PD-L1 expression levels were found to be predictive of improved outcomes with Opdivo (nivolumab) and the CTLA-4 inhibitor Yervoy (ipilimumab) in patients with clear cell renal cell carcinoma (ccRCC), whereas high KIM-1 expression led to worse outcomes in this patient population with Opdivo alone or with Yervoy, according to findings from the phase 3 CheckMate 914 trial presented at the 2024 SITC Annual Meeting.
Data showed that high KIM-1 levels were associated with worse disease-free survival (DFS) with Opdivo monotherapy versus placebo in patients with ccRCC, as well as a trend toward poor DFS with Opdivo and Yervoy, suggesting that micro-metastatic disease releases KIM-1 into the circulation, as well as that serum KIM-1 is a potential minimally invasive biomarker for resected RCC recurrence. However, KIM-1 levels were not found to be predictive of response to Opdivo alone or with Yervoy versus placebo.
When DFS was evaluated across study groups stratified by patients with PD-L1 expression lower than 1% (663 patients) and 1% or higher (87 patients), results showed that PD-L1 expression was determined to be predictive of response to Opdivo and Yervoy. Higher baseline PD-L1 levels were significantly associated with better DFS, showing consistency with results from the phase 3 KEYNOTE-564 trial of adjuvant Keytruda (pembrolizumab) in patients with RCC.
However, patients who had higher fibroblast levels within the tumor microenvironment had shorter DFS with Opdivo plus Yervoy compared with Opdivo alone.
“In the adjuvant setting, tumor PD-L1 expression is potentially predictive of favorable [Opdivo] plus [Yervoy] outcome, while high circulating KIM-1 levels are prognostic of worse clinical outcomes,” co-first study authors Sai Vikram Vemula, precision medicine/biomarker lead of immuno oncology at Bristol Myers Squibb, and Dr. Wenxin (Vincent) Xu, an assistant professor of medicine at Harvard Medical School/Dana-Farber Cancer Institute in Boston, Massachusetts, wrote alongside coinvestigators in a poster presented during the meeting. “Patients with PD-L1 expression may be enriched with immune cell populations, contributing to better immunotherapy response.”
Rationale and Design of This Biomarker Analysis
An unmet need exists for predictive biomarkers for immune checkpoint inhibitors in the treatment of patients with ccRCC. Prior data from part A of the CheckMate 914 trial showed that PD-L1 expression and serum KIM-1 levels are independently associated with treatment effect from Opdivo combined with Yervoy versus placebo in patients with localized ccRCC.
In the analysis presented at the 2024 SITC Annual Meeting, investigators further evaluated the role of PD-L1 and KIM-1 for association with Opdivo alone and with Yervoy in part B of the CheckMate 914 trial; they also explored a novel human-interpretable image feature–based platform to characterize the cell and tissue composition from hematoxylin and eosin whole-slide images. This was to assess the platform’s potential to identify novel prognostic and predictive biomarkers for immunotherapy response in RCC.
Part B of CheckMate 914 comprised 825 patients with RCC with predominant clear cell histology. Patients could not have any clinical or radiological evidence of residual disease or distant metastases after nephrectomy.
Additional Biomarker Findings
The median follow-up was 27 months. Additional results showed that serum KIM-1 levels were linked with age and nephrectomy status. Higher levels of KIM-1 were more commonly reported in those who were older than 65 years of age and had undergone partial nephrectomy.
Investigators also explored the association of on-treatment changes in KIM-1 with response to Opdivo alone and with Yervoy. Results showed that 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 Opdivo and Opdivo plus Yervoy in this setting.
Furthermore, patients with PD-L1 expression levels of 1% or higher had higher levels of macrophages, lymphocytes and neutrophils, which are all types of white blood cells, indicating a potentially inflamed tumor microenvironment; endothelial cell levels were also lower in this subgroup.
The primary end point was DFS for Opdivo versus placebo, and secondary end points were DFS for Opdivo versus Opdivo/Yervoy, overall survival (OS) for Opdivo versus placebo, OS for Opdivo versus Opdivo/Yervoy and safety.
The authors concluded that these observations should be explored in further clinical trials.
References:
- "Integrative biomarkers analysis from the Phase 3 CheckMate 914 trial of nivolumab plus ipilimumab or nivolumab versus placebo for adjuvant clear cell renal cell carcinoma (ccRCC)" by Dr. Vemula SV, et al., presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX.
- "Overall survival with adjuvant pembrolizumab in renal-cell carcinoma" by Dr. Choueiri TK, et al., New England Journal of Medicine.
- "Adjuvant nivolumab plus ipilimumab versus placebo for localized renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial" by Dr. Motzer RJ, et al., The Lancet.
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