Improved Safety Profile With 'Flip Dose' Nivo/Ipi Regimen in Patients With Advanced Melanoma

Jeffrey S. Weber, MD, PhD


July 05, 2019

This transcript has been edited for clarity.

Hello. I'm Dr Jeffrey Weber. I'm a medical oncologist and the deputy director at the Laura and Isaac Perlmutter Cancer Center in New York City.

I'd like to report to you today on a recently published article in the Journal of Clinical Oncology, which describes the mature results of the CheckMate 511 trial.[1] This was a randomized, phase 3 trial of either standard-dose ipilimumab and nivolumab, which were given as four induction doses over 12 weeks, followed by maintenance therapy of nivolumab alone every 4 weeks at 480 mg, or what we call the flip doses of ipilimumab and nivolumab, where the ipilimumab was given at a lower dose of 1 mg/kg and the nivolumab 3 mg/kg, also followed by maintenance nivolumab at 480 mg every 4 weeks.

This was a study that was designed not to look at clinical efficacy, but to look at reduction in toxicity with the so-called flip dose of ipilimumab and nivolumab. The study was powered to see a 15% difference in the outcome of grade 3-5 immune-related adverse events thought to be due to treatment. As we'll see, that's exactly what was achieved.

This was a very well-done study. A total of 360 patients were randomized, of which 358 were actually treated. In this study, there was excellent balance between the arms for whatever factor you wish to look at, whether it be age, gender, PD-L1 status, BRAF status, M stage, or ECOG performance status—all of these were extremely well balanced.

The clinical efficacy was actually impressively close between the arms. Looking at the response rate, it was 45% for the flip dose and 50.6% for the standard dose, which is pretty close to what we expected from routine practice.

If one looks at the progression-free survival, which was not the primary endpoint of the study, with an average of 18 months of follow-up and a minimum of 12 months for all patients, the curves look like they are completely overlapping. The progression-free survival in the standard-dose arm was 8.9 months and it was 9.9 months in the flip-dose arm, which is actually a little better, but with no real significant P value for the difference. I would say that those curves are exactly overlapping.

If you look at overall survival, which is what everyone should think about, again, the curves are almost exactly overlapping, with medians not reached. At approximately 12 months, we're looking at approximately 78% survival versus 81% survival—the 81% survival being in the slightly higher ipilimumab group versus the 78% in the flip dose, which makes it virtually identical.

The important endpoint, of course, was the toxicity. I told you that the study was powered to see a 15% difference. There was a 48% grade 3-5 treatment-related adverse event rate in the standard-dose group that was reduced to 33% in the flip-dose group, which is a pretty significant difference clinically and statistically.

If you look at the absolute chance of experiencing either a low grade 1/2 or a grade 3-5 toxicity, there was a significant decrease in the important morbid side effects of either increased AST/ALT or diarrhea and/or colitis, which is exactly what you would expect by having the flip dose.

All in all, this is a very favorable result for the CheckMate 511 trial. Because this was not a definitive, randomized phase 3 trial with long-term follow-up over years—there's only 18 months of follow-up—many investigators might not feel that this is practice-changing.

For me, absent a rapidly growing tumor, high disease burden, or brain metastases, I would actually prefer to use the flip-dose ipilimumab/nivolumab regimen than the standard-dose ipilimumab/nivolumab regimen in my patients, especially in the older or more frail patients.

Please feel free to comment if you have questions. I hope you've enjoyed this presentation. This is Dr Jeffrey Weber. Thank you.

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