Synergy With Checkpoint Inhibitors: Fact or Fiction?

Maurie Markman, MD


July 27, 2022

This transcript has been edited for clarity.

I'm Dr Maurie Markman from Cancer Treatment Centers of America. I would like to discuss a very interesting, important, and, I would argue, controversial topic in a recent paper published in Clinical Cancer Research. The paper was entitled, "Predictable Clinical Benefits Without Evidence of Synergy in Trials of Combination Therapy With Immune Checkpoint Inhibitors."

In oncology, when we see the effects of a single agent, we have, for decades, then looked at the potential of combination therapy. Combination cytotoxic therapy, for example, is a standard of care for a number of diseases.

The role of checkpoint inhibitors in an increasing number of diseases is evident. These therapies are leading to profound clinical outcomes, including cures, which we had not seen before. Naturally, we would want to look at the potential for two checkpoint inhibitors given together.

This particular analysis looked at existing trials and raised the provocative point that the benefits of combination therapy are literally [the same as] the effects of the single agents by themselves. In fact, there's no evidence of synergy or even additive effect. Which raises the question: Why give two drugs together? Instead, perhaps give them in sequence or, perhaps, give one drug, and if this drug doesn't work, then move on to the next drug. The obvious advantages of this are reductions in toxicity and the potential for reduction in cost.

Obviously, we're talking about a single paper here, but it is a provocative paper, very well researched and presented. The authors also raise the question that perhaps the preclinical data suggesting the benefits of combination therapy are — I'm going to use a strong word here — bogus because they look at highly sensitive, experimental models that are not representative of the human condition. But because they show synergy, they were able to get published in high-impact journals, even though again, they are not relevant for human cancers.

We need to readdress the relevance of clinical trials that are being done, their results, and very importantly, the experimental models that we are using to suggest the potential benefits of combination immunotherapy. Follow up by other investigators is clearly indicated.

But I think it's a question that should prompt all clinical and laboratory investigators in the cancer arena to pause, read the paper, review it, criticize it if they wish, but at least consider the implications of the findings.

I would encourage you to read it in Clinical Cancer Research; Adam Palmer is the first author. I thank you for your attention.

Maurie Markman, MD, is president of medicine and science at Cancer Treatment Centers of America in Philadelphia. He has more than 20 years of experience in cancer treatment and gynecologic oncology research.

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