Guidelines for Managing Metastatic Clear Cell Renal Cell Carcinoma

An interview with Dr. Tian Zhang from UT Southwester Medical Center in Dallas, TX, author on "Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline." Dr. Zhang reviews the guideline recommendations for the treatment and management of patients with metastatic clear cell renal cell carcinoma and it's implications for clinicians and patients. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Tian Zhang from UT Southwestern Medical Center in Dallas, Texas, one of the authors on 'Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline'. Thank you for being here, Dr. Zhang.

Dr. Tian Zhang: Absolutely. Thank you so much for having me, Brittany.

Brittany Harvey: Great! First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Zhang, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Tian Zhang: Yes, I have received past research funding from Novartis, Merck, and Pfizer, as well as advisory board and consulting fees from Merck, Exelixis, Pfizer, BMS, Eisai, and Aveo. All of these industry partners have approved therapies in renal cancer. For the complete list, our audience can refer to the guideline's publication.

Brittany Harvey: Great, thank you for those disclosures. Then starting off on the content of this guideline, can you give us an overview of the purpose and scope of this guideline?

Dr. Tian Zhang: Sure. This is a guideline for recommendations for the treatment and management of patients with metastatic clear cell kidney cancer. ASCO gathered 14 colleagues, including myself, that were considered kidney cancer experts from around the world, and we performed a systematic literature review to guide treatment recommendations in metastatic clear cell kidney cancer.

In the series of ASCO clinical practice guidelines for genitourinary cancers, we hope this guideline will provide recommendations for kidney cancer treatment with supporting data and evidence, particularly given the therapeutic landscape changes since about 2017.

Brittany Harvey: Then I'd like to review those recommendations that you just mentioned of this guideline. So, this guideline covers six overarching clinical questions. So, I'd like to go question by question for our listeners, starting with how is metastatic clear cell renal cell carcinoma is defined and how is it diagnosed?

Dr. Tian Zhang: In this portion, we recommended a gold standard of comparing metastatic tissue outside of the primary site to the primary tumor. We discuss adding in staining for PAX8 as well as CA-IX for clarity of clear cell histology.

The timing is also pretty important in the timing of initial diagnosis and nephrectomy until the appearance of metastatic sites on scans, and radiographic diagnosis is therefore used in settings where prior diagnoses of clear cell kidney cancer has been established and when a metastatic lesion is not accessible for biopsy or when there's clear, measurable disease within a year of the initial diagnosis.

Brittany Harvey: Understood. And then in the next section of the guideline, what is the role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma?

Dr. Tian Zhang: In this section, we recommend that cytoreductive nephrectomy should be considered for select patients who present with de novo metastatic clear cell kidney cancer to palliate hematuria or pain or to remove the bulk of tumor burden.

We discuss some past trials in the settings of interferon alpha, and VEGF inhibitors and also recommend consideration of ongoing clinical trials in the era of immunotherapies. There are two such trials that are ongoing, PROBE and Cyto-KIK, that are actively accruing patients.

Brittany Harvey: Great. And then the guideline goes into options for systemic treatment. So, what are the preferred options for first-line systemic treatment?

Dr. Tian Zhang: This is probably our most extensive section, as first-line systemic treatments have changed and expanded greatly over the past five years. First, we recommend considering active surveillance for select patients with the following criteria: those who have IMDC favorable or intermediate-risk disease, those with limited or no disease-related symptoms, and also those with a long interval between nephrectomy and the development of metastasis.

Second, we recommend IMDC risk stratification to then determine treatment selection. Those with IMDC intermediate or poor risk factors should be offered combination treatment with either two immune checkpoint inhibitors or an immune checkpoint inhibitor with an anti-angiogenic VEGF tyrosine kinase inhibitor.

We provide strong level of evidence with the completed phase three trials in this first-line setting of ipilimumab and nivolumab, axitinib with pembrolizumab, axitinib with avelumab, cabozantinib with nivolumab, and lenvatinib with pembrolizumab.

For patients with IMDC favorable-risk disease, we recommend an immune checkpoint inhibitor with a VEGF tyrosine kinase inhibitor which may be offered over VEGF TKI alone for those patients who are candidates for immunotherapy.

In addition, VEGF monotherapy or an immune checkpoint inhibitor monotherapy may be offered for select patients who have certain coexisting medical conditions.

In addition, we have discussed this long history of high dose interleukin-2 treatments and that this may still be considered in first-line treatments for certain patients while discussing the significant toxicity of IL-2 relative to the newer immunotherapy regimens.

And finally, we encourage the participation and enrollment into first-line clinical trials when available. A couple of the current ongoing ones include PDIGREE and the LITESPARK-012 Trial.

Brittany Harvey: I appreciate your reviewing those options and the level of evidence along with those ongoing trials for patients. So, then following those recommendations for first- line that you just went through, what is recommended for the second or later line systemic treatment?

Dr. Tian Zhang: Subsequent treatment in later lines after initial treatment of refractory renal cell carcinoma depends largely on the initial treatment choices.

We recommend nivolumab or cabozantinib for patients who had prior progression on a VEGF TKI alone based on the large phase three trials CheckMate 025 and METEOR respectively that gain the approvals for nivolumab and cabozantinib.

For patients with disease progression on a combination immunotherapy, a VEGF TKI should be considered. Those who progress after initial combination therapy with a VEGF TKI and an immune checkpoint inhibitor should then be offered an alternative VEGF TKI as a single agent.

And finally, for those who have limited sites of disease progression, local treatment with radiation, thermal ablation, or surgical excision could be offered with continuation of the immunotherapy.

Brittany Harvey: Thank you for reviewing those second and later line treatment options. So, then following that, what did the panel recommend regarding metastasis-directed therapy?

Dr. Tian Zhang: There have been some recent studies looking at metastasis-directed treatments, especially for patients with a low volume of metastases. These can include surgical resection, ablation, or radiation therapy. And surgical resection and radiation have not actually been directly compared.

And so, for those patients, we would recommend a tailoring treatment based on sites of disease. For those patients who do have surgical resection, subsequent VEGF TKIs are not usually recommended based on a prior phase two trial.

Brittany Harvey: Understood. And then this guideline addresses a couple special subsets of patients. And so, what are those subsets, and what considerations should be applied to the treatment of these special subsets of metastatic clear cell renal cell carcinoma?

Dr. Tian Zhang: For the special subsets of patients, we considered patients with bone metastases, patients with brain metastases, and also patients with sarcomatoid features on histology.

For those patients with bone metastases, we recommend bone-directed radiation as well as a bone resorption inhibitor with either a bisphosphonate or a RANK ligand inhibitor.

We do not have a recommendation on optimal systemic treatments, although given the presence of the MET receptor on bone metastases, regimens containing cabozantinib, which targets the MET receptor in addition to other receptors, may be preferred.

For those patients who have brain metastases, no definite guidance for treatment can be made given many patients with brain metastases were excluded from the initial trials.

The overall efficacy of the systemic therapies is low for controlling metastatic kidney cancer in patients with brain metastases. We do recommend local treatment with radiation and or surgery to be undertaken based on the pattern of intracranial metastases. And we refer readers and the audience to a recent guideline from ASCO, ASTRO, and SNO on the management of brain metastases.

And finally, for patients who have sarcomatoid features on pathology, an immune checkpoint inhibitor-based combination should be chosen in the first line setting. And this is based on multiple phase three trials that have shown improvement in clinical outcomes for patients treated with immunotherapy combinations compared to sunitinib alone.

Brittany Harvey: Thank you for viewing all these recommendations. The guideline expert panel certainly covered a lot of questions on the treatment and management of metastatic clear cell renal cell carcinoma.

So, then in your opinion, Dr. Zhang, what is the importance of this guideline and how does it impact clinicians?

Dr. Tian Zhang: Sure. You know, in the past 10 years, our treatment options for metastatic kidney cancer have greatly expanded and multiple options are now available. For busy clinicians who may not treat kidney cancer, especially in the metastatic setting often or on a routine basis, this set of guidelines provides a high-level approach to the common management scenarios that clinicians are often faced with.

My fellow committee members and I hope that these guidelines will provide a comprehensive one-stop document that is relevant and updated for the busy clinician taking care of patients with metastatic kidney cancer.

Brittany Harvey: Great! And then finally, how will these guideline recommendations affect patients with metastatic clear cell renal cell carcinoma?

Dr. Tian Zhang: The fact that our treatment options for metastatic kidney cancer have improved clinical outcomes, including extending the time until progression as well as overall survival, is truly wonderful news for patients who are diagnosed with metastatic kidney cancer today.

If patients are directly reading these guidelines, they can also see whether overall recommendations align with their recommended course of treatment, with the caveat that every patient's care is tailored to them based on coexisting medical conditions and concurrent medications. But we hope these guidelines will be helpful for all of our patients.

Brittany Harvey: Yes, it's great to see improved clinical outcomes for patients. So, I want to thank you for all of your work on this guideline and for taking the time to review the guideline recommendations and its impact.

Dr. Tian Zhang: Sure. I really appreciate ASCO giving this time and opportunity, Brittany, and also the audience for their interest in the clinical guidelines for metastatic clear cell renal cell carcinoma.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series.

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