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RCC Treatment Support Tool
Treatment Decision Support Tool Enhances Therapy Considerations for Metastatic Clear Cell RCC

Released: July 10, 2023

Wenxin Xu
Wenxin Xu, MD
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Key Takeaways
  • Although treatment decisions for patients with metastatic RCC have become more complex, combination therapy with either an immunotherapy and a TKI or 2 immunotherapies is recommended in the first-line setting.
  • Phase III trial data on optimal treatment after disease progression on immunotherapy are limited and decisions depend on clinical judgment of available options based on which regimens the patient already has received.
  • CCO’s Interactive Decision Support Tool, developed with a team of 5 experts in RCC, can help provide expert guidance on treatment options for your clinical practice cases.

Treatment options for kidney cancer have become much more complicated in the past 5 years—particularly for patients with metastatic clear cell renal cell carcinoma (RCC). Although numerous options are available, there can be subtleties as to which one is best for a patient in any given setting. Treatment decisions for patients with metastatic RCC include when to start systemic therapy vs continuing with active surveillance or metastasis-directed therapy, when cytoreductive nephrectomy is indicated, and, finally, which systemic therapy is optimal when the need for treatment arises. Multiple FDA-approved first-line treatment options are now available for metastatic RCC, and it can be difficult to decide which patients should receive an immunotherapy combination, immunotherapy in combination with a tyrosine kinase inhibitor (TKI), or a single-agent TKI.

To aid in some of these treatment decisions, my colleagues and I have developed an Interactive Decision Support Tool covering treatment selection for patients with metastatic RCC. This tool has been created, evaluated, and designed by 5 experts who treat patients with RCC. As a user of the tool, you will input key patient and disease characteristics to define a patient scenario. After entering these characteristics, you will select your intended treatment choice. Then you will be shown the recommendations from all 5 experts for your individual set of characteristics, along with additional information to consider.

As an oncologist, I find it helpful to see what my colleagues may consider when I see a new patient with kidney cancer, and this new decision support tool lets us do just that.

First-line Treatment Selection for Metastatic Clear Cell RCC
In the first-line setting, I typically recommend combination therapy for the majority of my patients with metastatic RCC. Currently, available combinations include immunotherapy with ipilimumab plus nivolumab or one of several combinations of immunotherapy plus a TKI—cabozantinib plus nivolumab, lenvatinib plus pembrolizumab, or axitinib plus pembrolizumab.

With each of these combination therapies, clinical trials showed an overall survival advantage compared with sunitinib for patients with intermediate- and poor-risk metastatic RCC. However, the overall survival advantage was less clear for patients with favorable-risk disease, In addition, the immunotherapy combination with ipilimumab plus nivolumab is approved by the FDA only for patients with intermediate- or poor-risk RCC. The decision of which combination to begin is a joint decision that needs to be made with each patient. For example, a patient who does not want to take an oral regimen and accepts the additional risk of toxicity from immunotherapy may consider ipilimumab plus nivolumab, or a patient who wants a high chance of response but may not be able to tolerate a potential increase in immune-related adverse events could consider an immunotherapy plus TKI combination.

In addition, the sites of metastasis and any symptoms resulting from metastatic disease can be important determinants for selecting therapy. For patients with high-risk sites of metastasis (eg, metastases in the brain, liver, bone, or spine) or metastases causing pain or fracture, more aggressive regimens such as lenvatinib plus pembrolizumab or cabozantinib plus nivolumab should be considered. For patients with intermediate- or poor-risk disease who have lower-risk sites of metastasis (eg, lung or lymph node metastases) or who are asymptomatic, ipilimumab plus nivolumab is a reasonable option.

There are times I may recommend using a single-agent TKI, but these are highly nuanced situations, such as for a patient with favorable-risk disease who seems to have highly angiogenically driven tumors. Often, these patients will have had a long interval from their original nephrectomy to time of recurrence. Disease recurrence may be relatively slow and found in sites such as the pancreas, where we know from transcriptomic and sequencing data that these tumors are more reliant on vasculature. These patients are likely to respond for a long time to single-agent TKIs, such as cabozantinib or pazopanib, and may be able to avoid immunotherapy-related toxicities. In addition, for patients with intermediate- or poor-risk disease who have a strict contraindication to immunotherapy (eg, an organ transplant on immunosuppression), single-agent cabozantinib is a reasonable option.

Treatment Beyond Progression for Metastatic Clear Cell RCC
What can be even more confusing for oncologists is what to do in the second- or third-line setting because many of the trials in refractory RCC were done prior to the use of immunotherapy in the first-line metastatic and adjuvant setting. Although we do have some trials that studied treatment options for second-line therapy and beyond, many of the trials that led to FDA approvals in this setting were done before modern combination regimens were approved. For example, second-line nivolumab showed overall survival benefit compared with everolimus in the CheckMate 025 trial, but this included only patients who received prior therapy with TKIs (before first-line immunotherapy was the standard of care). Nowadays, most patients already have had previous exposure to immunotherapy in the adjuvant setting or as part of first-line therapy, and response rates to further immunotherapy look to be much lower for patients who have already received immunotherapy.

In the absence of many randomized phase III studies in second- and third-line settings in the modern era, we rely on our judgment and understanding of the differences between each available option. For example, lenvatinib plus everolimus, cabozantinib, and axitinib are all reasonable second- or third-line options with evidence of activity after prior VEGFR TKI, but certain patients might benefit more from one of these agents vs another due to various factors, such as tolerability, depending on their clinical situation. In addition, the phase III TIVO-3 study demonstrated a progression-free survival improvement with tivozanib vs sorafenib in patients with advanced RCC after prior VEGFR TKI therapy, with previous immune checkpoint inhibitors allowed. Tivozanib is now approved for patients with advanced RCC after ≥2 prior lines of therapy and has some appealing characteristics, including its potency and selective VEGF targeting with somewhat less off-target toxicity compared with other TKIs.

It also is important to consider new data from the phase III CONTACT-03 trial, which compared atezolizumab plus cabozantinib vs cabozantinib alone after prior therapy with immunotherapy-based treatment. In the first report of this trial from ASCO 2023, there was no improvement in clinical outcomes with the addition of atezolizumab to cabozantinib in this patient population, suggesting that continuing or rechallenging patients with immunotherapy after progression on previous immunotherapy-based treatment may not be the path forward. However, other ongoing trials, such as the KEYMARKER-U03B study with belzutifan plus lenvatinib, are exploring new combinations and novel agents that may provide additional treatment options for our patients in this setting.

Your Thoughts?
In collaboration with Katy Beckermann, MD, PhD; Eric Jonasch, MD; Rana R. McKay, MD; Tian Zhang, MD, MHS; and myself, Clinical Care Options developed this online support tool to provide expert recommendations on RCC treatment. Try this tool when you are considering treatment options for your patients in clinical practice and let us know what you think.

Please answer the polling question by selecting all that apply and join the conversation by posting a comment in the discussion section.

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In your current practice, how often do you recommend an immunotherapy in combination with a TKI as first-line treatment for advanced RCC?

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