Cytoreductive Nephrectomy in the Era of Immunotherapy for Kidney Cancer

3D Rendered Medical Illustration of Male Anatomy - Kidney Cancer: © Sebastian Kaulitzki - stock.adobe.com

The PROBE trial (NCT04510597) is evaluating the addition of surgery to a standard of care (SOC) immunotherapy-based drug combination vs a SOC immunotherapy-based drug combination alone in patients with metastatic kidney cancer. This ongoing study was designed to determine if cytoreductive nephrectomy offers a survival benefit for patients with metastatic kidney cancer who are receiving modern immune checkpoint inhibitor-based combination therapies.¹

The randomized, phase 3 study is enrolling patients with metastatic kidney cancer who are initially treated with an FDA-approved immune checkpoint inhibitor-based combination regimen. After 10 to 14 weeks of this systemic therapy, patients who demonstrate stable disease or a partial response are then randomly assigned 1:1 to either continue systemic therapy alone or undergo cytoreductive nephrectomy followed by continued systemic therapy. The study aims to accrue 364 eligible patients.

The primary end point of the PROBE trial is overall survival. Secondary end points include progression-free survival, objective response rates in metastatic sites, and change in primary tumor diameter.

The trial is currently ongoing and actively accruing patients. While accrual has been a bit slower than initially anticipated, it is proceeding at a reasonable rate. The investigators are working to optimize eligibility criteria and educate potential participants and investigators on the importance of the trial to ensure its successful completion.

In an interview with Targeted Oncology^TM, Hyung Kim, MD, urologic oncologist and chair of urology at Cedars-Sinai Medical Center, further discussed the trial in progress.

Targeted Oncology^TM: What was the rationale behind the PROBE trial and its design?

Kim: The PROBE study is a randomized, phase 3 trial. It's sponsored by a cooperative group, SWOG, and it's asking the question, is there a survival benefit to performing a cytoreductive nephrectomy in patients with metastatic kidney cancer?

How was the study designed to determine clinical benefit?

Patients with metastatic cancer are initially started on a combination therapy where 1 of the 2 drugs has to be an immuno-oncology drug. And then after 3 months of therapy, patients who have either stable disease or [a] partial response are randomized to surgery or no surgery, and then all patients are followed for overall survival.

What insights have early data or the trial itself offered regarding patient selection?

The study is ongoing, and accrual has been a little bit slower than expected, but it's accruing at a reasonable rate. We are not at risk of shutting down, but when you are randomizing patients between surgery and no surgery, there's always some challenge there. We are trying to optimize the eligibility, and we are getting the word out about the trial and educating investigators on how best to present the study to potential patients.

Immune checkpoint inhibitors have transformed the treatment landscape. Based on what you have found so far in other trials, how does these agents remain a viable option to become a new standard in the kidney cancer space?

About 20 years ago, there were 2 randomized studies that showed that surgery provides a survival benefit, and then another study, the CARMENA trial [NCT00930033], came along and used a tyrosine kinase inhibitor, so something that was not an immuno-oncology drug, and there was no survival benefit. That study would suggest that we should stop doing cytoreductive nephrectomies. But then the field has again evolved, and now we are using combinations where at least 1 of those 2 drugs is an immuno-oncology drug. So, if you go back to the old trials where cytoreduction showed benefit, they used a cytokine and also an immunotherapy. The question now comes back to us. When 1 of the 2 drugs is immunotherapy, should we be doing cytoreduction? Of course, we do not know the answer to that question, so we are doing the trial.

What are the key end points being evaluated?

The primary end point is overall survival, which I think is important because we have so many therapies now for kidney cancer that patients who progress on one therapy will get others, and some of these will be kinase inhibitors, some will be more immuno-oncology drugs. The relevant end point really is not the response to one drug or frontline therapy, but just overall survival. You really want interventions that are going to impact the patient's complete survival.

REFERENCE:

Comparing the outcome of immunotherapy-based drug combination therapy with or without surgery to remove the kidney in metastatic kidney cancer, the PROBE trial (PROBE). ClinicalTrials.gov. Updated August 16, 2024. Accessed June 10, 2025. https://clinicaltrials.gov/study/NCT04510597