Low KIM-1 Levels Are Associated With Improved Clinical Outcomes in Advanced RCC

Marc Machaalani, MD

Lower baseline kidney injury molecule-1 (KIM-1) levels were associated with improved overall survival (OS) and progression-free survival (PFS) vs higher levels following treatment with avelumab (Bavencio) plus axitinib (Inlyta) or sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC), according to data from a post hoc analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006), highlighting the potential of the protein as a prognostic biomarker in the space.1

Data from the analysis were presented by Marc Machaalani, MD, during an OncLive National Fellows Forum on February 11, 2025, which preceded the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) from February 13 to 15, 2025, in San Francisco, California.

“During the Fellows Forum, I presented our work on KIM-1 in the JAVELIN Renal 101 trial, which was a major study of the PD-L1 inhibitor avelumab in combination with the VEGFR tyrosine kinase inhibitor axitinib vs standard-of- care sunitinib in patients with previously untreated metastatic RCC,” Machaalani, a research fellow in genitourinary oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, said in an interview with Oncology Fellows. “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.”

Prior data from JAVELIN Renal 101 supported the May 2019 FDA approval of
avelumab plus axitinib for the first-line treatment of patients with advanced RCC.2 The multicenter, open-label study enrolled patients with treatment-naive advanced RCC with a clear cell component, regardless of tumor PD-L1 expression, and patients were randomly assigned 1:1 to receive avelumab plus axitinib or sunitinib.3 The primary end points were PFS per blinded independent central review (BICR) and OS in patients with PD-L1–positive tumors. Secondary end points included BICR-assessed PFS and OS in all patients; investigator-assessed PFS; objective response rate; and duration of response.

At a minimum follow-up of 68 months, data from the final analysis of JAVELIN Renal 101 demonstrated that patients with PD-L1–positive disease who received the combination (n = 270) achieved a median OS of 43.2 months (95% CI, 36.5-51.7) vs 36.2 months (95% CI, 29.8-44.2) in the sunitinib arm (n = 290; HR, 0.86; 95% CI, 0.701-1.057; 1-sided P = .0755). The 66-month OS rates were 34.2% (95% CI, 28.4%-40.1%) vs 29.9% (95% CI, 24.5%-35.5%), respectively. The median PFS among patients with PD-L1–positive disease in the arms was 13.9 months (95% CI, 11.0-17.8) vs 8.2 months (95% CI, 6.9-9.1), respectively (HR, 0.57; 95% CI, 0.469-0.697; 1-sided P < .0001). The respective 66-month PFS rates were 12.9% (95% CI, 8.9%-17.6%) vs 3.1% (95% CI, 1.3%-6.1%).

In the overall population, the median OS in the combination arm (n = 442) was 44.8 months (95% CI, 39.7-51.1) vs 38.9 months (95% CI, 31.4-45.2) in the sunitinib arm (n = 444; HR, 0.88; 95% CI, 0.749-1.039; 1-sided P = .0669). The median PFS was 13.9 months (95% CI, 11.1-16.6) vs 8.5 months (95% CI, 8.2-9.7), respectively (HR, 0.66; 95% CI, 0.566-0.769; 1-sided P < .0001).

KIM-1 Shows Utility as Prognostic Biomarker in RCC

To conduct their post hoc analysis, Machaalani and coauthors performed a KIM-1 plasma analysis of evaluable patients in the combination (n = 323) and sunitinib (n = 289) arms of JAVELIN Renal 101.1 KIM-1 levels were measured via the Luminex microbead-based assay and a Meso Scale Discovery electrochemiluminescence-based assay. “We measured KIM-1 at baseline before the start of therapy and then 12 weeks later at [day 1] of cycle 3 of systemic therapy,” Machaalani noted.

In the overall post hoc cohort (n = 612), the median age at therapy initiation was 61 years (IQR, 55-67). Most patients were male (74.5%) and had an ECOG performance status of 0 (55.6%). Patients had International mRCC Database Consortium (IMDC) favorable- (22.4%), intermediate- (61.6%), or poor-risk (15.4%) disease; 0.6% were not evaluable for IMDC risk status.

Findings from the post hoc analysis showed that in the overall population, patients with low (< median) baseline KIM-1 levels (n = 306) experienced a significant OS benefit compared with those with high (> median) baseline levels (n = 306; P < .0001). A benefit in favor of patients with low baseline KIM-1 was also observed in terms of PFS (P = .0011).

Moreover, patients in the combination arm with low baseline KIM-1 levels (n = 170) experienced a PFS benefit compared with those with high baseline KIM-1 (n = 153; P = .015). This trend was also observed among patients with low (n = 145) and high (n = 144) baseline KIM-1 levels in the sunitinib arm (P = .013).

“KIM-1 [level] at baseline was prognostic for outcomes; higher KIM-1 levels predicted shorter PFS and OS,” Machaalani said. “Excitingly, [we observed that] the change in KIM-1 from baseline to the third cycle of therapy was also predictive of a better response to therapy. [We found that] patients who had a decrease in KIM-1 from baseline to 12 weeks [also] had a better PFS and OS.”

In the overall population, patients with a decrease in KIM-1 from baseline to day 1 of cycle 3 (n = 444) experienced a significant OS benefit compared with those who experienced a KIM-1 increase during the same time frame (n = 168; P = .00058). A benefit in terms of PFS was also observed over the same period in favor of patients whose KIM-1 levels decreased during treatment (P < .0001).

In the combination arm, patients with a decrease in KIM-1 from baseline to day 1 of cycle 3 (n = 257) experienced a significant PFS benefit compared with those whose KIM-1 levels increased (n = 66; P = .00084). A benefit in favor of those with decreased KIM-1 levels (n = 187) vs those with increased levels (n = 102) was also observed in the sunitinib arm (P = .0064).

“Our [data] support earlier findings from previous studies that have shown that there is value for KIM-1 as a prognostic biomarker in metastatic RCC; [however], before any implementation of KIM-1 in the clinical setting, there needs to be prospective validation of our findings,” Machaalani said. “[Additionally], 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.”

References

1. Machaalani M, Saliby RM, Zhong C, et al. KIM-1 as a circulating biomarker in metastatic RCC: post-hoc analysis of JAVELIN Renal 101. Presented at: OncLive American Society of Clinical Oncology Genitourinary Cancers Symposium Fellows Forum; February 11, 2025; San Francisco, CA.
2. FDA approves avelumab plus axitinib for renal cell carcinoma. FDA. Updated May 15, 2019. Accessed May 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avelumab-plus-axitinib-renal-cell-carcinoma
3. Choueiri TK, Penkov K, Uemura H, et al. Avelumab + axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase III JAVELIN Renal 101 trial. Ann Oncol. 2025;36(4):387-392. doi:10.1016/j.annonc.2024.12.008