Ipilimumab ‘Dose Matters’ Suggested For Unresectable Advanced Melanoma

A 10 mg/kg dose of ipilimumab was associated with longer overall survival but more side effects than the 3 mg/kg regimen for patients with unresectable stage III or IV melanoma

medwireNews: Increasing ipilimumab dosage led to significantly longer overall survival (OS) for patients with unresectable stage III or IV metastatic melanoma, albeit at the cost of greater toxicity, phase III findings show.

“The treatment landscape for first-line treatment of patients with advanced melanoma has changed since this study was initiated, with ipilimumab being succeeded by newer treatments”, the authors explain in The Lancet Oncology.

“However, the increased survival benefit of ipilimumab 10 mg/kg compared with 3 mg/kg suggests that the clinical utility of ipilimumab in refractory patients with high unmet medical need could warrant further assessment.”

Median OS was 15.7 months for the 364 patients who were randomly assigned to receive a 10 mg/kg infusion every 3 weeks versus 11.5 months for the 362 patients given the 3 mg/kg infusion, with a significant hazard ratio of 0.84.

The 1-year OS rate was 54.3% for the 10 mg/kg group and 47.6% for the 3 mg/kg group, with 3-year rates of 31.0% and 23.2%, respectively.

And OS findings for patient subgroup analyses “were consistent” with the overall result, write Paolo Ascierto, from Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and co-authors.

But Alexander Menzies and Georgina Long, both from The University of Sydney in New South Wales, Australia, observe in an accompanying comment that the higher dose of ipilimumab did not translate to superior median progression-free survival (2.8 months for both arms).

The 10 mg/kg and 3 mg/kg ipilimumab groups also had comparable rates of complete (2 vs 2%) and partial response (13 vs 10%), objective response (15 vs 12%), disease control (32 vs 28%) and median duration of response (16.3 vs 15.9 months).

Discussing this discrepancy in outcomes, they suggest that “perhaps a higher dose of ipilimumab has differing immunomodulatory effects, with increased frequency of pseudoprogression, or different kinetics of disease progression, or both, or perhaps the activity of subsequent therapy is increased after a higher dose of ipilimumab”.

Paolo Ascierto et al report that any-grade treatment-related adverse events occurred in 79% of the patients given 10 mg/kg ipilimumab and 63% of patients given 3 mg/kg infusions, with serious adverse events reported for 37% and 18%, respectively.

Patients given the 10 mg/kg regimen were also more likely to experience grade 3–4 adverse events that led to treatment discontinuation (24 vs 12%), and to experience immune-related adverse events of any grade (74 vs 54%) and grade 3–4 (30 vs 14%). Four patients in the 10 mg/kg group died from treatment-related adverse events, as did two patients in the lower dose group.

The researchers also report EORTC QLQ-C30 global health status questionnaire results, finding that both ipilimumab doses were associated with “[c]linically significant declines” in quality of life between baseline and week 12 and to the end of treatment, but these occurred more frequently and earlier with the 10 mg/kg dose.

The commentators believe the study has shown that “dose matters” and suggest that the “best chance of long-term survival (>5 years) might require higher doses of ipilimumab.”

Noting that there are ongoing trials to determine the impact of low-dose ipilimumab in combination with other agents such as high-dose interferon, nivolumab or pembrolizumab, Alexander Menzies and Georgina Long conclude: “In an era of increased awareness and prompt management of (predominantly reversible) immunotherapy toxicity, improvements in efficacy might outweigh additional toxicity.”

Reference

Ascierto PA, Del Vecchio M, Robert C, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol; Advance online publication 27 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30231-0

Menzies AM, Long GV. Optimum dose of ipilimumab in melanoma: too little, too late? Lancet Oncol; Advance online publication 27 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30228-0

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