In an interim analysis of the German phase II IMMUNED study reported in The Lancet, Zimmer et al found that adjuvant therapy with nivolumab/ipilimumab or nivolumab alone significantly prolonged recurrence-free survival vs placebo in patients with resected stage IV melanoma and no evidence of disease. Severe treatment-related toxicity and treatment discontinuation were substantially more common with the combination vs nivolumab monotherapy.

Study Details

In the multicenter double-blind trial, 167 patients with advanced melanoma and no evidence of disease after surgery or radiotherapy were randomly assigned 1:1:1 between September 2015 and November 2018. Patients received either nivolumab at 1 mg/kg every 3 weeks plus ipilimumab at 3 mg/kg every 3 weeks for four 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. 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 after occurrence of 90 relapse-free survival events.

Among all patients, median age was 55 years (26% ≥ 65 years); 57% were male; metastasis status in stage IV was M1a in 40%, M1b in 29%, and M1c (including 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% radiotherapy, and 11% both; 98% had less than three organ sites with disease; 45% had BRAF-mutant disease; and programmed cell death ligand 1 (PD-L1) expression was ≥ 5% in 49%.

Recurrence-Free Survival

Median follow-up was 28.4 months at time of analysis. The median number of doses received was 8 in the nivolumab/ipilimumab group, 18 in the nivolumab group, and 19 in the placebo group. 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/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 nivolumab combined with ipilimumab vs nivolumab alone.

Benefits of treatment with nivolumab/ipilimumab and nivolumab vs placebo were consistent across 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 alone 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 patients with PD-L1 expression < 5% and 0.24 (95% CI = 0.10–0.57) and 0.57 (95% CI = 0.29–1.11), respectively, for those with PD-L1 expression ≥ 5%.

Relapse occurred in 26.8% of patients in the combination group, 55.9% of the nivolumab group, and 80.8% of the placebo group. Relapse rates were 8.9%, 11.9%, and 25.0% for local relapse; 1.8%, 3.4%, and 7.7% for local and distant relapse; 14.3%, 39.0%, and 44.2% for distant relapse; and 0%, 1.7%, and 1.9% for new primary melanoma.

Outcomes for the secondary endpoint of overall survival 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/ipilimumab group, 27% of the nivolumab group, and 6% of the placebo group. The most commonly reported 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 patient in the nivolumab/ipilimumab group (due to pneumonia) and two in the nivolumab group (due to pneumonia and liver abscess); none of the deaths was considered related to treatment.

Commentary

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 tumor 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.”  

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.”

Dirk Schadendorf, MD, of the Department of Dermatology, University Hospital Essen, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit thelancet.com.