Alexander M M Eggermont1, Vanna Chiarion-Sileni2, Jean-Jacques Grob3, Reinhard Dummer4, Jedd D Wolchok5, Henrik Schmidt6, Omid Hamid7, Caroline Robert8, Paolo A Ascierto9, Jon M Richards10, Céleste Lebbé11, Virginia Ferraresi12, Michael Smylie13, Jeffrey S Weber14, Michele Maio15, Cyril Konto16, Axel Hoos16, Veerle de Pril17, Ravichandra Karra Gurunath18, Gaetan de Schaetzen18, Stefan Suciu18, Alessandro Testori19. 1. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr. 2. IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. 3. Aix-Marseille University, Hôpital de La Timone APHM, Marseille, France. 4. University of Zürich Hospital, Zürich, Switzerland. 5. Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 6. Aarhus University Hospital, Aarhus, Denmark. 7. The Angeles Clinic and Research Institute, Los Angeles, CA, USA. 8. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. 9. Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. 10. Oncology Specialists SC, Park Ridge, IL, USA. 11. Assistance Publique Hôpitaux de Paris, Dermatology and CIC Departments, Hôpital Saint Louis, University Paris 7, INSERM U976, France. 12. Istituti Fisioterapici Ospitalieri, Rome, Italy. 13. Cross Cancer Institute, Edmonton, Alberta, Canada. 14. H Lee Moffitt Cancer Center, Tampa, FL, USA. 15. University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. 16. Bristol-Myers Squibb, Wallingford, CT, USA. 17. Bristol-Myers Squibb, Braine-l'Alleud, Belgium. 18. EORTC Headquarters, Brussels, Belgium. 19. European Institute of Oncology, Milan, Italy.
Abstract
BACKGROUND:Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. METHODS: We did a double-blind, phase 3 trial in patients with stageIII cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS:Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. INTERPRETATION:Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb.
RCT Entities:
BACKGROUND:Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. METHODS: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb.
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