Adjuvant therapy for high-risk nonmetastatic RCC: Improving the treatment landscape

Pavlos Msaouel, MD, PhD

At the 2021 Society of Urologic Oncology Annual Meeting in Orlando, Florida, Pavlos Msaouel, MD, PhD, gave a presentation titled, “The future of adjuvant therapy for high-risk nonmetastatic RCC.” In this interview, Msaouel discusses some key points from this talk and provides an overview of current challenges in the high-risk non-metastatic renal cell carcinoma space. Msaouel is an assistant professor in the departments of genitourinary medical oncology and translational molecular pathology at the University of Texas MD Anderson Cancer Center, Houston.

You gave a presentation called, "The future of adjuvant therapy for high-risk nonmetastatic RCC" at the SUO annual meeting. Could you provide a brief overview of your presentation and discuss some of the highlights?

With the exciting results of the KEYNOTE-564 trial [NCT03142334], which led to the FDA approval of adjuvant pembrolizumab [Keytruda] for high-risk nonmetastatic renal cell carcinoma, the question now becomes, how do we choose whether or not to offer adjuvant therapy to our patients based on patient-level characteristics? In many cases, we do have enough knowledge to make such precise inferences, but in others we do not, and my talk will focus on identifying these unmet research needs that need to be addressed to further improve the adjuvant treatment landscape for our patients.

What are some current challenges in the treatment of high-risk non-metastatic RCC and what is being done to overcome them?

One challenge that is not discussed as often as it should be is the issue of end points. [One point that] I highlight in my talk is that the overall survival end point, which is a clinically meaningful critical end point, is at higher risk of being estimated in a biased way compared with other outcomes like disease-free survival, using our current methodology. It is an open challenge for us to develop methodology that can properly de-bias our overall survival estimates. Other challenges include unmet needs with regards to observational research. In some cases, we need interventional experimental types of research, but in other cases, we need observational research with representative real-world data. For example, we lack and need to develop contemporary risk nomograms for what the KEYNOTE-564 trial called M1 NED cancer. We need to develop more accurate risk nomograms for rare kidney cancer histologies. We need to improve our recurrence risk estimations by incorporating knowledge from genomics and other types of "omics" such as radiomics. In addition, we need interventional experimental-type research in order to accurately estimate the adjuvant treatment effects for rare kidney cancer histologies because trials like KEYNOTE-564 only included patients with the most common kidney cancer histology, clear cell renal cell carcinoma, and so we need to have accurate estimates for the more rare histologies. In addition, given these exciting results, other new regimens should now start to be explored—both single-agent drugs as well as combination therapies.

What have been some of the notable highlights in the kidney cancer space in 2021? What advances are you anticipating in 2022?

One key highlight is the introduction of adjuvant immunotherapy for the first time as an FDA-approved drug for patients with high-risk localized kidney cancer. That is certainly practice changing. The other exciting thing is that we're focusing more and more on the more rare histologies, which is very helpful to our patients. In 2022 and beyond, we'll see trials dedicated to rare histologies. At the same time, I anticipate that in the coming months and years, we will have trials reading out that test triplet therapies. We currently have doublet therapies for metastatic kidney cancer approved. The question is, can combining the current doublets or other doublets with a third drug meaningfully improve outcomes for patients with metastatic kidney cancer?

What is the current status of adjuvant treatment for RCC and what unanswered questions or unmet needs remain?

The current status has changed. It is very exciting to say that we now have, for the first time, an immunotherapy drug that is FDA approved as an adjuvant therapy for patients with kidney cancer. This will likely change the natural course of the disease and improve outcomes for our patients. But at the same time, more work is certainly necessary. We need to generate the kind of data that will allow us to make patient-specific decisions. How can we say, based on each specific patient, whether an adjuvant therapy is preferable or not, because in some patients, the side effects or other costs, including the financial and other logistical costs of adjuvant therapy may not be worth the benefit that they're getting. Figuring out how to balance that trade-off between risks and benefits for each individual patient is something that we need to work on more.