The Last 20 Years of Advancements Were 'Revolutionary' for Metastatic Kidney Cancer Treatment

Twenty years ago, patients with metastatic kidney cancer were barely living beyond one year after diagnosis, and there were not many effective treatment options. But thanks to scientific advancements and an abundance of Food and Drug Administration (FDA) drug approvals, patients now are living longer.

Dr. Chung-Han Lee explained in an interview with CURE® that kidney cancer had long been thought of as a malignancy that was highly resistant to treatments such as chemotherapy and radiation.

“I think that over the past 20 years we really have seen how the investments in scientific discovery have led to improved patient outcomes,” said Lee, who is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

“Kidney cancer, for the longest period of time, was a disease in which none of the systemic therapies worked. And then as soon as we truly understood the biology, we were able to rationally design treatments.”

Advancements With Approvals

Dr. James Brugarolas, director of the kidney cancer program at Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center in Dallas, noted that prior to 2005 there was only one drug approved by the FDA — limiting patients’ options.

“The past 20 years have been revolutionary for kidney cancer, perhaps more so than most other types of cancer,” he said in an interview with CURE®. “But since 2005 there have been more than a dozen drugs approved for kidney cancer therapy.”

The first metastatic kidney cancer treatments that demonstrated great progress were targeted therapies. They target proteins that control blood vessel growth and tumor nourishment.

Sutent (sunitinib) was approved in 2007 — Lee called this approval “pivotal.” It was based on an 11-month progression-free survival (time during and after treatment when the patient lives without disease progression).

“I think (Sutent) was the first proof of concept demonstrating that this is a key molecular pathway that’s important for kidney cancer,” he said.

And then there was a stream of targeted therapies that received approval, including:

• 2009: Votrient (pazopanib) demonstrated a reduced risk of tumor progression or death by 54%, compared with placebo, and a progression-free survival of 9.2 months.
• 2012: Inlyta (axitinib) showed a 43% improvement in median progression-free survival compared with Nexavar (sorafenib), which was standard of care at the time.
• 2016: Cabometyx (cabozantinib) was approved for the treatment of patients with advanced kidney cancer who received prior lines of therapy. It was approved again in 2017 for first-line treatment.
• 2016: Lenvima (lenvatinib) in combination with Afinitor (everolimus) demonstrated a 14.6-month progression-free survival and 63% reduction in risk of disease progression or death compared with Afintior alone.
• 2021: Fotivda (tivozanib) demonstrated a progressionfree survival of 5.6 months and objective response rate (the rate of a measurable response to the treatment) of 18%.

The past seven years brought the development of immunotherapy, Brugarolas said. These drugs boost a patient’s immune system to recognize and destroy cancer cells more effectively. They include immune checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors and CTLA-4 inhibitors.

Drugs that have been approved over the past few years for metastatic kidney cancer include Opdivo (nivolumab), Yervoy (ipilimumab), Keytruda (pembrolizumab) and Bavencio (avelumab), as well as combinations of these.

Brugarolas noted that the combination approvals have been groundbreaking in the field. The approval of Opdivo plus Yervoy has resulted in 50% survival rates at four years, he said.

“This has significantly changed how we treat patients with metastatic kidney cancer today,” Brugarolas explained. “The past 20 years have revolutionized the care and prognosis of patients with kidney cancer.”

Improving Quantity and Quality of Life

“The survival rates have changed profoundly,” Brugarolas said.

Prior to the development of these therapies, patients with metastatic kidney cancer had five-year survival rates of only 10%. But now, there are five-year survival rates of over 40%, and some combinations are resulting in response rates as high as 70%.

“Response rates are particularly high for combinations of immunotherapies with targeted therapies,” he added. A few years ago, the median time on a first-line tyrosine kinase inhibitor, a type of targeted therapy, was nine to 12 months, and a longterm response on these therapies was 18 months.

Now, with more recent combination therapies, the median response may extend to beyond 24 months, Lee added.

“We’re now taking the median and shifting it even beyond to what we used to think long-time responses would be,” he explained.

And with that comes a durability of response, which is progression-free survival that has exceeded three times that of the whole population. Years ago, it was uncommon for that to even be observed, but now with certain combinations, such as Opdivo plus Yervoy, one third of patients are achieving a long durability of response.

“We’re starting to entertain the idea that these people may actually be cured of their disease; however, certainly longer follow-up is necessary to establish that as the case,” Lee said.

And so, over the past 20 years it is clear survival has improved for patients with metastatic kidney cancer.

But what about the life they are living while receiving these treatments?

Lee noted that quality of life has not been negatively affected by any of these advancements. Although immunotherapy and targeted therapy have side effects, they are manageable, said Brugarolas.

Twenty years ago, patients were being treated with cytokines such as interferon and interleukin-2. The patients often felt like they had the flu, and many couldn’t continue taking therapy. Some also experienced cytokine release syndrome to an extreme that they had to be treated in a hospital’s intensive care unit.

But today, these treatments and their side effects are much more manageable in an outpatient setting. For example, with immune checkpoint inhibitors, some patients may develop autoimmune side effects, but those who do not can have a quality of life that is minimally affected by these drugs.

“I think that from an efficacy standpoint, a quality-of-life standpoint and a durability standpoint, we’ve seen significant progress,” Lee said.

Tackling the Next 20 Years

Both Lee and Brugarolas agreed that there is more work to be done, and that is what the next 20 years are for.

“I think that even though we have made a lot of progress in the past 20 years, until we get to the point where we’re curing all of our patients, I think there is still a tremendous amount of progress to be done,” Lee said.

Brugarolas agreed. “One challenge — and our dream — is to be able to cure all patients with metastatic kidney cancer,” he said.

He added another challenge will be in precision medicine, which tailors the drug to a particular patient and their genetic makeup. Lee also highlighted this and discussed a drug he is excited about, Welireg (belzutifan), which was developed based on seminal discoveries at UT Southwestern and targets a transcription factor at the root of the cancer.

They also both agreed that the treatment of non-clear cell kidney cancer will need more focus in the next 20 years. Approximately 70% of patients with kidney cancer have clear cell kidney cancer, so that is what most of the treatments are indicated for.

However, this leaves the rest — patients with non-clear cell kidney cancer — with an unmet need for more treatment options.

“There are a few challenges that we have to tackle over the course of the next 20 years,” Brugarolas concluded. “This is just the beginning.”

The kidney cancer field used to be “depressing,” Lee explained, as a lot of work went into developing treatments but not much panned out. But over the past 20 years there has been great success, which ultimately has benefited patients.

“It’s really blossomed as we’ve seen success,” he concluded. “This has truly translated to benefits for the patients. When we talk about these improvements and the number of years a patient has, that’s extra vacations, time with family, family reunions, anniversaries. I think it really does translate to very tangible outcomes.”

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