Kimryn Rathmell, MD, PhD, joins The Uromigos to discuss highlights from the kidney cancer guidelines presented at the American Society of Clinical Oncology Annual Meeting.
On June 21, 2022, the American Society for Clinical Oncology (ASCO) released its first ever guideline for the management of metastatic clear cell renal cell carcinoma (ccRCC), intended for all health care practitioners, social workers, patients and caregivers.1 The guideline explains that its focus on ccRCC, the most common form of kidney cancer, was motivated by the need for a guide to the increasing number of new therapeutic options, with the potential for disease control and extended survival that have emerged over recent years. The guideline was based on a review of English language, peer-reviewed literature published through March 2022, and written by a specially-convened ASCO Guideline Expert Panel. Co-chair of the guideline panel, W. Kimryn Rathmell, MD, PhD, joined Thomas Powles, MBBS, MD, (Barts Cancer Centre, London, UK) and Brian Rini, MD (Vanderbilt University, Nashville, TN) in a discussion of the new recommendations from US and global viewpoints. Dr Rathmell is the Hugh Jackson Morgan Professor and Chair of Medicine at Vanderbilt University Medical Center (VUMC), and Physician-in-Chief and Professor of Biochemistry for Vanderbilt University Adult Hospital and Clinics.
Dr Rathmell made some general points about the guideline, in particular the omission of words like “mandatory,” or “required” in support any of its recommendations. “We say, ‘ideally,’ she stressed. An important feature is the incorporation of the International Metastatic RCC Database Consortium (IMDC) risk classification throughout the guideline.2 I hope that the IMDC classification will become more widely used in the community as a tool to make clinical judgments,” Dr Rathmell said.
The ASCO panel identified six important clinical questions in the management of metastatic ccRCC. The first, how metastatic ccRCC is defined and diagnosed, was the one that instigated the most debate, Dr Rathmell admitted. “It isn’t necessarily where all guideline groups start, but we felt that there was a lot of heterogeneity in how people approach diagnosing metastatic renal cell carcinoma,” she explained. The guideline recommends comparing tissue in the metastatic site with primary histology using paired box gene 8 (PAX8), carbonic anhydrase IX (CAIX), or other traditional immunohistochemistry-type markers. Radiographic diagnosis may be used secondarily. “We understand that there are a lot of different caveats here, but I think we’ve all been burned when we’ve excluded histology in our diagnosis of metastatic RCC,” Dr Rathmell said.
Dr Powell expressed concern that the recommendation to biopsy metastatic sites appears to apply to the majority of patients. From a global perspective, many locations, such as community hospitals, will struggle with that, he commented. “Most patients we’re seeing who relapse within six months of a T3b tumor are not going to need that biopsy, and spending two months trying to get the tissue could actually be counterproductive,” he suggested. Could the guideline recommendation result in fewer patients longer delays in starting systemic therapy, he asked. “If that proves to be true, then we’ll need to revise our guidelines,” Dr Rathmell responded, “But I also think that we need to be encouraging people to be as rigorous as they can be.” There is a need to move away from the RCC NOS (not otherwise specified) diagnosis and be much more precise about the diseases being treated, she added.
The second clinical question covered by the guideline is the role of cytoreductive nephrectomy. “We knew everyone would have an opinion on this,” Dr Rathmell admitted, “but we could not say that we no longer do cytoreductive nephrectomy, because that’s not true and it’s really not in the best interest of patients.” So it remains an option in patients who have one IMDC risk factor and who can have most of their tumor burden removed at the time of surgery. Dr Rathmell stressed that “optimally,” was used to describe the ASCO recommendation. “I hope that it came through clearly enough that people should at least think about getting cytoreductive nephrectomy, but that we can’t advocate for it beyond that subgroup,” she said. The guidelines are appropriately cautious, Dr Rini agreed, adding that he believes there is a role for cytoreductive nephrectomy in selected patients.
Question 3, “a big topic,” reviews the options for first-line systemic treatment. including vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs), immune checkpoint inhibitors (ICIs), and combinations with anti-programmed death (PD-1) and anti-cytotoxic T-cell lymphocyte-4 (CTLA-4) agents. Knowing how to use those, in what order, and in which patient is complicated, Dr Rathmell noted. “We tried to make a best-case scenario of which type of combination or single agent to use in each IMDC risk group (poor, intermediate, favorable),” she explained.
According to the recommendations, however, some patients, especially those with favorable and intermediate risk, should be offered active surveillance. “We didn’t want people to forget that surveillance can buy people a lot of time and good time,” Dr Rathmell clarified. Recommended first-line treatment in patients with intermediate or poor risk is combination ICIs, such as ipilimumab plus nivolumab or an ICI plus a VEGFR-TKI. Select patients receiving systemic therapy in the first-line setting, including those with favorable disease, may receive monotherapy with either a VEGFR TKI or an ICI. Dr Rini noted that the panel “didn’t really take a stance on ipilimumab-nivolumab versus ICI-VEGFR TKI.” Dr Rathmell explained that the panel had discussed this extensively, but there were no data to support one over the other.
Dr Rini asked about ipilimumab-nivolumab in favorable-risk patients. “They’re clearly an immune-responsive subset, he pointed out. Dr Rathmell replied that although this was discussed, the panel did not include it in the guideline because of the lack of data showing which patients would benefit, or whether the additional toxicity associated with that combination warranted recommending that everyone should get it first.
Dr Powell pointed out that there is no clear survival signal for pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, or pembrolizumab plus axitinib in this setting. European groups, particularly payers, are now pushing back strongly now, especially in favorable-risk patients, invoking an immunotherapy ‘halo effect,’ he said. We may be embarking on a journey that will inevitably involve additional toxicity as well as additional cost, he suggested. “Is it unreasonable to offer them single agent VEGF TKI therapy?“ he asked. “There are definitely going to be scenarios where single agent VEGF TKI makes sense,” Dr Rathmell agreed. Although the data do not show big differences in survival, some patients have remarkable responses to immunotherapy that are quite durable, she noted.
Dr Powell expressed surprise that the guideline includes interleukin 2 (IL-2) as a first-line option, which he regards as “a chapter from the past.” Dr Rathmell acknowledged that there was a lot of debate about whether to omit it, but because it remains an available therapy, the view was that it needed to be addressed. The recommendation for IL-2 is “weak”, she noted, because the panel could not identify a patient base that would likely benefit from it. “We included practical information that the significant toxicity of the regimen has to be weighed in relation to newer immunotherapy. So I think we basically said, it’s on the shelf but don’t take it,” she said.
The fourth question focuses on second- or later-line systemic therapy. ”We did our best to help, but it gets much harder in the second and further line,” Dr Rathmell admitted. “The recommendation is basically, do your best, and mostly single agents.” Dr Rini pointed out that ongoing trials should provide more clarity about this setting. Question 5 is about the optimal application of metastasis-directed therapy, The basic question is whether there are patients for whom metastasectomy or ablative type therapies is appropriate, Dr Rathmell explained. “There aren’t any strong data for when to do it, but it’s something that you can consider,” she noted. Despite this, the recommendation for it is “strong.”
“We’re really talking here about oligometastatic single site resections, and we said that the evidence quality is ‘moderate’.” Dr Powell was concerned that this recommendation might be interpreted as a call for more of this therapy. Shouldn’t we rather be doing clinical trials to generate the data needed, he asked. Dr Rini pointed out that many treatments are adopted into clinical practice without prospective randomized trials, for example, stereotactic radiotherapy. “But we should be doing more trials of metastasis drug therapy to prove whether it’s useful or not, and to identify the patients who might benefit,” he added.
The sixth and final clinical question covers the treatment of special subsets of metastatic ccRCC, including bone and brain metastases and sarcomatoid carcinomas. Dr Powell and Dr Rini called attention the “strong” recommendation for giving bisphosphonates or receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors to patients with bone disease, agents they themselves use only sporadically. Dr Rathmell replied that there appeared to be good enough evidence for prevention of skeletal-related events.
Dr Rathmell also stressed the importance of braindirected local therapy with radiation, and /or surgery in patients with brain metastases. The decision about the type of radiation therapy is left to the individual provider. Dr Powell described this recommendation as a very good addition to the guideline. “I think we need to move away from whole brain and towards stereotactic radiation to the head,” he commented.
In ccRCC with sarcomatoid features, “we’d like to have biomarkers and more biologically segmented groups of ccRCC, but right now, we only have sarcomatoid and not sarcomatoid,” Dr Rathmell acknowledged. However, there was sufficient evidence to point to ICI-based combination therapy first-line (ipilimumab-nivolumab) or an ICI plus a TKI in sarcomatoid ccRCC, she said. Dr Rini pointed out that supporting data are strongest for ipilimumab-nivolumab, although all the data are retrospective with no central pathology review. Dr Powell predicted more data with immunotherapy will be coming soon.
Linda Brookes, MSc is a freelance medical writer/editor based in New York and London.