A post hoc analysis of the phase 3 JAVELIN Renal 101 trial has revealed that kidney injury molecule-1 (KIM-1) shows significant promise as a prognostic biomarker in patients with advanced renal cell carcinoma (RCC). The study demonstrated that patients with lower baseline KIM-1 levels experienced substantially improved clinical outcomes compared to those with higher levels, regardless of treatment regimen.
The analysis, presented by Marc Machaalani, MD, a research fellow at Dana-Farber Cancer Institute, evaluated 612 patients from the original JAVELIN Renal 101 study, which compared avelumab plus axitinib to sunitinib in treatment-naive advanced RCC patients. KIM-1, a transmembrane glycoprotein expressed on kidney cancer cell membranes and shed into the blood, was measured using plasma-based assays at baseline and at 12 weeks of treatment.
Baseline KIM-1 Levels Predict Clinical Outcomes
The analysis revealed striking differences in survival outcomes based on baseline KIM-1 levels. In the overall population, patients with low baseline KIM-1 levels (below median, n=306) experienced significantly improved overall survival compared to those with high baseline levels (above median, n=306; P < 0.0001). Similarly, progression-free survival was significantly better in patients with low baseline KIM-1 levels (P = 0.0011).
These prognostic effects were consistent across treatment arms. In the avelumab plus axitinib combination arm, patients with low baseline KIM-1 levels (n=170) demonstrated superior progression-free survival compared to those with high baseline levels (n=153; P = 0.015). The sunitinib arm showed a similar pattern, with patients having low baseline KIM-1 levels (n=145) experiencing better outcomes than those with high levels (n=144; P = 0.013).
Dynamic Changes in KIM-1 Levels Show Predictive Value
Beyond baseline measurements, the study revealed that changes in KIM-1 levels during treatment also correlated with clinical outcomes. Patients who experienced a decrease in KIM-1 from baseline to day 1 of cycle 3 (n=444) showed significantly improved overall survival compared to those whose KIM-1 levels increased during the same period (n=168; P = 0.00058). Progression-free survival was also significantly better in patients with decreasing KIM-1 levels (P < 0.0001).
This dynamic relationship held true within individual treatment arms. In the combination arm, patients with decreasing KIM-1 levels (n=257) experienced superior progression-free survival compared to those with increasing levels (n=66; P = 0.00084). The sunitinib arm demonstrated similar results, with patients showing decreased KIM-1 levels (n=187) outperforming those with increased levels (n=102; P = 0.0064).
Molecular Insights and Clinical Implications
The researchers conducted an integrative analysis across multiple platforms, including clinical, genomic, transcriptomic, and immunopathologic datasets, to better understand KIM-1's role in RCC. Higher KIM-1 expression correlated with more immunosuppressive tumor microenvironments and higher tumor burden, and was associated with genomic alterations known to confer aggressive disease phenotypes.
"KIM-1 is a glycoprotein expressed on the membranes of kidney cancer cells and shed into the blood. It is under investigation as a leading circulating biomarker in patients with kidney cancer," Machaalani explained. The protein is implicated in renal tubular injury and may reflect underlying tumor biology and immune modulation.
Path Forward Requires Validation and Standardization
While the retrospective data are compelling, Machaalani emphasized the need for prospective validation before clinical implementation. "We do have really compelling and robust data that are retrospective in nature, supporting the use of KIM-1 as a biomarker across the disease stages. However, eventually, prospective validation will be very important in order to support these findings to make it through into clinical practice," he stated.
The researchers also highlighted the need for assay standardization, as different studies have employed various measurement techniques. "Work needs to be done to standardize KIM-1 assays because different studies have used different assays with some being microbead-based and others being electroluminescence-based. We need to unify the assays and use one standardized cutoff to better analyze the results," Machaalani noted.
The study cohort had a median age of 61 years, with 74.5% male patients and 55.6% having an ECOG performance status of 0. Patients were distributed across International mRCC Database Consortium risk categories: 22.4% favorable-risk, 61.6% intermediate-risk, and 15.4% poor-risk disease.
If validated in prospective studies, KIM-1 could serve as a noninvasive biomarker to help inform treatment decisions, stratify risk, and guide therapeutic selection in patients with advanced RCC, potentially improving personalized treatment approaches in this challenging malignancy.
