipilimumab treatment has also been described in two small trials in the adjuvant and neoadjuvant setting in stages III and IV melanoma…. Data from IMMUNED as well as other trials … suggest that short but intense immune checkpoint inhibition with nivolumab plus ipilimumab might be sufficient to achieve long-lasting tumour control in a substantial subset of patients with melanoma with no or small tumor burden disease. Whether ipilimumab is required in the standard dose of 3 mg/kg needs further investigation. The risk-benefit profile and alternative dosing regimens of the immunotherapy combination will be further clarified by data from the ongoing double-blind, randomized, phase III CheckMate-915 trial ( identifier NCT03068455), which investigates two weekly, 240-mg flat-dose nivolumab plus ipilimumab (1 mg/kg, every 6 weeks) as an experimental group in resected stage IIIB/C/D or IV melanoma, compared with four weekly nivolumab (480-mg flat dose).”

They concluded: “Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3/4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease.” 

DISCLOSURE: The study was funded by Bristol Myers Squibb. For full disclosures of study authors, visit


1. Zimmer L, Livingstone E, Hassel JC, et al: Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy vs placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 395:1558-1568, 2020.


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