Reassessing Immunotherapy Use in Advanced Renal Cell Carcinoma

There is currently no strong evidence that additional immune therapy benefits patients with renal cell carcinoma who were treated in the advanced setting: © stock.adobe.com.

Among patients who have received immune therapy in the advanced setting for renal cell carcinoma, “at present, there's no great evidence that more immune therapy is of benefit,” Dr. Brian I. Rini explained in an interview with CURE.

Rini is chief of clinical trials at Vanderbilt-Ingram Cancer Center and Ingram Professor of Cancer Research and a professor of medicine at Vanderbilt University in Nashville. He was among the authors of a review of immunotherapy strategies following immune checkpoint inhibitor exposure among patients with renal cell carcinoma that was published in the journal, JAMA Oncology.

He discussed his and his colleagues’ findings with CURE.

CURE: To begin, can you expand on what you hope patients will take away from this conversation?

Rini: This was a review article, so we were summarizing the current approaches to treating patients with kidney cancer after they have been exposed to immunotherapy. The central idea was that the majority of patients, either in the adjuvant setting or as their initial treatment for advanced disease, receive some form of immunotherapy. Therefore, there is this emerging and growing population of patients who have had prior exposure to immunotherapy. That was the context for asking, "Well, let's examine the treatment options in that circumstance."

So, we first looked at some other diseases, including lung cancer and melanoma, which have some data in this setting. This was to provide context for the reader, outlining what we know about this area in other cancers. We were particularly focused on whether patients should receive more immunotherapy. There have been trials in kidney cancer—initially case reports, then case series, then single-arm trials, and finally randomized trials—investigating this idea of sequential immunotherapy and whether it provides a benefit in kidney cancer. The review article really goes into detail about all that data, laying out for the reader the evidence of benefit of giving patients more than one immunotherapy.

What findings were generated from this research?

The short answer, working backwards from the most recent, largest trials, is maybe. Currently, there's no strong evidence that more immune therapy benefits patients who have already received it in the advanced setting. Two large, randomized trials yielded negative results. However, as is the case with most trials, they don't address every question. Some lingering unanswered questions include the role of a regimen like Yervoy (ipilimumab) and Opdivo (nivolumab) in that setting, as it wasn't tested in these trials. So, we don't have definitive evidence for or against that. Probably the most important factor is that more and more patients are receiving adjuvant Keytruda (pembrolizumab), which is single-agent PD-1 therapy in the adjuvant setting. In the two large negative trials I mentioned, only a very small number of patients had prior exposure to immune therapy in the adjuvant setting.

So, really, one of the major questions in kidney cancer now is: if someone received adjuvant Keytruda, which is the only approved immune therapy, and a year or two later, or whenever their disease worsens despite that therapy, what is the role of further immune therapy? The article discusses this and offers opinions and editorializes about the potential role, but it's truly an unanswered question.

What other unanswered questions remain, in light of everything that you and your colleagues found?

Maybe the final area is novel immune mechanisms. Right now, in kidney cancer, and to my knowledge, in all cancers, the established immune therapies are PD-1 and PDL-1-based therapies, and perhaps CTLA4-based therapies. However, we really don't know the role of novel immune therapies, such as LAG-3 inhibitors or other immunostimulators, in this immune-refractory setting; it simply hasn't been tested. But that remains an unanswered question.

Reference:

“Immunotherapy Strategies After Immune Checkpoint Inhibitor Exposure in Renal Cell Carcinoma: A Review” by Dr. Giulia Claire Giudice et al., JAMA Oncology.

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