In 2021, an estimated 76,080 new cases of kidney cancer will be diagnosed. Among those cases, the majority will be renal cell carcinomas (RCC). In this excerpt of the transcript from their continuing medical education/nursing continuing professional development (CME/NCPD)–approved activity, Expert Guidance on New Advances in Renal Cell Carcinoma, Bradley McGregor, MD, Clinical Director of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute, and Robert Motzer, MD, Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, discuss the current therapeutic options and the possibilities for advancement in treatment for patients with renal cell carcinoma.
Robert Motzer, MD: Historically, kidney cancer has been what's considered to be one of the most difficult cancers to treat and is associated with a very poor prognosis, mostly because of the lack of response to chemotherapy. Cytotoxics made up the mainstay of treatment until the last two decades. The median survival for people with advanced kidney cancer was less than 12 months. This really changed with the advent of the tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, which are vascular endothelial growth factor (VEGF) inhibitors; and with studies comparing to interferon and placebo, they became standards of care. Based on the use of sunitinib or pazopanib and other TKIs, the overall survival for this disease tripled, but it remains an area of high unmet need to find better therapeutics and improve survival.
Bradley McGregor, MD: We had great data from sunitinib and pazopanib, and then we had subsequent studies looking at the two to try to determine if one is superior. There was no superiority, but there are potentially different toxicity profiles and patient preferences for pazopanib. That really was the mainstay for a long time until the advent of combination therapies in 2017. I think that's really revolutionized the management of RCC.
Dr. Motzer: It seems that there are kind of really two kinds of phenotypes of RCC in terms of response to drugs. There's an inflammatory RCC type, which seems to be more amenable to immunotherapy, and there are tumors that are more VEGF-driven that respond well to TKIs. This was somewhat apparent clinically initially, with the studies with programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, where it seemed the best responses were in the worst prognoses or in the patients that had sarcomatoid-variant RCC, which carries a bad prognosis.
Dr. McGregor: At the end of the day, I think safety is important, and these are all great regimens, although they have different toxicity profiles, as you look at it. Immunotherapy with nivolumab/ipilimumab has immune-related adverse events managed with steroids. When we start looking at the TKI immune-oncology (IO) combinations, you have a lot of overlapping toxicities.
Dr. Motzer: The toxicity profiles of the ipilimumab/nivolumab and the TKI IO combinations are quite different. For one thing, with the ipilimumab/nivolumab, as you mentioned, these are all immune-related toxicities. They usually seem to occur more upfront in treatment when patients are receiving the ipilimumab in addition to the nivolumab. They can sometimes be difficult to diagnose and sometimes can be potentially serious, including colitis, which requires hospitalization. But once the patient's program is past the induction phase with the two given together, and your patient's receiving monotherapy with nivolumab, then that becomes a well-tolerated program. It's more upfront toxicity which is difficult to diagnose and could be a challenge to manage with ipilimumab/nivolumab. For the IO TKI combinations like pembrolizumab/axitinib, for the most part, the toxicities are driven by the TKI, so they are also more predictable in terms of hypertension, diarrhea, and some skin toxicity.
As oncologists, we've also become much more adept at managing TKI toxicities since we've been using this class of medication for so much longer. But the downside is that the TKI is continued chronically, and patients do develop chronic toxicities that are associated with drugs like axitinib or cabozantinib, which really can impact quality of life later in therapy. We also don't know in terms of whether these drugs, these TKIs, can be discontinued.
Quality of life is very important, especially when patients are on long-term therapy.
Dr. McGregor: There are several trials that we're looking forward to in the frontline setting: the CLEAR trial, looking at lenvatinib/pembrolizumab in the frontline setting versus lenvatinib/everolimus versus sunitinib. We hope to see the results of that soon, as well as different approaches: COSMIC 313, looking at the triplet therapy, cabozantinib and nivolumab/ipilimumab versus nivolumab/ipilimumab. Or PDGREE, where we're trying to customize therapy with nivolumab/ipilimumab to nivolumab versus nivolumab/cabozantinib based on response. I think these will be important trials to advance the frontline therapy.
Dr. Motzer: The other really promising area that IO therapy could move into and make a huge impact in is the adjuvant setting. There was a trial of atezolizumab versus placebo that completed accrual, and similarly, a trial of pembrolizumab versus placebo that completed accrual. We're eagerly waiting for the results of that. The trial that continues to accrue is the CheckMate 914 trial, which started out as a clinical trial of nivolumab plus ipilimumab versus placebo but then expanded and now has an arm for nivolumab monotherapy. This is a large 1,300-patient trial comparing nivolumab/ipilimumab versus placebo versus nivolumab that I think will really help define the role and hopefully establish a benefit for IO therapy in patients who have had a nephrectomy but are at higher risk for relapse.
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American Cancer Society (2021). Cancer facts & figures 2021. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf
About Dr. McGregor and Dr. Motzer
Bradley McGregor, MD, is the Clinical Director of the Dana-Farber Cancer Institute's Lank Center for Genitourinary Oncology and an Instructor in Medicine at Harvard Medical School. His medical oncology practice covers all genitourinary malignancies, including kidney tumors. He is active in clinical trial research, exploring with others the role of combination immunotherapy in rare genitourinary cancers, but also leading clinical trials exploring novel combinations of immunotherapies with other agents in a variety of tumor types while also exploring the role of antibody drug conjugates in heavily treated cases of kidney and bladder cancer.
Robert Motzer, MD, is the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center. His clinical expertise includes renal cell cancer and immunotherapy. He is a recipient of a Career Development Award from the National Institutes of Health, the Willet F. Whitmore Award for Clinical Excellence from Memorial Sloan Kettering, and the Eugene P. Schonfeld Award from the Kidney Cancer Association.
Edits have been made to this excerpt for the sake of clarity and brevity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.