Early Intervention and Individualization Are Key to Improving Kidney Cancer Outcomes

Although the incidence of kidney cancer has stabilized after decades of increase with mortality rates on the decline, an emphasis on early intervention and treatment personalization is needed to maintain and build upon these improved outcomes for patients, according to Neil Mendhiratta, MD, MS.¹

“Kidney cancer is one of the most common urologic malignancies that we treat as urologists and as medical oncologists,” Mendhiratta, an assistant professor of urology at the GW School of Medicine & Health Sciences in Washington DC, said in an interview with OncLive®. “[Although] there’s excellent prognosis for [patients with] early-stage disease, there are still patients who require early intervention. It’s important to get the word out there about advances in treatment options and to [ensure] that patients follow up with their providers and understand those options so that they can benefit from early intervention in these situations.”

In honor of Kidney Cancer Awareness Month, which occurs annually in March, OncLive spoke with Mendhiratta and Toni K. Choueiri, MD, to get their perspectives on how new data from clinical trials are affecting the kidney cancer treatment landscape, remaining unmet needs in the space, and how treatment individualization and other strategies could be poised to further improve outcomes for patients in the future.

Choueiri is the director of the Lank Center for Genitourinary Oncology and the medical director for International Strategic Initiatives at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts.

How have recent clinical trial updates affected the treatment landscape of kidney cancer?

Mendhiratta noted that the phase 3 KEYNOTE-564 (NCT03142334) and LITESPARK-022 (NCT05239728) trials are among the most important trials in kidney cancer that have reported data in recent years. KEYNOTE-564 evaluated pembrolizumab (Keytruda) as postnephrectomy adjuvant therapy for patients with renal cell carcinoma (RCC). Data from KEYNOTE-564 supported the November 2021 FDA approval of adjuvant pembrolizumab for the treatment of patients with RCC who are at an intermediate-high or high risk of disease recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.²

At a median follow-up of 69.5 months (range, 60.2-86.9), findings from the 5-year follow-up of KEYNOTE-564 presented during the 2025 ASCO Annual Meeting demonstrated that patients who received adjuvant pembrolizumab (n = 496) achieved a median investigator-assessed disease-free survival (DFS) that was not reached (NR; 95% CI, NR-NR) compared with 68.3 months (95% CI, 51.7-NR) among patients who received placebo (n = 498).³ Treatment with pembrolizumab conferred a DFS HR of 0.71 (95% CI, 0.59-0.86). Additionally, patients in the pembrolizumab arm experienced a reduction in the risk of death of 34% (HR, 0.66; 95% CI, 0.48-0.90) compared with those in the placebo arm.

“[Data from] KEYNOTE-564 showed that the addition of adjuvant pembrolizumab can improve outcomes with respect to not only DFS but also overall survival [OS],” Mendhiratta commented. “[These findings] have certainly been practice changing for many providers.”

Choueiri explained that LITESPARK-022 aimed to build upon the success of adjuvant pembrolizumab that was observed in KEYNOTE-564 by adding the HIF-2α inhibitor belzutifan (Welireg). LITESPARK-022 enrolled patients with clear cell RCC who received no prior systemic therapy and underwent surgery 12 weeks or less prior to random assignment.⁴ Choueiri presented findings from the first interim analysis of LITESPARK-022 during the 2026 Genitourinary Cancers Symposium.

At a median follow-up of 28.4 months (range, 15.0-40.1), results from LITESPARK-022 revealed that patients who were treated with pembrolizumab plus belzutifan (n = 921) experienced a median investigator-assessed DFS that was NR (95% CI, 36.9 months-NR) compared with NR (95% CI, NR-NR) among patients who received pembrolizumab monotherapy (n = 920; HR, 0.72; 95% CI, 0.59-0.87; P = .0003). Interim OS data demonstrated a trend in favor of the investigational arm (HR, 0.78; 95% CI, 0.51-1.19; P = .1220), but these findings did not reach statistical significance at the time of the presentation. Choueiri noted that additional follow-up is needed to further assess this key secondary end point.

“We’re very pleased that this study met its primary end point [of DFS],” Choueiri said. “Many [investigators] will now be looking at biomarkers, because in any adjuvant setting, there is always concern about overtreating some patients. Others will want to see more mature OS data. Another question will be what to use upon progression once this combination becomes available, because it creates a space where there is not yet a clear standard. Overall, it is an exciting time for patients.”

Findings from LITESPARK-022 supported the February 2026 FDA acceptance of supplemental applications for priority review seeking the approval of belzutifan plus pembrolizumab or berahyaluronidase alfa-pmph (Keytruda Qlex) for the adjuvant treatment of adult patients with RCC with a clear cell component at an increased risk of recurrence following nephrectomy.⁵ A Prescription Drug User Fee Act target action date of June 19, 2026, has been set by the FDA for the belzutifan supplemental news drug application and the pembrolizumab and berahyaluronidase alfa supplemental biologics license applications..

“Oncologists should become familiar with belzutifan because it will likely become part of the treatment armamentarium across multiple lines of therapy, including the adjuvant setting,” Choueiri noted.

How are investigators working to develop biomarkers and improve treatment personalization?

Mendhiratta noted that treatment for patients with kidney cancer should no longer follow a one-size-fits-all approach in the localized or advanced settings. “Some of the ways we are trying to individualize treatments strategies [include] identifying patients who are at risk of developing more aggressive RCC vs those who may have more indolent disease. Some of the risk factors [for developing more aggressive disease] can include family history that can indicate a hereditary syndrome. We know that recognition of those hereditary syndromes can make a difference in terms of outcomes for these patients,” he explained.

Investigators are also working to solidify biomarkers that can identify which patients may be suitable candidates for treatment with adjuvant and/or combination approaches, Mendhiratta said. Traditional predictive biomarkers that are often applied in other tumor types such as tumor mutational burden and PD-L1 staining are not currently actionable in RCC.⁶ Although features such as the loss of function of PBRM1, the presence of CA9, and the levels of kidney injury molecule-1 have shown potential utility as biomarkers in limited data sets, these have yet to be fully validated and further investigation is needed.^6,7

“We’re still looking to identify good biomarkers for patients who are going to benefit from, for example, adjuvant treatments or certain IO [immuno-oncology] combinations or IO/TKI [tyrosine kinase inhibitor] combinations,” Mendhiratta said. “That remains one of the challenges in kidney cancer treatment, but certainly [it’s] one we’re looking forward to understanding better so we can more specifically tailor our treatment strategies to each patient.”

Another approach that is being examined for treatment personalization in kidney cancer is the use of cytoreductive nephrectomy. “We’re seeing that the paradigm has shifted from upfront cytoreductive nephrectomy to potentially delayed cytoreductive nephrectomy and [we need to understand] whether that may benefit patients,” Mendhiratta explained.

One such trial that is examining the effect of the addition of cytoreductive nephrectomy to standard-of care (SOC) immunotherapy-based combinations for the treatment of patients with metastatic RCC is the ongoing phase 3 SWOG 1931/PROBE trial (NCT04510597).⁸ The study will randomly assign patients to receive treatment with SOC nivolumab (Opdivo), pembrolizumab plus axitinib (Inlyta), or avelumab (Bavencio) plus axitinib, or continued SOC systemic immunotherapy plus radical or partial nephrectomy within 8 weeks of random assignment. The primary end point of the study is OS; secondary end points include progression-free survival, objective response rate, and the change in the maximum diameter of the primary tumor.

“We’ve seen a major shift over the past decade or so [with] the introduction of immunotherapy agents for [patients with] advanced and metastatic disease, which has really changed the outlook for [patients with] metastatic [disease],” Mendhiratta said. “We’re seeing many patients who have long-term, durable responses, which was rarely seen before. The outlook is very promising, and we are still determining the best sequencing of therapies for these patients. Certainly, it’s an exciting [time in the] field, and I am looking forward to seeing what comes next.”

References

1. Siegel RL, Kratzer TB, Wagle NS, Sung H, Jemal A. Cancer statistics, 2026. CA Cancer J Clin. 2026;76(1):e70043. doi:10.3322/caac.70043
2. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. News release. FDA. November 17, 2021. Accessed March 23, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma
3. Haas NB, Powles T, Tomczak P, et al. Five-year follow-up results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab (pembro) for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2025;43(suppl 16):4514. doi:10.1200/JCO.2025.43.16_suppl.4514
4. Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. J Clin Oncol. 2026;44(suppl 7):LBA418. doi:10.1200/JCO.2026.44.7_suppl.LBA418
5. Keytruda (pembrolizumab) plus Welireg (belzutifan) given as adjuvant therapy reduced the risk of disease recurrence or death by 28% compared to Keytruda monotherapy in certain patients with earlier-stage renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed March 23, 2026. https://www.merck.com/news/keytruda-pembrolizumab-plus-welireg-belzutifan-given-as-adjuvant-therapy-reduced-the-risk-of-disease-recurrence-or-death-by-28-compared-to-keytruda-monotherapy-in-certain-patients-with/
6. Saliby RM, Saad E, Kashima S, Schoenfeld DA, Braun DA. Update on biomarkers in renal cell carcinoma. Am Soc Clin Oncol Educ Book. 2024;44(2):e430734. doi:10.1200/EDBK_430734
7. 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
8. Comparing the outcome of immunotherapy-based drug combination therapy with or without surgery to remove the kidney in metastatic kidney cancer, the PROBE trial (PROBE). ClinicalTrials.gov. Updated September 9, 2025. Accessed March 23, 2026. https://clinicaltrials.gov/study/NCT04510597