ASCO Releases First Comprehensive Evidence-Based Guidelines for Metastatic Clear Cell Renal Cell Carcinoma

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ASCO has released the first comprehensive set of guidelines for the management of metastatic clear cell renal cell carcinoma (RCC).1 The guidelines are subdivided into six main sections: diagnosis, the role of cytoreductive nephrectomy, first-line systemic treatment, second- or later-line systemic treatment, metastasis-directed therapies, and special population subsets.

W. Kimryn Rathmell, MD, PhD

W. Kimryn Rathmell, MD, PhD

“It was really time for [a comprehensive guideline to be released] because, for the first time, we have multiple options for treating patients with [clear cell RCC],” said W. Kimryn Rathmell, MD, PhD, of Vanderbilt University Medical Center, and Co-Chair of the ASCO guideline expert panel. “Up until this point, there were fairly limited options. We had an array of tyrosine kinase inhibitors, which were all very interchangeable, so it didn’t seem like we needed high-level recommendations. Now, there are even more [tyrosine kinase inhibitors] and immunotherapies. As metastatic kidney cancer is fairly rare, it’s not at all uncommon for a busy oncologist to see one or two cases a year. For oncologists who don’t treat [clear cell RCC] all the time, it can be overwhelming.”

The panel comprised a multidisciplinary team of surgeons, radiation oncologists, pathologists, basic scientists, and patient advocates. Dr. Rathmell explained that they prioritized the inclusion of diverse scientific perspectives, and the patient experience, to ensure the recommendations were robust.

The guidelines were formulated using data obtained from a systematic review of literature published between 2007 and March 2022. In total, 46 randomized trials, 3 systematic reviews, 1 retrospective review, and 1 clinical practice guideline were considered.

Guideline Recommendations

The guidelines begin by emphasizing that, ideally, all patients with suspected metastatic clear cell RCC should have a histologic evaluation of the metastatic lesion.1“It’s actually quite prevalent in the field to make a diagnosis purely based on radiographic imaging, which can fool you,” Dr. Rathmell said. “You have to be rigorous and really sure in what you’re treating. It may seem quite obvious, but obtaining a biopsy is really important.”

The guidelines next discuss available treatment options. “Cytoreductive nephrectomy is one of the options that has been a standard of care for a while. We’ve had multiple new options and alternatives, and I think it has become a little unclear about whether cytoreductive nephrectomy may still play a role,” said Peter J. Van Veldhuizen, MD, of the University of Rochester Medical Center, and Co-Chair of the ASCO guideline expert panel.

Peter J. Van Veldhuizen, MD

Peter J. Van Veldhuizen, MD

The guidelines suggest that patients with favorable to intermediate International Metastatic RCC Database Consortium disease risk who have undergone successful removal of the majority of their tumor burden could be candidates for cytoreductive nephrectomy.1

For pharmacologic intervention, there are currently five U.S. Food and Drug Administration–approved combinatorial therapies for first-line metastatic clear cell RCC treatment: avelumab/axitinib, ipilimumab/nivolumab, nivolumab/cabozantinib, pembrolizumab/axitinib, and pembrolizumab/lenvatinib.1

Dr. Van Veldhuizen explained that the difficulties involved in treating metastatic clear cell RCC have changed in the past 2 decades, from having limited treatment options available (mainly, high-dose interleukin-2), to having multiple options but with no predictive biomarkers or comparative studies to help inform therapy selection.1

“These recommendations provide a more sophisticated roadmap for clinical practice—in particular, for selecting whether to use immunotherapy in combination with a VEGF receptor [tyrosine kinase inhibitor] or a dual immunotherapy regimen,” Dr. Rathmell said.

Additional Considerations and Future Directions

The guidelines close by highlighting long-standing disparities in care for racial and ethnic minority populations and by discussing the high cost of clear cell RCC care, as well as what impact these factors may have on patients.

“I think it’s good to highlight and remind everyone that there is disparity. Even if you don’t always see it in front of you, it still needs to be acknowledged,” Dr. Van Veldhuizen explained. “I think it’s important to address this real issue that we continue to struggle with, and we need to find ways to close that gap. These guidelines don’t fix disparity, but we felt it important to highlight that there are data behind that concern.”

In the future, Dr. Rathmell anticipates an expansion of the current toolbox for fighting clear cell RCC. Although there are multiple options available, these therapies have similar mechanisms of action. There are currently several drugs using alternative targets in clinical trials.

“I think, with completely new mechanisms of action, we’ll be able to see a bit more of true precision oncology, where we take subsets of [clear cell RCC] and say this subset should get this targeted therapy and a separate subset should be treated in a different way,” Dr. Rathmell concluded. 


1. Rathmell WK, Rumble RB, Van Veldhuizen PJ, et al: Management of metastatic clear cell renal cell carcinoma: ASCO guideline. J Clin Oncol. June 21, 2022 (early release online).

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, June 22, 2022. All rights reserved.