Currently, adjuvant ipilimumab represents an important treatment option for patients with high-risk stage III melanoma.— Alexander Eggermont, MD
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Patients with stage III melanoma who were considered to be at high risk for recurrence derived an overall survival benefit from adjuvant treatment with ipilimumab (Yervoy), although it came at the price of considerable toxicity, according to updated survival results from the phase III European Organisation for Research and Treatment (EORTC) 18071 trial. The results were presented at the 2016 European Society for Medical Oncology (ESMO) Congress by Alexander Eggermont, MD, Director General of the Institut Gustave Roussy in Villejuif, France,1 and simultaneously published in The New England Journal of Medicine.2
After a median follow-up of 5.3 years, 162 of 475 patients receiving ipilimumab had died, compared with 214 of 476 patients on the control arm. “We had 52 more deaths in the placebo arm,” Dr. Eggermont announced. “Currently, adjuvant ipilimumab represents an important treatment option for patients with high-risk stage III melanoma.”
The caveat, he acknowledged, is that this benefit “comes at the price of toxicity,” as grade 3/4 treatment-related adverse events were observed in 42%. “All those patients came off treatment. I think we can only administer this treatment at centers with experience in using ipilimumab and where patients are meticulously instructed to get in touch with their prescribing physicians. Otherwise, their safety is not guaranteed.”
EORTC 18071 randomized 951 high-risk patients with stage III completely resected melanoma (median age, 51) to induction with ipilimumab at 10 mg/kg every 3 weeks for 4 cycles followed by maintenance ipilimumab at 10 mg/kg every 12 weeks for up to 3 years or placebo induction and maintenance. The arms were well balanced, including proportions of patients with one node involved (46%), two or three nodes involved (33%–34%), or four or more nodes involved (20%–21%).
In 2015, the study met its primary endpoint at a median follow-up of 2.3 years, showing a significant 25% reduction in the risk of recurrence (P = .0013).3 This finding led to the drug’s approval as adjuvant therapy for stage III melanoma, but the overall survival data were immature. After a median follow-up of 5.3 years, the analysis of overall survival is now mature.
Patients receiving ipilimumab had a 28% reduction in the risk of death at 5 years (hazard ratio [HR] = .72; P = .001), based on an overall survival rate of 65%, vs 54% with placebo—an 11% benefit. Recurrence-free survival per independent radiology committee, the study’s primary endpoint, was significantly improved with ipilimumab, from a median of 17.1 months with placebo to 27.6 months with the checkpoint inhibitor (HR = .76; P = .0008). Distant metastasis–free survival was 48.3 months vs 27.5 months (HR = .76; P = .002). The benefit of ipilimumab was consistent across all endpoints and in virtually all subgroups.
“Ipilimumab as adjuvant therapy brings a significant improvement in overall survival and has a favorable risk/benefit ratio. It clearly represents a serious option for patients with stage III disease,” Dr. Eggermont commented.
Toxicity a Concern
There were no additional adverse events beyond those reported in the initial report at 2.3 years; however, these rates were relatively high. Among ipilimumab-treated patients, treatment was discontinued for disease recurrence by only 29%, but nearly 50% stopped treatment because of an adverse event related to the drug. In the placebo arm, nearly 60% came off study due to recurrence, but only 2% discontinued treatment due to toxicity.
Patients in the placebo arm received a median of eight doses, whereas ipilimumab-treated patients averaged only four doses. A total of 42% of the ipilimumab arm received at least one maintenance dose, and 29% received at least seven, totaling 1 year of therapy. Only 13% of the ipilimumab arm compared with 30% of the placebo arm completed all 3 years of treatment, Dr. Eggermont reported.
Grade 3/4 adverse events were observed in 42% of patients on ipilimumab, which included gastrointestinal events in 16%, hepatic toxicity in 11%, and endocrine toxicity in 8%. There were five deaths potentially related to ipilimumab (but none since the first analysis), which included three from colitis, one from autoimmune myocarditis, and one from multiorgan failure and Guillain-Barré syndrome.
These events were managed by established algorithms and usually resolved within 4 to 8 weeks. However, the endocrinopathies were often prolonged or permanent, requiring hormone-replacement therapies.
Dr. Eggermont fully acknowledged this treatment may be difficult for patients to tolerate. “Safety in the adjuvant setting is everything,” he stressed. “Although rash (63%) can be a nuisance for patients, we worry about gastrointestinal toxicities, which in this study were driven by diarrhea and full-blown colitis. We saw this overall in 16%, and this is where we had three deaths. Endocrinopathies are also a concern, especially hypophysitis, for which patients sometimes need hormone-replacement therapy for a lifetime.”
When asked if 3-mg/kg dosing could be used instead of 10-mg/kg dosing, Dr. Eggermont predicted this dose might be less toxic, but its safety and efficacy are unproven as adjuvant treatment. The decision to use 10 mg/kg was made before 3 mg/kg of ipilimumab was established in metastatic disease. “In 2018, we will find out about the lower dose from ECOG 1609,” he added. ■
Disclosure: Dr. Eggermont is on the scientific advisory board and receives honoraria from Actelion, Bayer, Celldex, Bristol-Myers Squibb, GlaxoSmithKline, Incyte, MSD, Nektar, Novartis, and Pfizer.
1. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Ipilimumab vs placebo after complete resection of stage III melanoma: Final overall survival results of the EORTC 18071 randomized double-blind, phase 3 trial. 2016 ESMO Congress. Abstract LBA2_PR. Presented October 8, 2016.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. October 7, 2016 (early release online).
3. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol 16:522-530, 2015.
The findings of the EORTC 18071 trial are a new landmark in our quest for the optimal treatment of melanoma in the adjuvant setting.— Olivier Michielin, MS, MD, PhD
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