Biomarker analysis from part B of the phase 3 CheckMate 914 trial reveals that PD-L1 expression levels are predictive of improved outcomes with nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with clear cell renal cell carcinoma (ccRCC), while high KIM-1 expression is associated with worse outcomes with nivolumab alone or with ipilimumab. The findings were presented at the 2024 SITC Annual Meeting.
The data indicated that high KIM-1 levels correlated with poorer disease-free survival (DFS) with nivolumab monotherapy compared to placebo in ccRCC patients. A trend towards poor DFS was also observed with nivolumab/ipilimumab, suggesting that micro-metastatic disease releases KIM-1 into circulation, making serum KIM-1 a potential biomarker for resected RCC recurrence. However, KIM-1 levels were not predictive of response to nivolumab alone or with ipilimumab versus placebo.
PD-L1 Expression and Treatment Response
When DFS was evaluated based on PD-L1 expression levels, patients with PD-L1 expression of 1% or higher (n = 87) showed a significantly better DFS with nivolumab/ipilimumab. This aligns with findings from the phase 3 KEYNOTE-564 trial of adjuvant pembrolizumab (Keytruda) in RCC. Sai Vikram Vemula, precision medicine/biomarker lead of immuno oncology at Bristol Myers Squibb, and Wenxin (Vincent) Xu, MD, an assistant professor of medicine at Harvard Medical School/Dana-Farber Cancer Institute, noted that "tumor PD-L1 expression is potentially predictive of favorable nivolumab plus ipilimumab outcome, while high circulating KIM-1 levels are prognostic of worse clinical outcomes."
Study Design and Patient Population
Part B of the CheckMate 914 trial included 825 patients with RCC, predominantly clear cell histology, who had undergone radical or partial nephrectomy with negative surgical margins. Patients were randomized (2:1:1) to receive nivolumab (240 mg IV every 2 weeks for 12 doses) plus placebo, placebo alone, or nivolumab plus ipilimumab (1 mg/kg IV every 6 weeks for 4 doses). The primary endpoint was DFS per blinded independent central review (BICR) for nivolumab vs placebo.
Additional Biomarker Findings
The median follow-up was 27.0 months (range, 18.0-42.4). Higher levels of KIM-1 were more commonly reported in those older than 65 years and had undergone partial nephrectomy. An on-treatment increase in circulating KIM-1 was linked with shorter DFS, suggesting that KIM-1 could be an early predictor for response to single-agent nivolumab and nivolumab/ipilimumab in this setting. Patients with PD-L1 expression levels of 1% or higher had higher levels of macrophages, lymphocytes, and neutrophils, indicating a potentially inflamed tumor microenvironment; endothelial cell levels were also lower in this subgroup.
