Adjuvant Ipilimumab Shows Sustained Efficacy at 7 Years for Stage III Melanoma

Alexander Eggermont, MD, PhD

Adjuvant ipilimumab (Yervoy) elicited a 25% reduction in the risk of recurrence or death compared with placebo for patients with surgically resected high-risk, stage III melanoma, according to an updated analysis of findings from the phase III EORTC 18071 study.¹

For the analysis, which was conducted after 6.9 years of median follow-up, the estimated 7-year relapse-free survival rate was 39.2% (95% CI, 34.5%-43.9%) for ipilimumab compared with 30.9% (95% CI, 26.7%-35.2%) with placebo (HR, 0.75; 95% CI, 0.63-0.88; P <.001). At the 6.9-year analysis, 60.0% (95% CI, 55.0%-64.7%) of patients remained alive in the ipilimumab arm compared with 51.3% (95% CI, 46.5%-55.9%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002).

“These long-term follow-up results are important as we have firmly established that adjuvant therapy with the first immune checkpoint inhibitor, ipilimumab, provides sustained and durable survival benefit,” lead study author Alexander M.M. Eggermont, MD, PhD, general director of Institute Gustav Roussy, said in a statement. “This is encouraging, for what we now may expect to see, is overall survival benefits from more recently conducted trials with the more effective and less toxic anti—PD-1 molecules, such as nivolumab and pembrolizumab.”

In 2015, the FDA approved ipilimumab as an adjuvant therapy for patients with stage III melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection including total lymphadenectomy. Since this approval, the PD-1 inhibitor nivolumab (Opdivo) was shown to be superior to adjuvant ipilimumab, leading to an FDA approval for the PD-1 inhibitor in 2017. In the study that led to approval for nivolumab, CheckMate-238, the PD-1 inhibitor reduced the risk of recurrence or death by 35% compared with ipilimumab (HR, 0.65; 97.56% CI, 0.53-0.80; P <.001).²

“We have seen tremendous progress. The natural next step is to try to cure patients, and not wait until they have relapsed,” invited poster discussant David B. Page, MD, Earle A. Chiles Research Institute and Providence Cancer Institute, said during a session at ASCO. “The next natural step [after ipilimumab] is to look at nivolumab.”

The EORTC 18071 study randomized 951 patients with high-risk, stage III, completely resected melanoma to receive ipilimumab (n = 475) or placebo (n = 476). In the initial induction phase of the trial, ipilimumab was administered at 10 mg/kg every 3 weeks for 4 cycles. In a subsequent maintenance phase, ipilimumab was administered at 10 mg/kg every 12 weeks for 3 years.

Overall, 81% of patients in the ipilimumab arm who experienced a recurrence went on to receive a second-line treatment, as compared with 87.3% in the placebo group. The most common subsequent treatments in the ipilimumab and placebo arms, respectively, were surgery (39.6% vs 36.2%), chemotherapy (31.1% vs 32.5%), BRAF inhibitor (25.6% vs 27.6%), and radiotherapy (15.4% vs 19.2%). The trial was conducted before the widespread use of immunotherapy. As such, just 12% of patients received a subsequent PD-1 or PD-L1 inhibitor.

The estimated 7-year distant metastasis-free survival rate was 44.5% with ipilimumab (95% CI, 39.5%-49.3%) compared with 36.9% for placebo (95% CI, 32.4%-41.4%), representing a 24% reduction in the risk of distant metastasis or death (HR, 0.76; 95% CI, 0.64-0.90; P = .002). The median OS following first recurrence event was 1.8 months in the ipilimumab arm compared with 1.9 months with placebo (HR, 0.90; 95% CI, 0.74-1.10).

“If we reset the survival question at the time of recurrence, patients did just as well whether or not they received preceding ipilimumab,” said Page. “This gives me a little bit of reassurance that we can use these agents in early-stage disease without affecting the course afterwards.”

Adverse events (AEs) were a limiting factor for adjuvant ipilimumab, which has shifted the standard of care toward nivolumab. In the CheckMate-238 trial,² treatment-related grade 3/4 AEs were experienced by 45.9% of patients in the ipilimumab group compared with 14.4% in the nivolumab arm. The treatment discontinuation rate due to AEs was 42.6% in the ipilimumab arm compared with 9.7% with nivolumab. There were 2 grade 5 AEs in the ipilimumab arm compared with none with nivolumab.

Although it may be limited by safety, Page noted that an ongoing study is examining the combination of nivolumab and ipilimumab as an adjuvant treatment for patients with melanoma. This phase III study, known as CheckMate-915, is comparing nivolumab plus ipilimumab with nivolumab alone after complete resection of stage III or IV melanoma. The study enrolled 1943 patients, with primary results anticipated in November 2020 (NCT03068455).

References

1. Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: Long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial. J Clin Oncol. 2019; 37 (suppl; abstr 2512).
2. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824-1835.

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