Two Ipilimumab Trials Show Survival Benefit, and More Toxicity

Jeffrey S. Weber, MD, PhD


October 31, 2016

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This is Dr Jeffrey Weber. I am a medical oncologist at the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center in New York City. Today we'll be talking about a couple of abstracts that were presented at the European Society for Medical Oncology (ESMO) meeting, which just took place a couple of weeks ago in Copenhagen, Denmark. Two very important melanoma abstracts described randomized clinical trials that took quite a bit of time to mature in terms of survival.

The first was a study in metastatic disease, in which patients received ipilimumab alone as a single agent at either 3 or 10 mg/kg.[1] This was a study with fairly long follow-up. The main issue was whether there is a difference in overall survival between the higher dose of ipilimumab and the lower dose of ipilimumab, which is now the standard approved dose in the United States at 3 mg/kg. Interestingly, 10 mg/kg is the approved adjuvant dose in the United States, but in metastatic disease, we tend to use 3 mg/kg, which is already approved by the US Food and Drug Administration (FDA).

The results of this randomized trial of over 720 patients suggest that with a hazard ratio of 0.84 and a P value of .04, there was an improvement in overall survival for the arm that had the higher dose. However, it was with a significantly higher rate of toxicity: a 26% versus 16% rate of grade 3/4 toxicities causing discontinuation, which is not a trivial issue. There is no question that the treatment at 10 mg/kg is more toxic. There was about an 8%-9% absolute difference overall in survival over time, which is not trivial.

Interestingly, the progression-free survival (PFS) was not significantly different at 2.8 months. So again, what we know about ipilimumab is that it really doesn't change your PFS, but it does appear to have an impact on overall survival. The impact of this study is that for patients who are in very good condition and failed to respond to a prior PD-1 inhibitor, and are candidates for single-agent ipilimumab, a discussion will need to be held with patients about whether to consider a dose of 10 mg/kg, if it is approved. Whether this will be pursued by the manufacturer is an open question.

The other trial that was very important was a randomized trial, the adjuvant EORTC trial of either ipilimumab—at 10 mg/kg for up to 3 years with an induction phase every 3 weeks up to 12 weeks, followed by maintenance every 12 weeks for up to 3 years—or placebo.[2] Patients had stage IIIa, IIIb, and IIIc disease, and the survival data were presented. The relapse-free survival data had clearly shown an advantage with a hazard ratio of 0.75, but now we have a survival advantage with a hazard ratio of 0.72.

There is no question that there's an absolute advantage of about 11 percentage points over time. The 5-year survival was 65% overall for the ipilimumab arm versus 54% for the placebo arm, suggesting two things: Patients without initial treatment actually do fairly well in stage III disease, but more importantly, there is a clear benefit to survival in giving ipilimumab at 10 mg/kg for up to 3 years. The average patient received it for only about 18 months, but that regimen is approved for up to 5 years by the FDA in the United States only.

In contrast, there was a 41% rate of grade 3/4 immunorelated adverse events in the ipilimumab arm versus none, of course, in the placebo arm. The rate of immunorelated adverse events that caused discontinuation was about 1 in 3, so 33%. Again, the issue here is, who would you treat with this FDA-approved regimen that is clearly effective versus no treatment, yet has significant toxicity? I think the answer is that it should be used judiciously in patients who have a good performance status and who would feel comfortable going on this potentially toxic regimen.

This is an FDA-approved regimen that has had some traction in the United States. It is not approved by the European Medicines Agency yet. We'll see whether that will be pursued by the manufacturer Overall, these two randomized trials demonstrate significant toxicity with a high dose of ipilimumab, which we knew before, but with clear evidence of survival prolongation both in the metastatic mode and in the adjuvant mode—the adjuvant mode versus placebo, and in the metastatic mode, 10 mg/kg versus 3 mg/kg.

This is Jeffrey Weber. I am at the Perlmutter Cancer Center at NYU. Please call us with your comments. Thank you very much for your attention.


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