Kidney injury molecule 1 (KIM-1) is a promising biomarker in adjuvant clear cell renal cell carcinoma (ccRCC), but its relevance in advanced ccRCC or papillary RCC (pRCC) remains unclear.
CALYPSO (NCT02819596) was a prospective, multi-arm trial that evaluated durvalumab alone or in combination with tremelimumab or savolitinib in metastatic ccRCC and pRCC. Circulating KIM-1 levels were measured at baseline and on-treatment. The primary endpoint was to explore if KIM-1 levels were raised in pRCC. Analyses were exploratory and p values were nominal.
KIM-1 was measured in 123 patients with ccRCC and 31 patients with pRCC. Higher median concentrations occurred in pRCC compared to ccRCC (7835 vs 5470 pg/ml, p = 0.05). Reductions in KIM-1 levels occurred with systemic therapy in both ccRCC and pRCC (−59.2% and −32% respectively). In pRCC, radiological responders had significantly lower baseline KIM-1 levels (p = 0.025). In ccRCC, high baseline KIM-1 levels were associated with significantly shorter overall survival (OS) (hazard ratio [HR] 1.77; 95% CI, 1.15–2.72; p = 0.01). Also, an increase in KIM-1 during therapy was linked to worse progression-free survival (HR 1.7; 95% CI, 1.13–2.58; p = 0.01) and OS (HR 1.95; 95% CI, 1.23–3.08; p = 0.004) in ccRCC.
This exploratory analysis supports the utility of KIM-1 in advanced ccRCC and pRCC.
Biomarker development in renal cell carcinoma (RCC) has been exceptionally difficult, and the field still lacks robust biomarkers that can reliably guide treatment decisions. However, the recently published translational analysis of the CALYPSO trial evaluating durvalumab alone or in combination with tremelimumab or savolitinib in metastatic clear cell (ccRCC) and papillary (pRCC) RCC, doesadd to a growing body of evidence positioning kidney injury molecule-1 (KIM-1) as one of the most promising circulating biomarkers.
In this prospective translational analysis, circulating KIM-1 levels were elevated in patients with advanced ccRCC as well as advanced pRCC , a patient population in which this biomarker has been less extensively studied. Moreover, elevated baseline KIM-1 levels were associated with more aggressive disease biology and inferior clinical outcomes. Importantly, dynamic changes in KIM-1 during treatment correlated with radiological response, supporting the notion that KIM-1 may serve as a real-time biomarker of therapeutic efficacy. This raises the possibility that serial KIM-1 monitoring could complement conventional imaging by providing earlier insight into treatment response or emerging resistance, thereby facilitating more timely therapeutic adaptation.
The present study establishes the use of KIM-1 beyond solely the ccRCC setting and extends its potential use to pRCC. Additionally, it reinforces the concept of a circulating biomarker that provides prognostic and potentially predictive information in RCC patients.
Previously, KIM-1 has been identified as a potential marker of molecular minimal residual disease (MRD) in the adjuvant setting. In the biomarker analysis of the IMmotion010 study, evaluating adjuvant atezolizumab following nephrectomy in patients at high risk of recurrence, elevated plasma KIM-1 was associated with worse oncological outcomes but also enriched for benefit of adjuvant immunotherapy. Thus, the biomarker was both prognostic, identifying patients at higher risk of relapse, as well as predictive, identifying patients most likely to benefit from adjuvant therapy in this setting.
The current, as well as previous studies on KIM-1 have been very promising, but several limitations should be acknowledged. Such biomarker analyses have so far been exploratory, and standardisation of assay methodology and clinically relevant thresholds will also be necessary before widespread implementation can occur. Nevertheless, the consistency of findings across disease settings and treatment contexts makes KIM-1 one of the most compelling biomarker candidates currently under investigation in RCC. Across all settings, and likely beyond solely ccRCC, KIM-1 appears capable of reflecting tumour burden, MRD, treatment response, and long-term clinical outcomes. Therefore, the accumulating evidence now justifies moving beyond retrospective and exploratory analyses: KIM-1 should be prospectively incorporated into future RCC clinical trials to definitively evaluate its prognostic and predictive utility and to determine how biomarker-guided treatment strategies may improve patient outcomes.