Study Looks for Optimal Dosing of Single-Agent Ipilimumab in Metastatic Melanoma

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There has been debate as to the optimal dose of single-agent ipilimumab (Yervoy) in metastatic melanoma. A phase III study presented at the 2016 European Society for Medical Oncology (ESMO) Congress—the first to directly compare these doses—concluded that 10 mg/kg is more effective, but also more toxic, than 3 mg/kg.1

This phase III study showed a statistically significant improvement in overall survival with ipilimumab at 10 mg/kg vs 3 mg/kg in patients with melanoma who had not received a prior BRAF inhibitor or checkpoint inhibitor.
— Paolo A. Ascierto, MD

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The CA184-169 study was presented by Paolo A. Ascierto, MD, of the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy. “This phase III study showed a statistically significant improvement in overall survival with ipilimumab at 10 mg/kg vs 3 mg/kg in patients with melanoma who had not received a prior BRAF inhibitor or checkpoint inhibitor,” he reported.

The higher dose was associated with more treatment-related adverse events, including more deaths, and adverse events leading to treatment discontinuation.

“Although ipilimumab is approved for the treatment of melanoma at 3 mg/kg, a previous dose-ranging phase II trial2 suggested that longer overall survival but more treatment-related adverse events were seen with ipilimumab at 10 mg/kg, vs 3 mg/kg,” he said. “The current trial is the only phase III study directly comparing the benefit-risk profile of ipilimumab at 10 mg/kg vs 3 mg/kg in melanoma.”

Study Details

CA184-169 enrolled 727 patients with unresectable stage III/IV melanoma who may or may not have received chemotherapy but could not have received a BRAF inhibitor or checkpoint inhibitor. A little more than half the patients had received some prior treatment.

Patients were randomized to either 3 mg/kg or 10 mg/kg given every 3 weeks for 4 cycles. Patients who responded or who achieved stable disease for at least 3 months could be re-treated at 24 weeks on the same dose and schedule, but few patients did. Crossover was not allowed. Both arms received a median of four cycles of treatment in the initial phase and four in the retreatment phase. There was a very low percentage of patients treated with reinduction: 6% and 9% with 10 mg/kg and 3 mg/kg, respectively, and consistently with the previous studies.

Ipilimumab Dosing in Melanoma

  • The phase III CA184-169 study directly compared two doses of ipilimumab in metastatic melanoma.
  • Ipilimumab at 10 mg/kg every 3 weeks led to better overall survival (median = 15.7 months) than 3 mg/kg every 3 weeks (11.5 months; HR = 0.84; P = .04).
  • Three-year survival rates were 31% vs 23%, respectively.
  • Treatment-related adverse events leading to discontinuation were about 31% in the 10-mg/kg arm vs 19% in the 3-mg/kg arm.

Median overall survival was 15.7 months with ipilimumab at 10 mg/kg vs 11.5 months with 3 mg/kg (hazard ratio [HR] = 0.84; P = .04) and was improved at all time points. Overall survival was 54% and 48%, respectively, at 1 year; 38% and 31%, respectively, at 2 years; and 31% and 23%, respectively, at 3 years, Dr. Ascierto reported.

Virtually all subgroups benefited from the 10-mg/kg dose, with the most impressive results seen for BRAF-positive patients (without prior treatment with a BRAF inhibitor), whose hazard ratio was 0.65.

Median progression-free survival, however, was not improved with the higher dose, being 2.8 months in each arm. Similar as well were the objective response rate (15% vs 12% for 10 mg/kg vs 3 mg/kg, respectively) and disease control rate (32% vs 28%).

High Dose Led to Higher Toxicity Rates

Ipilimumab at 10 mg/kg, however, was far less tolerable than the 3-mg/ kg dose, primarily because of diarrhea, which led to the deaths of 4 patients (1%) in the 10-mg/kg arm vs 2 (< 1%) in the 3-mg/kg arm.

In the 10-mg/kg arm, 4 patients died after diarrhea led to general deterioration, fulminant colitis, multiorgan failure, and bowel perforation. The 2 deaths in patients receiving 3 mg/kg were due to multifocal colon perforation and a myocardial infarction from complications of diarrhea and colitis.

During the initial treatment phase, treatment-related adverse events of any grade occurred in 79% of the 10-mg/kg arm and 63% of the 3-mg/kg arm; they were grade 3 to 5 in 34% and 19%, respectively. Immune-related adverse events of any grade were observed in 74% and 54%, respectively, and were grade 3 to 5 in 30% and 14%, Dr. ­Ascierto reported.

Diarrhea occurred in 37% of patients taking 10 mg/kg and 23% taking 3 mg/kg; diarrhea grade 3 or 4 was experienced by 10% and 6%, respectively. Other toxicities were far less common.

Treatment-related adverse events leading to discontinuation were about 31% in the 10-mg/kg arm vs 19% in the 3-mg/kg arm. Both arms had deterioration in quality of life, but the 10-mg/kg group had a far greater diminishment at week 12, compared to the 3-mg/kg arm. By the end of the study, reduction in quality of life compared with baseline was approximately the same in magnitude between the arms. But this was what we saw in the first 16 weeks only…. We don’t know how patients did with longer follow-up,” he said.

Dr. Ascierto concluded that the results of this trial may be less relevant today than they were at study inception, since combinations are now the preferred first-line choice, but the results are still important. “Although the treatment landscape has evolved for first-line metastatic melanoma,” he said, “the clinical utility of ipilimumab in refractory patients warrants further evaluation.” ■

Disclosure: Dr. Ascierto has had a consultant/advisory role for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Amgen, Array, and Merck Serono and has received research funding from Bristol-Myers Squibb, Roche-Genentech, and Array.


1. Ascierto P, Del Vecchio M, Robert C, et al: Overall survival and safety results from a phase 3 trial of ipilimumab at 3 mg/kg vs 10 mg/kg in patients with metastatic melanoma. 2016 ESMO Congress. Abstract 1106O. Presented October 8, 2016.

2. Wolchok JD, Neyns B, Linette G, et al: Ipilimumab monotherapy in patients with pretreated advanced melanoma: A randomized, double-blind, multicenter, phase 2, dose-ranging study. Lancet Oncol 11:155-164, 2010.

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The [CA184-189] study brings very important information from an immunologic and clinical standpoint and will be key for the design of subsequent trials.
— Olivier Michielin, MS, MD, PhD

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Olivier Michielin, MS, MD, PhD, Head of Personalized Analytical...