COSMIC-313 Trial: KIM-1 Associated With Clinical Outcomes in Advanced RCC

A retrospective analysis of the phase 3 COSMIC-313 (NCT03937219) trial found that decreased kidney injury molecule-1 (KIM-1) level was significantly associated with improved clinical outcomes in patients with advanced renal cell carcinoma (RCC) treated with nivolumab (Opdivo) plus ipilimumab (Yervoy).¹

The COSMIC-313 trial evaluated the effect of the triplet combination of cabozantinib (Cabometyx) plus nivolumab and ipilimumab compared with nivolumab plus ipilimumab. The present analysis, which investigated the role of circulating KIM-1 as a potential biomarker, demonstrated that baseline KIM-1 levels are a strong indicator of disease burden, which correlates with poor-risk features and worse overall survival (OS). Plasma samples were collected from patients at baseline at weeks 1, 4, 7, 10, and 14. KIM-1 levels were profiled using a Meso Scale Discovery. There was a total of 347 patients in the nivolumab plus ipilimumab arm and 356 patients in the cabozantinib plus nivolumab and ipilimumab arm.

The analysis findings were presented at the 2025 European Society for Medical Oncology Congress on October 19, 2025, in Berlin, Germany, by Wenxin Xu, MD, assistant professor of medicine, Harvard Medical School.

Compared with patients who received cabozantinib plus nivolumab and ipilimumab, patients in the nivolumab plus ipilimumab arm achieved a higher overall response rate (ORR) at weeks 4 and 7, which was significantly associated with decreased KIM-1 levels (P < .001). Comparatively, in patients receiving the triplet therapy, KIM-1 and ORR were only significantly associated at week 7 (P = .03).

Additionally, patients in the nivolumab plus ipilimumab arm who experienced a KIM-1 decrease at week 7 demonstrated a substantially greater reduction in target lesions compared with patients with a KIM-1 increase.

A decrease in KIM-1 from baseline was also associated with improved progression-free survival (PFS) in both treatment arms, although the effect was more immediate and consistently significant in the nivolumab and ipilimumab arm. At week 4, the hazard ratio (HR) for PFS comparing patients receiving nivolumab plus ipilimumab with triplet therapy was 0.52 (95% CI, 0.39-0.69; P < .01). In the subsequent weeks, the HR was 0.35 (95% CI, 0.26-0.47) at week 7, 0.34 (95% CI, 0.25-0.46) at week 10, and 0.32 (95% CI, 0.22-0.44) at week 14 (all P < .01).

Patients in the nivolumab plus ipilimumab arm achieved a decrease in KIM-1, a predictor of improved OS. These improvements were not observed in patients in the cabozantinib plus nivolumab and ipilimumab arm. In weeks 4, 7, 10, and 14, the respective HRs for OS comparing patients in the nivolumab plus ipilimumab arm with the triplet therapy arm were 0.49 (95% CI, 0.36–0.68), 0.48 (95% CI, 0.35–0.66), 0.53 (95% CI, 0.37–0.74), and 0.46 (95% CI, 0.31–0.67) (all P <.01).

A moderate correlation (R = 0.58; P <.001) was observed between baseline KIM-1 levels and the sum of the longest diameters of target lesions.

Baseline KIM-1 levels were well-balanced between the 2 treatment arms, with a mean concentration of 6324.4 pg/mL for patients in the cabozantinib plus nivolumab and ipilimumab arm, and 6333.1 pg/mL for patients in the nivolumab plus ipilimumab arm. The analysis revealed that higher baseline KIM-1 levels were significantly associated with more advanced disease characteristics such as tumor burden, IMDC risk, and prior nephrectomy. Patients with poor-risk disease, as defined by the IMDC, had significantly higher KIM-1 levels than those with intermediate-risk disease (P <.001). Patients who had not undergone a prior nephrectomy also had significantly higher baseline KIM-1 levels compared with those who had (P <.001).

“These results likely reflect the differing mechanisms of action of immune checkpoint inhibitors and VEGFR [tyrosine kinase inhibitors],” said Xu during the presentation.

This research was supported by previous research from the phase 3 CheckMate 214 (NCT02231749)² study, which showed that a reduction in circulating KIM-1 levels after 3 weeks was associated with long-term efficacy in patients receiving first-line nivolumab plus ipilimumab, but not in patients receiving sunitinib (Sutent).

DISCLOSURES: Wenxin Xu declared interests with Arsenal Biosciences, Aveo, Celdara, Dana-Farber Cancer Institute, Deciphera, Eisai, Exelixis, Merck, Oncohost, and Xencor.

REFERENCES

1. Xu W, Choueiri T, Powles T, et al. 2594MO: Association of circulating kidney injury molecule-1 (KIM-1) levels with clinical outcomes in advanced renal cell carcinoma (aRCC): Retrospective analysis of COSMIC-313. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 2594MO.

2. Nivolumab combined with ipilimumab versus sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 214). ClinicalTrials.gov. Updated June 26, 2025. Accessed November 6, 2025. https://clinicaltrials.gov/study/NCT02231749