Cabozantinib/Nivolumab Appears Safe Up to 14 Days Before Cytoreductive Nephrectomy in RCC

In an interview with Targeted Oncology, Karie Runcie, MD, provided an assessment on the Clavien-Dindo classification system and discussed initial results of the Cyo-KIK trial.

Cabozantinib (Cabometyx) in combination with nivolumab (Opdivo) can safely be administered in patients with metastatic renal cell carcinoma (RCC) for up to 14 days prior to cytoreductive nephrectomy, according to findings from the phase 2 Cyto-KIK trial (NCT04322955).

At the 2022 International Kidney Cancer Symposium (IKCS), updated data showed that 3 evaluable patients completed nephrectomy within the 21-day interval and 5 completed nephrectomy within the 14-day interval after discontinuation of cabozantinib.

Cyto-KIK currently has enrolled 16 patients with metastatic clear cell RCC but plans on enrolling a total of 42. Patients in the trial received cabozantinib at 40mg daily and intravenous nivolumab at 480mg on the first day of each 28-day cycle for 12 weeks prior to cytoreductive nephrectomy.

The trial is using a 3+3 design to evaluate the safety of the interval of 21 or 14 days. Investigators are assessing the primary end point of percentage of patients with complete response and the secondary end points of median size reduction of the primary tumor, progression-free survival, response rate, overall survival, and surgical outcomes.

“So far, the study showed that a 14-day interval between the discontinuation of cabozantinib and nivolumab prior to surgery is safe. This has broader implications for patients who are on cabozantinib or another targeted kinase inhibitor, and who may need surgery for whatever reason,” said Karie Runcie, MD, in an interview with Targeted OncologyTM.

In the interview, Runcie, hematologist, oncologist, assistant professor of medicine at Columbia University Irving Medical Center, provided an assessment on the Clavien-Dindo classification system and discussed initial results of the Cyo-KIK trial.

Targeted Oncology: Can you discuss the Clavien-Dindo classification system and how it's currently used in RCC?

Runcie: The Clavien-Dindo classification system is a classification to look at surgical complications post-surgery. It's used throughout surgery, not specifically in RCC, it's a standard, it's reproducible, and it looks at whether there are pharmacological, surgical, and radiologic interventions that are required post-surgery. It was developed in the 1990s because there was no standard way to measure complications, so it's used across all surgical subspecialties to evaluate complications post-surgery.

Can you provide some background on your study and explain the unmet needs with metastatic clear cell renal cell carcinoma?

The study is Cyto-KIK. It is a phase 2, open-label clinical trial of cytoreductive surgery plus immunotherapy with nivolumab and targeted kinase inhibition with cabozantinib in metastatic kidney cancer. It's based on the background that cytoreductive surgery has always been a part of the care for kidney cancer, especially in the 1990s in the era of interferon. There were 2 large randomized controlled trials with SWOG and EORTC in Europe, which showed that there was a benefit of cytoreductive surgery with immunotherapy, which was interferon at the time. As treatment evolved, we've always wondered what the role is of cytoreductive surgery with the new treatment options. With CARMENA [NCT00930033] in 2018, with sunitinib [Sutent], which was a non-inferior trial, it showed that there was no difference between sunitinib alone vs sunitinib plus cytoreductive nephrectomy.

An unmet need in kidney cancer right now is whether cytoreductive nephrectomy still plays a role with our current standard of care which is immunotherapy combination or immunotherapy plus targeted kinase inhibition. One goal of this study is to assess whether we see a benefit in this patient population who received 1 of the frontline regimens with cabozantinib or nivolumab. Another goal of this study is to understand mechanisms of resistance to immunotherapy plus TKI combination with cabozantinib and nivolumab. One cool part of this study is that we have specimens before and we have the kidney, the cytoreductive nephrectomy in order to have tissue after and we're able to look at the tumor microenvironment to understand some of these mechanisms which can help us to develop new therapies, which is definitely needed in kidney cancer.

Can you discuss the findings that you presented during IKCS?

In the study, our target enrollment is 42. We currently have 16 patients enrolled, but what we were presenting was some of the surgical safety data using Clavien-Dindo classification. There was limited surgical data surrounding the use of cabozantinib prior to surgery, and what a safe interval of discontinuation between the drugs is. In this trial, when the patients are receiving cabozantinib and immunotherapy, we built in a 3+3 trial design to assess the safety of the interval of discontinuation between the drug and surgery. We started with 21 days because we know the half-life of cabozantinib is 99. At 21 days, it would have been completely washed out from the system and Exelixis wanted us to be conservative based on prior data, so we did 21 days.

We found that 3 evaluable patients were able to complete nephrectomy without any surgical outcomes. We moved on to our second cohort of 14-day intervals between the discontinuation of cabozantinib and nephrectomy and we had 5 evaluable patients, which completed surgery without any complications. So far, the study showed that a 14-day interval between the discontinuation of cabozantinib and nivolumab prior to surgery is safe. This has broader implications for patients who are on cabozantinib or another targeted kinase inhibitor, and who may need surgery for whatever reason. We know that a 14-day interval between stopping the drug and any surgical procedure should be safe.

What are the next steps with this research?

Our trial enrollment is ongoing, and we're really excited to continue accruing and get to our overall goal of the trial. Our primary objective is to assess the complete response rate in this patient population. Our hypothesis is that with the primary tumor in place, giving these drug combinations prior to surgery will enhance the immune system, increase the peripheral T-cell response, and that we can probably cure more people with this mechanism of giving perioperative immunotherapy plus targeted kinase inhibition. The overall objective is to test the complete response rate. Then our secondary objectives include progression-free survival, overall survival, and we've built in some correlative studies. The next steps are to continue accruing. We're also doing some more analysis right now doing single cell analysis to look at the tumor microenvironment and the response to treatment in some of these patients.

After the presentation, there were a few comments. One of our colleagues in Europe mentioned that he operates on patients up to 5 days after discontinuation of cabozantinib or sunitinib and that we could probably push the study even further since we proved that it's safe at 14 days. With the growth in the turnover of the fibroblasts, 5 days may be a safe interval. We completely agree there are other studies that use sunitinib until the day prior to surgery. At least for the patient's benefit, we could try to shorten that interval so that they can get more benefit from the drug prior to surgery.

REFERENCE:
CYTO reductive surgery in kidney cancer plus immunotherapy and targeted kinase inhibition (Cyto-KIK). ClinicalTrials.gov. Updated April 4, 2022. Accessed November 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04322955