Past, Present and Future: How Non-Clear Cell Kidney Cancer Has Evolved

Those with non-clear cell kidney cancer have much to look forward to as oncologists’ understanding of the disease is evolving.
BY Kristie L. Kahl
PUBLISHED October 16, 2019
Making up a smaller portion of those with renal cell carcinoma, people with non-clear cell kidney cancer have much to look forward to as researchers are homing in on the biology of their disease, according to Dr. Vivek Narayan, an assistant professor of medicine at the Hospital of the University of Pennsylvania.

At A Vision of Hope: A Kidney Cancer Educational Symposium, which was hosted by the Judy Nicholson Kidney Cancer Symposium and Penn Medicine Abramson Cancer Center, Narayan discussed the past, present and future of the treatment of non-clear cell kidney cancer.

Non-clear cell kidney cancer accounts for 15% to 20% of kidney cancers and consists of papillary type 1 and 2, chromophobe and unclassified disease, as well as several additional less common subtypes. However, with all of these types, oncologists’ understanding of treatment for non-clear cell kidney cancer has evolved over the last several years, Narayan explained.

“Where, instead of viewing this as a single uniform entity, we began to appreciate that this actually represents a spectrum of different diseases, all with distinctive molecular and genetic clinical courses and variable responses to treatment,” he said.

In the past, most initial trials evaluated agents only for clear cell kidney cancer — which comprises 80% of patients — with little consensus on how to treat non-clear cell disease.

Two trials evaluated systemic treatments for non-clear cell kidney cancer — the ESPN and ASPEN trials, both comparing Sutent (sunitinib) with Afinitor (everolimus). Although both drugs appeared effective in patients with clear cell kidney cancer, outcomes were merely modest for those with non-clear cell disease.

Moving forward to present day, oncologists began to think about the disease differently. “We've begun to change our thinking in terms of how we think about non-clear cell kidney cancer. Instead of acting as lumpers, we begin to think (of the disease) more as splitters and recognize that this is truly a heterogeneous disease,” Narayan said.

With this, oncologists began to think about their improved understanding of the molecular underpinnings of each subtype of the disease, and defined characteristics based on chromosomal alteration, tumor metabolism and more, he added.

As part of the Cancer Genome Atlas, a collaborative project to create comprehensive maps of the key genomic changes in different cancer types, oncologists were able to define pathways among each subtype.

“There are areas of overlap with clear cell kidney cancer, but also some very important and unique differences with each of the subtypes of non-clear cell,” Narayan explained. “So as we start to think about how to use this information to improve the treatments for patients with non-clear cell disease, we’re really starting to have a change in the treatment paradigm. Instead of simply extrapolating treatments from clear cell kidney cancer, and testing them in non-clear cell patients, it would be ideal to have biology-driven clinical trials that assess specific treatments for specific subtypes.”

He added that there are challenges with this ideology, however, because it is difficult to accrue patients in a trial for uncommon kidney cancers, but the benefit of having uniform biology to test the rationale for new treatment strategies could help.

Currently, researchers have evaluated Sutent, Cabometyx (cabozatinib), savolitinib (an experimental drug) and Xalkori (crizotinib) in patients with papillary renal cell carcinoma types 1 and 2. More recently, however, Sutent and Cabometyx have become the only two “horses in the race,” Narayan said.

In the future, he is hopeful that oncologists’ understanding of overlap and the differences seen with conventional clear cell kidney cancer will continue to evolve.

“In thinking about the treatment of non-clear cell kidney cancer, especially as we move to the future, it's clear that our understanding of this disease is evolving,” Narayan concluded. “Our clinical trials will hopefully evaluate treatment strategies to target unique biology.”
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