While kidney cancer has long been known to be immune responsive, the treatment focus for metastatic clear cell renal cancer switching “from vascular endothelial growth factor-targeted therapies to immune checkpoint inhibitors and novel combinations of therapies” on the horizon signals a new approach to combating the disease (J Clin Oncol 2018;(36):3639-3644).
In this review article, Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, and Director of Barts Cancer Centre in London; and Brian Rini, MD, Professor of Medicine at the Lerner College of Medicine and Leader of the Genitourinary Program at Cleveland Clinic Cancer Center, attribute the changing mindset in the treatment of advanced kidney cancer to “recent data with programmed death ligand inhibitors that is revolutionizing the standard approach to metastatic renal cell carcinoma (RCC).”
The oncologists examined novel agents and classes of compounds under development that may complement available immunotherapies and targeted drugs considered to be the backbone of advanced kidney cancer therapies. The pair, both of whom have written extensively on kidney cancer, review novel treatments, promising combinations, and consideration in both trial design and clinical applications of therapeutics in the future, as well as speculation surrounding potentially therapeutic targets, such as indoleamine 2,3-dioxygenase, transforming growth factor-β (TGF-β), interleukin-10, and adenosine.
A unifying theme of “immune system manipulation” emerged when researching the article, noted Rini, who believes checkpoint inhibitors will be at the core of therapeutic combinations for kidney cancer going forward.
“Most of the new drugs in kidney cancer are immunotherapy drugs and the ones that are starting to be approved, and even some of the novel ones that are in phase II studies, are newer forms of stimulating the immune system,” he explained.
Powles and Rini chose to focus on endpoints and how to develop new drugs in kidney cancer given the plethora of available agents, while also recognizing that immune agents may not produce traditional and immediate responses like targeted therapy or chemotherapy.
“We tried to delve into novel endpoints and duration of therapy, time off therapy, complete response rate, and other things that may not be traditional in terms of drug development,” Rini told Oncology Times.
“The great thing with immunotherapy is that if people respond then, presumably, you can stop the therapy,” he added. “So, a couple of things that we focused on in the review article were changing the mindset to curing the disease, not just controlling the disease, and also treating people for a while before potentially stopping treatment. That's a change in terms of how we have approached RCC. Immune therapy allows you to do things that you just can't do with targeted therapy.”
According to Przemyslaw Twardowski, MD, Professor of Medical Oncology and Director of Clinical Research in the Department of Urology and Urologic Oncology at John Wayne Cancer Institute at Providence Saint John's Health Center in Santa Monica, Calif., the furthest along in development are regimens combining the most effective classes of drugs approved in kidney cancer, namely PD-1 inhibitors and VEGF inhibitors.
“It turns out that the VEGF inhibitors, in addition to their main anti-angiogenic mechanism of action, allow for more immune permissive tumor microenvironment, thus enhancing checkpoint inhibitors effectiveness. These combinations have already reported impressive phase III data,” Twardowski told Oncology Times.
Other drugs in early clinical development lack strong single-agent activity but are postulated to complement immune response and mostly fall into the category of immunotherapies or agents affecting kidney cancer metabolism. Examples include TGF-β inhibitors, recombinant IL-10, pegylated IL-2 prodrug, adenosine inhibitor, and glutamate inhibitor. However, “while some of these agents appear moderately promising, at this point, it is impossible to predict if any of them will find its way to clinical practice,” he noted.
According to Twardowski, checkpoint inhibitor therapy (PD-1 +/- CTLA-4 inhibition) represents the cornerstone of modern immunotherapy of kidney cancer. Two drugs are currently approved—PD-1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab. Nivolumab was originally approved by the FDA in 2015 for treatment of patients who progressed on prior antiangiogenic therapy.
“More recently, nivolumab in combination with ipilimumab earned approval in the first-line setting in patients with intermediate or poor risk metastatic disease. This, by the way, accounts for the vast majority (75-80%) of patients with metastatic kidney cancer,” he stated.
The experience with checkpoint inhibitors in kidney cancer in many ways replicates observations in other tumor types, in particular, the durability of responses is long and a small fraction of patients may achieve a curative effect, Twardowski noted.
“As impressive as these results are, currently approved drugs still ultimately fail in the majority of patients and the side effect profile of the combination of nivolumab and ipilimumab is not trivial,” he explained. “Nevertheless, it is hard to imagine the next decade of advances of kidney cancer therapy without checkpoint inhibitors at the center of the action. The potential path forward focusing on combinational approaches is outlined in the excellent Powles and Rini review.”
Primed for Response
Although it is too soon to know which novel agent or drug under development holds the most promise in the treatment of metastatic clear cell renal cancer, Rini said those in the latest stages of clinical testing may bear watching, such as an interleukin-2. This product will be developed in combination with either nivolumab or the combination of nivolumab and ipilimumab, he noted.
Meanwhile, it is clear that immune system manipulation will be the core focus of research and drug development for the treatment of advanced kidney cancer in the foreseeable future.
“Kidney cancer has always been immune responsive. It has PD-L1 expression and the fact that it is infiltrated with key leukotrienes has been known for decades, so it has the right immune environment for response,” Rini noted. “A lot of what we are doing now in kidney cancer is immune system manipulation. Certainly, that's the latest wave of approved therapy. And it's going to be the next immediate wave of therapy as well, I think.”
Chuck Holt is a contributing writer.
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