Dr Nguyen on the Evolving Landscape of Adjuvant Therapy in Localized ccRCC

"The story of adjuvant therapy in kidney cancer has been quite perplexing. In the TKI era, we had studies showing disease-free survival benefits with sunitinib in the adjuvant setting, but there was no overall survival benefit and there are also a lot of toxicities."

Charles B. Nguyen, MD, an assistant clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, discussed the evolving role of adjuvant therapy in patients with localized clear cell renal cell carcinoma (ccRCC), highlighting recent data that are beginning to shift clinical practice in this historically challenging treatment setting.

Nguyen explained that during the TKI era, the use of adjuvant systemic therapy was largely informed by the phase 3 S-TRAC trial (NCT00375674), which demonstrated a disease-free survival (DFS) benefit with sunitinib (Sutent) vs placebo in patients at high risk of recurrence. However, this benefit did not translate into improved overall survival (OS), and treatment was associated with substantial toxicity, limiting enthusiasm for widespread adoption of adjuvant TKI administration. Subsequent trials of other TKIs, including the phase 3 ASSURE (NCT00326898) and PROTECT (NCT01238527) studies, failed to demonstrate a DFS or OS benefit, further contributing to uncertainty regarding the utility of adjuvant TKIs.

As immune checkpoint inhibitors (ICIs) emerged in the therapeutic landscape, several studies were initiated to evaluate their role in the adjuvant setting. However, trials such as the phase 3 IMmotion010 study (NCT03024996) evaluating atezolizumab (Tecentriq), the phase CheckMate 914 trial (NCT03138512) evaluating nivolumab (Opdivo) in combination with ipilimumab (Yervoy), and phase 3 PROSPER RCC trial (NCT03055013) assessing perioperative nivolumab, did not demonstrate consistent or statistically significant improvements in DFS or OS, leading to continued uncertainty about the role of ICIs in this setting.

The phase 3 KEYNOTE-564 trial (NCT03142334), however, marked a significant shift, Nguyen said. This study evaluated adjuvant pembrolizumab (Keytruda) in patients with intermediate- to high-risk localized ccRCC following nephrectomy. The trial met its primary end point, demonstrating a significant improvement in DFS. With longer follow-up, an OS benefit was also observed—establishing pembrolizumab as the first ICI to show both DFS and OS benefit in the adjuvant RCC setting, Nguyen continued.