EORTC 18071
PubMed • Full text • PDF
Clinical Question
In patients with completely resected, high-risk Stage III melanoma, does ipilimumab improve survival compared to placebo?
Bottom Line
Ipilimumab improves survival in patients with completely resected Stage III melanoma.
Major Points
Despite new advances in immunotherapy and BRAF-targeted therapy for metastatic melanoma, there has been minimal data to drive the management of patients with Stage III melanoma, aside from complete surgical resection. Despite classification in the same stage, patients with Stage III melanoma represent a wide array of risk of recurrence and mortality. These patients may be stratified by other clinical features in order to inform risk-benefit discussions regarding active surveillance vs. systemic therapy.
This 2016 trial demonstrated a 5-year survival benefit (65% vs 54%) from initiating ipilimumab shortly after surgical resection rather than placebo, mirroring systemic therapy vs. active surveillance in patients with high risk Stage III melanoma. In subgroup analysis, though not statistically significant, this appears to be driven largely by Stage IIIC patients with 4 or more lymph nodes involved. Given the substantial treatment intolerance (40% discontinuation rate, 1.1% drug-related mortality), risk-benefit analysis is still necessary, however this trial helps isolate the subset of Stage III melanoma patients who benefit from early systemic therapy.
Guidelines
NCCN Melanoma 2016, adapted
- Ipilimumab or observation are recommended options for patients with Stage III cutaneous melanoma with positive sentinal node >1mm or clinically positive node(s), in addition to surgical resection.
Design
- Multicenter, double-blind, randomized, controlled trial
- N=951
- Ipilimumab (n=475)
- Placebo (n=476)
- Setting: 99 centers in 19 countries (in North America, Europe, Australia)
- Enrollment: July 2008 - August 2011
- Mean follow-up: 5.3 years
- Analysis: Intention-to-treat
- Primary outcome: Recurrence-free survival
- Secondary outcomes: Overall survival and metastasis-free survival
Population
Inclusion Criteria
- Cutaneous melanoma metastatic to regional lymph node (Stage III)
- Complete surgical resection
- Complete regional lymphadenectomy within 12 weeks
- Age>18
Exclusion Criteria
- ECOG > 1
- <1mm micrometastasis for Stage IIIA disease
- Previous systemic therapy for melanoma
- Autoimmune disease
- NYHA III-IV cardiovascular disease
- Uncontrolled infection
- LDH >2x normal
- Systemic glucocorticoids
Baseline Characteristics
- No significant differences
- Demographics: Age 51.5, 62% male
- Stage IIIA (21%), IIIB (44%), IIIC (36%) with 1-3 nodes (16%) vs. 4+ nodes (20%)
Interventions
- Randomized to high-dose ipilimumab vs. placebo
- Dose: 10mg/kg IV q3wk x 4 doses (adjuvant), then q3mo x 3 yrs (maintenance) or until recurrence/intolerance
- Stratified by Stage IIIA vs. IIIB vs. IIIC (1-3 lymph nodes) vs. IIIC (4+ lymph nodes) and by continent
Outcomes
Comparisons are ipilimumab vs. placebo
Primary Outcomes
- Recurrence-free survival (5-year)
- 40.8% vs. 30.3% (HR 0.76; 95% CI 0.64-0.89; P<0.001)
Secondary Outcomes
- Overall survival (5-year)
- 65.4% vs. 54.4% (HR 0.72; 95% CI 0.58-0.88; P=0.001)
- Metastasis-free survival (5-year)
- 48.3% vs. 38.9% (HR 0.76; 95% CI 0.64-0.92; P=0.002)
Subgroup Analysis
- No significant differences based on stage, number of lymph nodes involved, ulceration presence, or micro/macroscopic LN involvement
- Trend towards mortality benefit driven by patients in Stage IIIC with 4+ LN
- Stage IIIC with 4+ LN: HR 0.48 (0.28–0.81)
- Stage IIIC with 1-3 LN: HR 1.00 (0.56–1.80)
- Stage IIIB: HR 0.75 (0.50–1.14)
- Stage IIIA: HR 0.98 (0.46–2.09)
Adverse Events
- Treatment discontinuation rate: 40% by 3 months, 87% by 3 years
- 5 drug-related patient deaths (1.1%)
- Drug-related adverse event: Grade 5 (1.1%), Grade 4 (6%), Grade 3 (36%), Total (90%)
- Most common: Diarrhea (41%), Rash (34%), Transaminitis (17%), Colitis (16%), Hypophysitis (16%)
Criticisms
- Unclear if 3-year maintenance phase is necessary given extremely high rates of discontinuation during this period
- Higher sample size would have powered important subgroup analysis
- Effect size and subgroup analysis also limited by high discontinuation rates
Funding
Funded by Bristol-Myers Squib, makers of ipilimumab.