A recent report in the prestigious New England Journal of Medicine (NEJM), has spawned reports like this one, regarding the risk of death in patients treated with combination checkpoint treatments. The first author of the NEJM story is MRA-funded investigator, Doug Johnson at Vanderbilt.
Melanoma patients who were the main focus of this article experienced immune-mediated cardiac toxicity after treatment with the Ipilimumab/Nivolumab (Ipi/Nivo) combination therapy regimen. What happened? It seems the patients’ immune systems launched an attack against the heart. While immune side effects are known with checkpoint therapies, this particular one is quite rare and potentially quite serious.
The authors report this complication is observed in just over 0.25% of patients treated with the Ipi/Nivo combination. How likely is that? It’s a bit more likely than heads coming up in 9 consecutive coin flips. The data indicate the cardiac toxicity is more common in patients treated with the combo compared to patients receiving Nivo alone, in whom the risk was much lower (0.06%). Overall, 18 cases of cardiac toxicity were reported in just over 20,500 patients treated with either Nivo or Ipi/Nivo, with 6 fatalities. In a separate report published in August in the Journal for Immunotherapy of Cancer, 8 melanoma patients were described who experienced cardiac toxicity related to treatment with checkpoint inhibitors – either Pembrolizumab, Ipi, or the Ipi/Nivo combo. It appears that the approved checkpoint inhibitors may have this undesirable and as of yet unpredictable toxicity. The use of steroids and other immunosuppressants appear to be helpful in some cases for managing side effects, though, unfortunately, not yet for everyone. To put the latest news in broader context, there are other kinds of immune-related side effects that are also potentially fatal, and we were already aware that the Ipi/Nivo combo in melanoma has more side effects than Nivo monotherapy.
While a cause for concern and highlighting the need for better monitoring, it’s important to keep focused on the significant benefit that checkpoint therapy offers many melanoma patients. As a reminder, for melanoma patients with metastatic melanoma treated with Ipi alone, one in five is alive at 10 years. For patients treated with anti-PD-1 antibody alone, about one-third will remain alive at 5 years. Contrast that with the risk of cardiac toxicity of ~0.25% in Ipi/Nivo treated patients. While there is a lot of work to be done to further improve all of these numbers, there should be no loss of optimism around checkpoint treatments and the benefits they offer for many patients.
It is up to the field to continue furthering the research to develop new, improved treatments while simultaneously working to monitor and manage the unwanted side effects of these agents.