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