Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

By A. Eggermont, V. Chiarion-Sileni, J. Grob, R. Dummer, J. Wolchok, H. Schmidt, O. Hamid, C. Robert, P. Ascierto, J. Richards and 17 more. New England Journal of Medicine, 2016

1,211 citations recorded by the source corpus.

BACKGROUND On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis–free survival, and safety. RESULTS At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P = 0.001). The rate of distant metastasis–free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P = 0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis–free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168, and EudraCT number, 2007-001974-10.)

Subfields: Molecular Biology, Oncology

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In Molecular Biology

1. C. Robert
2. M. Lacouture
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In Oncology

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Citations in the corpus

• Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2017, background): “With ipilimumab (3 mg/kg), the incidence was reported to be between 1% and 5% [1, 2], but higher incidence (up to 10%) has been observed with the higher doses of ipilimumab (10 mg/kg) [4].”
• Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence (2020, methodology): “Ipilimumab was further expanded by the FDA as an adjuvant treatment of cutaneous melanoma in patients with pathologic involvement of regional lymph nodes (stage IIIA, > 1 mm nodal involvement, IIIB, and IIIC (with no in-transient metastasis) who have undergone complete resection and total lymphadene”
• Melanoma Staging: Evidence-Based Changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual (2017, background): “Moreover, adjuvant therapy with new agents has shown impressive ability to improve clinical outcomes in patients with resected stage III melanoma.(22-24) It is against this background that the AJCC appointed a Melanoma Expert Panel to undertake the task of revising the cutaneous melanoma staging sys”
• Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group (2017, background): “10 mg/kg), and with combination ipilimumab/nivolumab (incidence ≤13%) [10, 13, 16, 17, 57].”
• Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. (2019, result): “0013) in the adjuvant setting compared to placebo in the EORTC 18071 trial [53].”
• Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2018, background): “With ipilimumab (3 mg/kg), the incidence was reported to be between 1% and 5% [1, 2], but higher incidence (up to 10%) has been observed with the higher doses of ipilimumab (10 mg/kg) [4].”