Uzzo Elucidates the Potential Role of KIM-1 as a Biomarker in RCC

Following the presentation of exploratory findings from the phase 3 IMmotion010 trial (NCT03024996) at the 2024 ASCO Annual Meeting (ASCO 2024), KIM-1’s utility as a potential biomarker in renal cell carcinoma (RCC) has generated excitement. Robert Uzzo, MD, noted that the most promising role for KIM-1 as a biomarker may be to distinguish patients who will benefit from additional therapies following resection and who are at the highest risk of recurrence.

“There is currently no biomarker that helps us predict recurrence risk 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,” Uzzo said in an interview with OncLive^®. “If we had that biomarker, it would fundamentally change the landscape of diagnosis, prognosis, and risk management. 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.”

Findings from IMmotion010 demonstrated that patients with RCC and KIM-1–high status at baseline (n = 300) experienced a median disease-free survival (DFS) of 35.88 months vs 57.23 months for those with KIM-1–low status at baseline (n = 452; HR, 1.75; 95% CI, 1.40-2.17); 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. Additional data revealed that patients with high baseline KIM-1 serum levels experienced an improvement in DFS when treated with atezolizumab (n = 151) vs placebo (n = 149) as the median DFS was not estimable vs 21.16 months, respectively (HR, 0.72; 95% CI, 0.52-0.99).¹

In the interview, Uzzo detailed data from the IMmotion010 study on KIM-1 and how the biomarker could be used as well as future directions for investigating it in RCC. Uzzo is president and CEO of Fox Chase Cancer Center, executive vice president for Cancer Services at Temple University Health System, senior associate dean of Clinical Cancer Research at the Lewis Katz School of Medicine at Temple University, and the G. Willing “Wing” Pepper Chair in Cancer Research at Fox Chase Cancer Center, Temple Health, in Philadelphia, Pennsylvania.

OncLive: What was the rationale for examining KIM-1 as a biomarker in RCC?

Uzzo: A clear cell cancer is the most common type of kidney cancer [and] papillary kidney cancer is the second most [common] type that also seems to overexpress KIM-1. [Therefore], it might be a useful tool to stratify patients [by their] risk [status]. A couple of [studies] have looked at KIM-1 expression in the plasma before surgery. [After] a patient with a kidney tumor has a blood test taken, a biomarker—perhaps plasma KIM-1 level—[can be examined]. [When] it seems to correlate at a higher level with a high area under the curve, [this shows] a high likelihood that higher levels of KIM-1 may predict the distinction between kidney cancer and a benign mass.

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.

What did the biomarker analysis of the IMmotion010 study presented at ASCO 2024 demonstrate?

[IMmotion010] was one of the biggest adjuvant studies in kidney cancer. [Patients were randomly assigned] to atezolizumab for 1 year vs placebo for 1 year to try to decrease the risk of recurrence. [Eligible patients included those] whose tumor was taken out with intermediate- or high-risk kidney cancer, so that would be grade 4, T2 or worse [disease] including metastatic disease as long as it could be resected. Before the random assignment, the tumor had to be fully resected and removed.

This study [examined] whether giving immediate adjuvant immunotherapy would decrease the risk of recurrence and improve DFS. Unfortunately, it was a negative study—the addition of atezolizumab did not improve DFS. But in this cohort, we had a lot of serum [samples]. We took that serum and at the various expressions of KIM-1 in the plasma to see whether that could be a circulating biomarker to help us identify patients better. We found [that] a high KIM-1 level at baseline was associated with a worse DFS rate in [the overall] cohort.

The higher the level of KIM-1 at baseline [before surgery], the worse those patients tended to do—they recurred more frequently. Additionally, patients with high KIM-1 levels [at baseline] who received atezolizumab tended to do better than if they had low KIM-1 levels. The subgroup of patients who had high KIM-1 levels pre-operation had an approximate 28% improvement in DFS when they received atezolizumab vs placebo.

[Additionally], the level of KIM-1 increased at time of disease recurrence. When the disease starts to recur, that number goes back up. That’s another thing—it might be low and as you start to see KIM-1 going up it might precede the scans—that still requires some investigation. Like most biomarkers, they may be more sensitive than the scans themselves. We’re going to have to start to contend with biomarkers in the future. For example, PSA [levels] might rise, [and] scans may still be negative. There’s going to be this learning phase we’re going to have to go through if we use KIM-1 as a biomarker as to when to intervene in the setting of earlier ability to diagnose the recurrence.

What patient population could KIM-1 serve as a promising potential biomarker for?

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? 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; we would be able to give patients adjuvant immunotherapy who are most likely to benefit from it and would avoid giving it to patients who are less likely to benefit from it.

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. The most important first [question] is, Can we enrich the group of patients who are at the highest risk of recurrence by using this biomarker to improve our current risk stratification tools like nomograms, and therefore have a better idea of who to offer adjuvant therapy to once the tumor is fully resected?

What does future research around KIM-1 need to focus on?

It makes a lot of sense that [KIM-1] should work [as a biomarker] because one of the cardinal or sentinel molecular events in kidney cancer is ischemia. If I were to take a normal kidney and stop the blood flow and clamp the kidney, KIM-1 would be overexpressed because it’s a marker of ischemic injury.

We have all these new mechanisms that we’re understanding that are interconnected about the origins of kidney cancer and how they may [serve as] biomarkers and prognostic markers. Hopefully, they’ll lead to additional therapies for kidney cancer based upon pathways that are druggable, but not completely effective [when drugged]—that is the ischemic pathways involved with kidney cancer.

But for the time being, the first and most promising thing is using KIM-1 as a biomarker to distinguish patients who will benefit from additional therapies following resection and who are at the highest risk of recurrence. Even if you’re not going to give these patients adjuvant therapies, can we tailor our surveillance for these patients to be more specific to their risk of recurrence? This biomarker may be able to help us [do that].

Reference

1. 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