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Nivolumab–ipilimumab combination should be considered standard of care
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Editor’s Note: Results of the randomized phase 2 CheckMate 069 trial showed the addition of nivolumab (Opdivo, Bristol-Myers Squibb) to ipilimumab (Yervoy, Bristol-Myers Squibb) significantly extended median PFS among treatment-naive patients with BRAF wild-type melanoma (not reached vs. 4.4 months; HR = 0.35; P < .0001). Researchers also reported longer median OS (not reached vs. 24.8 months) among BRAF wild-type patients assigned the combination.
Mario Sznol, MD, professor of medicine at Yale Cancer Center, spoke with HemOnc Today about the trial’s potential implications.
This was a randomized phase 2 trial, so it did not include a large number of patients. However, the survival of the combination arm was outstanding, and it was numerically higher than the ipilimumab arm, although the analysis was exploratory. Sixty-two of patients progressing on ipilimumab alone in this trial subsequently received an anti–PD-1 drug. That would explain the high rate of survival in the ipilimumab-alone arm.
The real question is whether the combination is better than nivolumab alone. Certainly, the survival appears better than what we have seen in other trials of nivolumab alone at 2 years. The absolute difference could be 10% to 15% at 2 years, which is substantial reduction in risk for death, and the differences could increase at subsequent landmarks.
I don’t think we are going to see a different result when we see more data from the CheckMate 067 trial, which was designed to assess nivolumab alone or the nivolumab–ipilimumab combination vs. ipilimumab alone in previously untreated advanced melanoma. However, it is important to remember that trial was not designed to compare the combination to nivolumab alone and, therefore, any comparison of the combination to nivolumab will also be exploratory.
My overall impression is that the nivolumab–ipilimumab combination is going to provide superior survival — certainly over ipilimumab alone and probably over nivolumab alone, and likely better than ipilimumab and nivolumab used in either sequence. Again, if the increment is 10% to 15% at 2 years, that is a substantial risk reduction, and that survival advantage may even improve over time because the curve for the ipilimumab–nivolumab combination may remain relatively flat beyond 2 years. I also expect the combination to improve survival regardless of the BRAF mutation status. The optimal sequence of immune therapy vs. targeted agents in the BRAF–mutant population remains an open question, but the survival data from noncomparative trials suggests starting with immune therapy first in most patients.
There is no question there is more toxicity with the combination. Although a modest percentage of patients will develop substantial symptoms, most of these toxicities are manageable and eventually reversible. We learned how to manage them during the period of ipilimumab development.
I think the vast majority of patients will tolerate this therapy well. Clinicians have to re-educate themselves about how to manage these toxicities. If we could select patients who would do really well with nivolumab alone, that would be preferable, but we don’t have a really good predictive biomarker yet.
So, despite the increased toxicity of the combination, I think this should be considered the standard of care.
We are doing very well in the field of melanoma, and I expect more than 50% of the patients we treat are going to do very well in the long term. However, the other 50% need better therapies.
That means it is critical that we try to understand the mechanisms of resistance. We know the nivolumab–ipilimumab combination works well in patients who are PD-L1 positive and PD-L1 negative, but the mechanisms of resistance may be different in these groups.
As for what is next, researchers are looking at a variety of options, including combinations with IDO inhibitors, other checkpoint inhibitors and costimulatory agents. Another possibility might be adoptive cell transfer. But at this point, we don’t have a good handle on how to bring that long-term durable response rate up. There are possibilities out there, but we are still struggling to find that next best approach in melanoma.
Reference:
Postow M, et al. Abstract CT002.
Disclosure: Sznol reports consulting fees from Bristol-Myers Squibb.