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Article

Ipilimumab evaluated as adjuvant therapy

Ipilimumab has been evaluated in the adjuvant setting. One expert predicts that ipilimumab’s positive effect on progression-free survival will translate into improvements in overall survival; however, he cautions that there is a risk:benefit ratio to be weighed.

Ipilimumab has been evaluated in the adjuvant setting, reports Reinhard Dummer, M.D., associate professor and vice chairman of dermatology at the University of Zurich in Switzerland. Current adjuvant therapy options include irradiation therapy, chemotherapy, cytokine therapy (interferons), vaccination, and kinase inhibitors.

“Because of positive outcomes for ipilimumab in metastatic melanoma, trials have been initiated in the adjuvant setting,” Dr. Dummer says.

The EORTC 18071 randomized 951 stage 3 high-risk patients with completely resected melanoma to induction ipilimumab (10 mg/kg, four cycles) or induction placebo, followed by maintenance ipilimumab (10m mg/kg every 12 weeks for up to 3 years) or maintenance placebo.  The results, presented at the annual meeting of the American Society of Clinical Oncology (Chicago, 2014), were positive.1

Ipilimumab increased the rate of relapse-free survival at 24 months from 17.1 months to 26.1 months (P = .0013). Ipilimumab was favored in all subgroups, including patients with microscopic nodal involvement (HR = .68) and macroscopic involvement (HR = .83), and for those with ulceration (HR = .67) and no ulceration (HR = .84).

“We may have overcome the problem that microscopic involvement cannot be treated adjuvantly. That’s not the case with ipilimumab,” Dr. Dummer says. He notes the impact was less for microscopic disease, and so these patients should not receive it. 

Toxicity, however, was high. Only 42% of patients completed induction and at least one maintenance dose; 29% completed one year or more of treatment. Adverse events were the reason that 49% of patients discontinued treatment, and while most resolved, only 56% of endocrinopathies did.

“These patients may need hormone replacement treatment until the end of life, and this is a significant point to consider with adjuvant therapy,” he suggests.

The Intergroup Adjuvant Phase 3 E1609 trial will compare ipilimumab (10 mg/lg and 3 mg/kg) to high-dose interferon in 1600 patients, with overall survival and relapse-free survival as endpoints.

Dr. Dummer says that for patients with nodal micrometastases (N1/2a), especially with ulceration, he recommends adjuvant therapy with pegylated interferon for two years, since it has been shown to improve progression-free survival. He discusses the potential for toxicity with his patients, and together they decide (often after a six-week trial) whether the impact on quality of life will justify the potential benefit.

For the patient at higher risk, interferon has less benefit, therefore, ipilimumab can be tried. This patient’s best option may actually be a clinical trial of an anti-PD1/PD-L1 agent, should one be available, he says.

Dr. Dummer predicts that ipilimumab’s positive effect on progression-free survival will translate into improvements in overall survival.

“But we will have to see the ratio of risk versus benefit,” he adds. “This is not a trivial question. A few patients have died due to treatment complications, and even if this is 1%, in the adjuvant setting this must be considered. The non-resolving toxicities also make me nervous. This treatment has an impact, but we can do better, maybe with anti-PD1 or targeted agents.”

References

1 Eggermont AM et al. ASCO 2014. Abstract LBA9008

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