Ipilimumab prolongs survival in stage III melanoma: The EORTC 18071 trial

1. Patients with resected stage III melanoma treated with adjuvant ipilimumab lived significantly longer than those who received placebo.

2. High dose ipilimumab is associated with potentially severe gastrointestinal, hepatic, and endocrine immune-related adverse events.

Evidence Rating Level: 1 (Excellent) 

Study Rundown: Ipilimumab is an immune checkpoint inhibitor that blocks cytotoxic T-lymphocyte antigen 4 that was approved in 2011 as a first-line treatment for advanced melanoma. The EORTC 18071 trial subsequently demonstrated its effectiveness in the context of adjuvant treatment after 2.3 years median follow-up. The present study assessed the effectiveness and safety of adjuvant treatment at 5.3 years median follow-up. The primary endpoint – recurrence-free survival rate assessed by an independent review committee – was significantly higher with adjuvant ipilimumab. Secondary endpoints included overall survival, distant metastasis-free survival, safety, and health-related quality of life. Though all measures of effectiveness were significantly more favorable with adjuvant ipilimumab, the treatment also carried significantly immune-related health risks.

This was a large, blinded, randomized trial that demonstrated for the first time the overall survival benefit of adjuvant therapy for high-grade melanoma. It was also the first attempt to use an immune checkpoint blockade as adjuvant treatment for melanoma. Though a favorable risk-benefit ratio was demonstrated, the high dose of ipilimumab treatment carries severe potential toxicities and must be used with caution.

Click to read the study, published today in NEJM

Relevant Reading: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial

In-Depth [randomized controlled trial]: This randomized, double-blinded, phase 3 trial randomized 945 patients to either ipilimumab (n = 471) or placebo (n = 474). The primary outcome was recurrence-free survival, defined from randomization until the date of the first local, regional, or distant metastasis or death of any cause. Secondary outcomes included overall survival from randomization, distant metastasis-free survival, and adverse events.

Overall, 53.3% of patients in the ipilimumab group discontinued treatment due to adverse events, compared to 4.6% receiving placebo. The recurrence-free survival rate at 5 years was 40.8% in the ipilimumab group compared to 30.3% with placebo (HR 0.76; 95%CI 0.64 to 0.89; p < 0.001). The 5-year overall survival rate in the ipilimumab group was 65.4% vs. 54.4% with placebo (HR 0.72; 95%CI 0.58 to 0.88; p = 0.001). The 5-year rate of distant metastasis-free survival was 48.3% with ipilimumab vs. 38.9% with placebo (HR 0.76; 95%CI 0.64 to 0.92; p = 0.002). Immune-related grade 3 or 4 adverse events occurred in 41.6% patients in the ipilimumab group vs. 2.7% in placebo. The most common immune-related adverse events in the ipilimumab group were gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%).

Image: PD

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