The Noninvasive Biomarker KIM-1 Is Front and Center in RCC Investigations

Brian Rini, MD, and

Robert Uzzo, MD, MBA, FACS

The transmembrane glycoprotein KIM-1, expressed by injured renal proximal tubular cells and renal cell carcinoma (RCC) cells, has emerged as a potential biomarker and all eyes are on next steps for the marker following encouraging exploratory analysis data presented at the 2024 American Society of Clinical Oncology Annual Meeting.¹ 

Exploratory findings came from the phase 3 IMmotion010 trial (NCT03024996), which in its primary analysis failed to show prolonged disease-free survival (DFS) with adjuvant atezolizumab (Tecentriq) vs placebo in patients with RCC who had an increased risk of disease recurrence.

Data from the retrospective, exploratory analysis of the trial demonstrated that high postnephrectomy KIM-1 serum levels were associated with worse DFS overall. The findings, although exploratory, provided a welcome signal in a disease in which response biomarkers have been lacking. Results showed that patients with KIM-1–high status at baseline (n = 300) experienced a median DFS of 35.88 months compared with 57.23 months among those with KIM-1–low status at baseline (n = 452; HR, 1.75; 95% CI, 1.40-2.17).² A baseline KIM-1 level of 86 pg/mL was identified by investigators as the optimized threshold for determining KIM-1–high vs KIM-1–low subgroups.

“Now that there are approved adjuvant therapies [in high-risk RCC]—pembrolizumab [Keytruda] is approved—the question is, ‘Can [KIM-1] be added to current risk stratification tools and nomograms to improve or enrich the group of patients who are at highest risk of recurrence?’” Robert Uzzo, MD, MBA, FACS, said in an interview with OncologyLive. “Right now, we offer adjuvant pembrolizumab to patients with a clinical high risk of recurrence, but we realize that not all patients are going to benefit from it. If we could take our current risk stratification models and nomograms and add KIM-1 to [them to determine] the group of patients who would benefit the most, that would be a big win.”

In IMmotion010, patients with high baseline KIM-1 serum levels experienced an improvement in DFS when treated with atezolizumab (n = 151) vs placebo (n = 149). The median DFS was not estimable (NE) for patients with high baseline KIM-1 serum levels treated with atezolizumab compared with 21.16 months for those given placebo (HR, 0.72; 95% CI, 0.52-0.99). In the KIM-1–low subgroup, the median DFS was 57.23 months for those treated with atezolizumab (n = 229) and was NE for those given placebo (n = 223; HR, 1.12; 95% CI, 0.88-1.63) (Table).²

DFS in Exploratory Analysis of IMmotion010

“There’s [also] still not uniform consensus on who the patients are [with RCC who are] most suitable for adjuvant therapy. Despite the DFS and overall survival [OS] benefit with pembrolizumab, there’s still some debate in the field, and different doctors who know a lot about this, do things differently, which tells you it’s not uniform,” Brian Rini, MD, said in an interview with OncologyLive. “What if you have a patient who’s technically high risk, but only has a 30% risk of recurrence, [and] you’re exposing them to potential lifelong or life-threatening toxicities [with adjuvant therapy]?”

Rini added that he tends “to give adjuvant pembrolizumab [to patients at] the higher end of the phase 3 KEYNOTE-564 [NCT03142334] risk [criteria], but other doctors give it to everybody, and other doctors don’t give it to anybody. If this could at least help refine that, remove some of those lower-risk patients or include them appropriately, much like [with] circulating tumor DNA, the treating physician would feel a lot better about exposing that patient to the risk [of adverse effects].”

Further Examining Data From IMmotion010

Patients in the KIM-1–high subgroup were less likely to experience an on-treatment increase in KIM-1 levels with atezolizumab (9%) vs placebo (15%; P < .0001), according to findings from IMmotion010. In the KIM-1–low subgroup, rates of increased KIM-1 levels were 16% vs 14%, respectively (P = .57). Investigators noted that an on-treatment increase in KIM-1 level was associated with worse median DFS in patients in both the KIM-1–high and KIM-1–low subgroups.²

“It would be great to see data in that [adjuvant] setting [and] to understand whether it can be complementary to our risk stratification models. To estimate risk of recurrence for an individual patient, you look at T stage and N stage, grade, and perhaps necrosis,” Rini said. “But those models are 2 to 3 decades old, and they’re not very good. You can put the same patient data into 3 different models and get 3 very different estimates of recurrence, which tells you none of them are very good [or] accurate.”

Additionally, patients with KIM-1–high disease who had an increase in KIM-1 level on-treatment with atezolizumab (n = 12) experienced a median DFS of 14.8 months, whereas median DFS was NE for those with no increase on atezolizumab (n = 126; HR, 1.68; 95% CI, 0.77-3.69). In the placebo arm, these figures were 4.8 months (n = 36) vs 45.4 months (n = 105) in patients with and without on-treatment increases in KIM-1 (HR, 3.53; 95% CI, 2.24-5.58), respectively. Patients treated with atezolizumab with KIM-1–low disease who experienced an increase in KIM-1 level on-treatment (n = 34) experienced a median DFS of 11.5 months vs survival length that was NE among those with no increase (n = 179; HR, 3.56; 95% CI, 2.21-5.75). These figures were 29.0 months in 28 patients and NE in 179 patients who received placebo (HR, 2.51; 95% CI, 1.42-4.44), respectively.²

Comparison of serum levels from the trial also showed that KIM-1 was the most significantly enriched circulating protein in recurrence vs baseline serum samples.

Could KIM-1 Distinguish Benign From Malignant Tumors?

“KIM-1 levels are currently being explored as a biomarker to identify kidney tumors and distinguish cancerous lesions from benign ones. That’s something you can’t currently do with a plasma test, urine test, or any imaging including PET scans. It’s only done on biopsy. If these findings hold up to be true, then this biomarker may very well change the way we make diagnoses of kidney cancer,” Uzzo said. “As a derivative to that, this could this be used for preoperative diagnosis of any large kidney mass prior to making treatment decisions, and if the test is robust enough it could even be used for smaller renal masses to help clarify current treatment dilemmas.”

Prenephrectomy plasma KIM-1 was associated with malignant pathology, worse metastasis-free survival, and risk of death in patients with renal masses, according to data from the prospective K2 trial and an academic biorepository published in a Journal of Clinical Oncology study. Data from K2 making up cohort 1 of the study showed that plasma KIM-1 distinguished RCC vs benign masses with area under the receiver operating curve (AUC-ROC, 0.81; 95% CI, 0.76-0.86). Findings from cohort 2 including data from the academic biorepository revealed that plasma KIM-1 distinguished RCC vs benign masses in patients with clinical T1a RCC (AUC-ROC, 0.74; 95% CI, 0.67-0.80).³

Further, a plasma KIM-1 cut point identified using data from cohort 2 showed a sensitivity of 92.5% and specificity of 60% for identifying RCC in cohort 1. Long-term follow-up data from cohort 1 revealed that higher prenephrectomy plasma KIM-1 was also associated with worse OS (multivariable HR, 1.31 per unit increase in log plasma KIM-1; 95% CI, 1.10-1.54).

Further Findings With KIM-1 in RCC

“The most relevant and recent [data on KIM-1] are from 3 prospective studies—the adjuvant phase 3 ASSURE [NCT00326898] study with sorafenib [Nexavar] and sunitinib [Sutent] vs placebo, the phase 3 CheckMate 914 [NCT03138512] trial with ipilimumab [Yervoy]/nivolumab [Opdivo] or nivolumab vs placebo, and more recently IMmotion010 with atezolizumab vs placebo,” Rini said. “Each of those looked at KIM-1, which is a soluble protein at baseline, a couple of postnephrectomy time points, and recurrence roughly—not all the studies did it exactly the same way.”

In ASSURE, findings demonstrated that elevated plasma KIM-1 levels postnephrectomy were associated with worse DFS and OS in patients with resected high-risk RCC. Investigators noted that a Kaplan-Meier analysis revealed a trend toward worse OS for patients who had higher baseline KIM-1 levels (log-rank P = .056).¹

Findings from an exploratory post hoc analysis of CheckMate 914 published in Cancer Research in March 2024 were in line with those of IMmotion010: When examining patients in the highest quartile of pretreatment KIM-1 level, DFS was improved with the combination vs placebo (HR, 0.60). However, unlike in IMmotion010 where an increase in KIM-1 levels on treatment was positively associated with higher DFS only in the investigational arm, an increase in KIM-1 levels in CheckMate 914 was associated with higher DFS rates in both the nivolumab plus ipilimumab and placebo arms.⁴

However, IMmotion010 investigators noted that additional validation studies of the minimally invasive circulating biomarker are needed to confirm its utility for identifying minimal residual disease, predicting outcomes to checkpoint inhibitor therapy, and longitudinal monitoring of disease recurrence.¹

“There is currently no biomarker that helps us predict recurrence risks in kidney cancer, and there is no biomarker that can currently help us diagnose kidney cancer in a noninvasive way. The only way to do that is with biopsy or resection with their attendant risks. If we had that biomarker, it would fundamentally change the landscape of diagnosis, prognosis, and risk management,” Uzzo said. “KIM-1, where there have been very early studies in the past several years, is now coming to the fore as potentially the most promising biomarker in kidney cancer.”

References

1. Xu W, Puligandla M, Halbert B, et al. Plasma KIM-1 is associated with recurrence risk after nephrectomy for localized renal cell carcinoma: a trial of the ECOG-ACRIN Research Group (E2805). Clin Cancer Res. 2021;27(12):3397-3403. doi:10.1158/1078-0432.CCR-21-0025
2. Albiges L, Bex A, Suárez C, et al. Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: a randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection.J Clin Oncol. 2024;42(suppl 16):4506. doi:10.1200/JCO.2024.42.16_suppl.4506
3. Xu W, Gaborieau V, Niman SM, et al. Plasma kidney injury molecule-1 for preoperative prediction of renal cell carcinoma versus benign renal masses, and association with clinical outcomes. J Clin Oncol. Published online May 3, 2024. doi:10.1200/JCO.23.00699
4. Vemula SV, Xu W, Wang Y, et al. High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma. Cancer Res. 2024;84(suppl 6):5151. doi:10.1158/1538-7445.AM2024-5151