Expert Explains Role of Perioperative Therapy in Kidney Cancer

Pre- and post-surgical treatment could benefit patients with kidney cancer who are at high risk for disease recurrence, according to Dr. Naomi B. Haas, director of the Abramson Cancer Center’s Kidney and Prostate Cancer Clinical Trial Programs.

Perioperative therapy is the additional treatment before, during or after surgery; however, in kidney cancer, this is typically limited to the kidney area, Haas explained.

Drugs used or evaluated in this setting include vascular endothelial growth factor tyrosine kinase inhibitors (VEGF TKIs), such as Sutent (sunitinib), Inlyta (axitinib), Votrient (pazopanib) and Nexavar (sorafenib), as well as immune checkpoint inhibitors like the combination use of Yervoy (ipilimumab) plus Opdivo (nivolumab) or Opdivo alone, Keytruda (pembrolizumab) and Tecentriq (atezolizumab).

VEGF TKIs target blood vessels, which kidney cancer tumors are full of, Haas explained. “Half of our tool chest is going after the blood vessels and cutting off the blood supply to the tumor.” Meanwhile, immune checkpoint inhibitors stimulate the immune system to look for things that are foreign in the body, like cancer.

At A Vision of Hope: A Kidney Cancer Educational Symposium, hosted by the Judy Nicholson Kidney Cancer Symposium and Penn Medicine Abramson Cancer Center, Haas discussed five clinical trials that evaluated VEGF TKI agents in the perioperative setting for kidney cancer: the ASSURE, S-TRAC, PROTECT, ATLAS and SORCE trials.

Among all five trials, no overall survival benefit was observed; however, treatment with Sutent improved disease-free survival and led to its approval in the adjuvant setting.

In the phase 3 PROTECT trial, researchers evaluated the efficacy and safety of Votrient compared with placebo in patients with locally advanced renal cell carcinoma who already underwent nephrectomy. They found that those who have higher drug levels of Votrient in their bodies might benefit from treatment; however, it is difficult to determine who those patients are.

With that, adjuvant VEGF TKI inhibitors are associated with severe side effects in more than half of patients, therefore, Haas said, it is important to understand who should be offered this therapy.

Currently, the EVEREST trial is ongoing and evaluating Afinitor (everolimus), an mTOR inhibitor, in patients with kidney cancer.

In the immune checkpoint inhibitor space, researchers are evaluating the following, according to Haas:

• Does leaving the kidney tumor in, when immune therapy is started, make treatment work better?
• Does immune checkpoint inhibition cure high-risk kidney cancer?
• Does immune checkpoint inhibition cure low volume resected metastatic disease?
• Does immune checkpoint inhibition delay relapse of cancer?
• Can immune or other profiled be identified to predict benefit to these agents?

In particular, two completed phase 3 studies — the IMmotion010 and Keynote 564 studies – evaluated single agent immunotherapy in the adjuvant setting (given in addition to primary treatment, like surgery).

“We're waiting to get that information and what we're hoping to get with that information is that they're curing more patients with kidney cancer,” Haas said.

In addition, the Checkmate-914 trial is currently ongoing and evaluating Yervoy in combination with Opdivo compared with placebo in patients with high-risk disease.

On the other hand, researchers are also evaluating the use of immune checkpoint inhibitors in patients prior to their surgery, followed with additional immunotherapy treatment after surgery.

“We think that these drugs might actually work better if you have a little bit of cancer in there to start with,” Haas said.

In the EA8143 PROSPER trial, one that is evaluating adjuvant therapy “with a twist,” Haas said, randomized patients to receive Opdivo, then undergo a partial or radical nephrectomy followed by nine doses of Opdivo.

“We are hopeful,” Haas said. “But surveillance clinical trial participation or adjuvant sunitinib remain to be our choices for patients with kidney cancer at high risk for recurrence.”