Long-term adjuvant ipilimumab results showed 11% improvement in overall survival versus placebo in melanoma patients

“Finally we have an adjuvant therapy option that has consistent benefits in terms of overall survival, distant metastasis free survival and relapse-free survival,” reported Professor Alexander Eggermont, Director General, Institut Gustave Roussy, Paris, France, adding that the findings were true throughout the spectrum of stage 3 disease – with microscopic or with palpable nodal involvement, but stressed that, “it [ipilimumab] needs experienced centres to manage it.”

“It clearly represents a serious option for patients with stage III melanoma.” Professor Alexander Eggermont, Director General, Institut Gustave Roussy, Paris, France.

OS showed a 28% reduction in risk of death in patients on ipilimumab versus placebo. In absolute terms, the consistency is 11% for OS (65% versus 54%), 11% for DMFS (48% versus 39%) and 11% for RFS (41% versus 30%) for ipilimumab and placebo respectively, Professor Eggermont reported.

“It clearly represents a serious option for patients with stage III melanoma,” he added, discussing the final overall results of the randomised, double-blind, phase III trial.

Ipilimumab was the first checkpoint inhibitor approved in 2011 for metastatic melanoma. The EORTC 18071 trial compared the anti-CTLA-4 therapy, used as an adjuvant therapy after complete resection of high risk, stage III melanoma (lymph-node positive), to placebo.

Results presented in 2015 showed that the trial met its primary endpoint with ipilimumab significantly improving recurrence-free survival (HR=0.75). Now at ESMO 2016, OS findings were presented.

Between 2008 to 2011, 951 eligible patients, over 18 years of age, who had undergone complete resection (42% ulcerated primary, and 58% macroscopic lymph node involvement), were randomised 1:1 to ipilimumab (10 mg/kg, n=475) or placebo (n=476) every 3 weeks for four doses, then every 3 months for up to 3 years until completion, disease recurrence or unacceptable toxicity. The primary endpoint was RFS, and secondary endpoints included DMFS, OS and safety.
With respect to RFS, at 5.3 years of median follow-up, a hazard ratio of 0.76 (p=0.008) or a 24% risk reduction was observed in patients on the active agent. “The absolute difference in terms of median relapse-free survival is 10.5 months (27 versus 17),” Professor Eggermont said.
OS had a hazard ratio of 0.72 (p=0.001), translating into a 28% reduction in relative risk of death for patients on ipilimumab versus placebo. “In absolute numbers, the death rate difference is 11% with a survival rate of 65% for ipilimumab and 54% with placebo.”

He added that, based on these findings, there is prolonged survival in patients who are sentinel node positive with only microscopic involvement of regional lymph nodes, but also those with palpable nodal disease. “In these patients [with palpable nodal disease], we have never before seen benefit with adjuvant interferon therapy, but we now see benefit with adjuvant ipilimumab.”

Adverse events higher with ipilimumab

However, overall immune-related adverse events occurred in 42% versus 2% in the ipilimumab and placebo arms respectively. “This all comes at a price of side effects and toxicity of course, with the majority of adverse events being immune-related,” reported Professor Eggermont. However, there were no additional toxicities or deaths since the initial report at 2.3 years, he added, and the most important grade 3-4 adverse events were gastrointestinal (16%), hepatic (11%) and endocrine (8%). Grade 5 events occurred in 1.1% of patients on ipilimumab.

“Gastrointestinal events are very important because some patients experienced colitis, which can be associated with perforation and can lead to death without appropriate treatment,” he reported. Endocrine events were mainly hypothyroiditis, but more importantly hypophysitis, which occurs in around 4.5% of patients and means lifelong hormone replacement therapy is needed. “One patient experienced the neurologic adverse event of Guillain-Barre but died of septic shock,” he added.

“Ipilimumab is not an easy drug to handle, but my recommendation is to keep it in [specialist cancer treatment] centres. There is an increased rate of adverse events with this dose of ipilimumab, but it does now present an important treatment option for patients.”

Commenting on the results, Dr Olivier Michielin, Head of Personalised Analytical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said: “This was the first attempt to use checkpoint blockade in the adjuvant setting of melanoma. In the adjuvant setting there is microscopic residual disease and, until now, it was not clear if there was a sufficient amount of antigen to trigger a response.”

“We are currently waiting for the results of several trials including EORTC 1325 which is investigating pembrolizumab, a PD-1 checkpoint blocking antibody, compared to placebo in the adjuvant setting.”

Based on Mirza M, Monk B et al. A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial) (LBA3_PR). Presented on Saturday 8 October 2016

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