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RCC FAQs
Advanced Renal Cell Carcinoma: Experts Answer Your Questions

Released: July 14, 2023

Eric Jonasch
Eric Jonasch, MD
Brian Rini
Brian Rini, MD, FASCO
Tian Zhang
Tian Zhang, MD, MHS
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Key Takeaways
  • In advanced RCC, the optimal treatment after disease progression on first-line combination therapy with immune checkpoint inhibitor-based therapy is not well defined.
  • Consideration of patient performance status and patients’ desire for good quality of life is important when selecting later lines of therapy in RCC; they may have difficulty tolerating multiple lines of therapy, and the intent of therapy is not curative.
  • More research is needed on ctDNA blood testing in RCC before it is incorporated into the care of patients with advanced RCC according to experts.

If a patient received frontline therapy for advanced renal cell carcinoma (RCC) with cabozantinib, nivolumab, and ipilimumab, what would you consider using at disease progression?

Brian Rini, MD, FASCO:
In advanced or metastatic RCC, the optimal treatment after disease progression on first-line therapy is not well-defined. I have patients who have been enrolled on the COSMIC-313 trial and have received the triplet therapy combination of cabozantinib, nivolumab, and ipilimumab up front. At progression for these patients, I think a single-agent tyrosine kinase inhibitor (TKI) or a lenvatinib and everolimus combination may be options—or another clinical trial. I think we likely will use triplet therapy for RCC in the future, but it is not a standard of care at present. This question will become more important as other data become available. Once therapy has been given and the disease progresses, the patients may be refractory to both immune checkpoint inhibitors and VEGF inhibitors. This is troubling because these are the currently approved options. If belzutifan were approved, it may make a good choice in this setting. For now, single-agent TKI would be the choice.

Eric Jonasch, MD:
You reported data with single-agent axitinib in patients with metastatic RCC previously treated with immune checkpoint inhibitors. A TKI following immunotherapy is a good recommendation in general. The problem is that we may be getting the patient into a bind if all of our options were used up front.

Brian Rini, MD, FASCO:
We also have to consider the performance status of the patient. Patients likely will have difficulty tolerating multiple lines of therapy, and the intent of therapy is not curative. Patients desire good quality of life. I will titrate axitinib up and down or consider tivozanib. That choice may be moved earlier. We will be watching how this evolves.

Do you use a circulating tumor DNA (ctDNA) blood test in either the adjuvant or metastatic setting for patients with RCC?

Tian Zhang, MD, MHS:
In the postoperative setting, some of my urology colleagues are using the ctDNA blood test. The thing about ctDNA is that these tumors are low ctDNA shedding. Will there be another type of ctDNA characteristic like methylation profile or other factors? I am interested to see if ctDNA blood testing pans out, but most of the results I have seen have been negative in the postoperative setting. How much it will add to adjuvant therapy decision-making is not clear.

Brian Rini, MD, FASCO:
I agree. I am hesitant to use ctDNA blood testing in clinical practice without supporting data. Given the current evidence, I worry that the test results create more anxiety or false security than they should. In RCC, the methodology for detection is still developing, and there are different methods out there. I am hoping that in several years, this type of testing will help us better direct individualized treatment.

Eric Jonasch, MD
I totally agree. It is interesting that some ctDNA blood tests are available, but no studies have evaluated the sensitivity and specificity of the tests in various disease settings. Yes, you might be able to measure ctDNA, but what does that mean? How does that influence treatment? Additional research needs to be done with ctDNA blood tests, although the concept has some promise.

When do you consider cytoreductive nephrectomy?

Tian Zhang, MD, MHS:
For patients with locally advanced disease and big, bulky tumors, the immunotherapy-based combinations likely will not shrink primary tumors to zero; in those patients, who probably will not get to a partial nephrectomy, the kidney is going to come out regardless. When I am seeing patients with very large tumor burden in the primary site, I consult with my surgical colleagues about who may be appropriate for upfront nephrectomy.

Can any biomarkers predict the response to adjuvant immunotherapy in RCC?

Brian Rini, MD, FASCO:
Currently in RCC, there are no clinically impactful biomarkers. PD-1 expression enriches for response to ipilimumab/nivolumab, but we are not using it as a marker in practice to determine therapy choice because patients who are PD-L1 negative also will benefit. Everybody on this panel and others have been involved in researching biomarkers. We have tried to build on existing  RNA signature data, and we are doing a prospective study. We are at a crucial point in RCC where trials are necessary to develop biomarkers. The design of the trials can be very difficult, as the need for fresh biopsy tissue is not always feasible. I hope that in several years, we will not have to rely on the International Metastatic RCC Database Consortium or our individual biases for risk stratification and treatment selection. We would be able to say, “This patient has expression of these genes; they should get this specific treatment”—and personalize therapy accordingly.

What do you foresee as the role of belzutifan in RCC?

Eric Jonasch, MD:
I see many patients with von Hippel-Lindau (VHL) disease, so I have a lot of experience with belzutifan. It is indicated for adults with VHL disease who need treatment for RCC or a few other malignancies. If the anemia and hypoxemia are appropriately monitored for and managed, patients receiving it can have a decent quality of life. I am looking forward to seeing the phase III trial results in RCC.

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