Early Recurrence Post-Pembrolizumab Inspires Zanzalitinib Trial in ccRCC

In a conversation with CancerNetwork®, Karie Danielle Keera Runcie, MD, assistant professor of Medicine at Columbia University Irving Medical Center, discussed the rationale behind initiating the phase 2 EXACT trial (NCT06863311) evaluating zanzalitinib (XL092) with nivolumab (Opdivo) in patients with clear cell renal cell carcinoma (ccRCC) who experienced disease progression after adjuvant therapy. Runcie gave a presentation on the design of the trial during the 2025 Kidney Cancer Research Summit.1

She initially outlined her experience with patients who had experienced early recurrence after adjuvant pembrolizumab (Keytruda), which was approved for patients with RCC based on results from the phase 3 KEYNOTE-564 trial, noting that there was no set treatment option regarding subsequent therapy.2 In the absence of any known optimal regimens following recurrence on adjuvant pembrolizumab, Runcie expressed that it was an area of opportunity to conduct a trial.

Citing promising data from early, ongoing phase 1 trials evaluating zanzalitinib in patients with ccRCC, she explained that she reached out to the drug’s developer, Exelixis, to conduct a phase 2 trial to ascertain its benefit in these patients’ following recurrence after adjuvant therapy.

Transcript:

After [data from the KEYNOTE-564 trial were published] and adjuvant pembrolizumab was approved, I had a few patients who [experienced recurrence] early on, and I noticed that they had received several [differing] opinions. In New York City, a lot of the hospitals are close by, and [patients] sometimes seek multiple opinions. Going to different institutions, they had different recommendations.

I realized that this was an [opportunity for a] new therapy. There is no optimal regimen that is currently known after adjuvant pembrolizumab. I thought it would be a great area to do a trial. Zanzalitinib is a novel TKI, and at that time, the early phase 1 studies were ongoing, and the data looked promising. I reached out to Exelixis to study the treatment in this area.

References

1. Runcie K. EXACT: A randomized phase II trial of XL092 (zanzalintinib) in combination with immunotherapy in patients who progress on adjuvant therapy in clear cell RCC [NCT06863311]. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025. Boston, Massachusetts.
2. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. News release. FDA. November 17, 2021. Accessed July 25, 2025. https://bit.ly/3Cukjfk