Trial Updates Influence Upfront Therapy Selection in Renal Cell Carcinoma

For oncologists navigating the rapidly evolving landscape of renal cell carcinoma (RCC), the data presented at the 2026 ASCO Genitourinary Cancers Symposium offer significant implications for both adjuvant and front-line metastatic treatment decisions. In a recent interview with Targeted Oncology, Deepak Kilari, MD, a medical oncologist and leader of the early phase solid tumor program at the Medical College of Wisconsin, shared his analysis of key trials and how they might shape clinical practice.

A New Standard in the Adjuvant Setting?

One of the most anticipated presentations at the meeting was the analysis of the phase 3 LITESPARK-022 trial (NCT05239728).¹ The trial enrolled patients with intermediate or high risk of recurrence following nephrectomy. Patients with intermediate risk features included those with pT2 grade 4 or sarcomatoid disease, or pT3 any grade with N0 status. High risk was defined as pT4 any grade N0, or any pT with node positive disease.

The trial randomly assigned nearly 1800 patients to receive either the standard of care, pembrolizumab (Keytruda) for 1 year, or the combination of pembrolizumab with belzutifan (Welireg) for the same duration. According to Kilari, the results were striking.

“The disease-free survival was significantly better with the combination,” Kilari said, noting that the benefit was consistent at 12, 24, and 30 months, with the combination showing a roughly 7% to 10% higher disease-free survival rate compared with pembrolizumab alone. The hazard ratio was 0.72 (P = .0003). While median disease-free survival was not reached in either arm, the data already point to a clinically meaningful improvement.¹

Regarding safety, the combination did lead to higher rates of grade 3 or higher adverse events, 52.1% vs 30.2% with monotherapy, driven primarily by expected toxicities such as anemia and fatigue. However, Kilari noted that treatment discontinuation rates were not vastly different, at 10% for the combination and 7% for pembrolizumab alone.¹

Importantly, despite concerns about hypoxia with belzutifan, only 4.6% of patients experienced grade 3 hypoxia, with dose reductions in 3.5% and discontinuation in just 1.6%.¹

“I think the number of patients [who] had to discontinue or reduce belzutifan was a little bit lower than what I expected, which is actually good,” Kilari said. He said that pending overall survival data, “there’s a high probability that this might be the next standard of care.”

Navigating Frontline Therapy Choices by Risk Group

The discussion then turned to the practical challenge of selecting therapy for patients with metastatic disease, particularly those in the favorable risk category by International Metastatic RCC Database Consortium criteria. Kilari acknowledged the long-standing debate, noting that while initial data from the CheckMate 214 trial (NCT02231749) did not show a survival benefit for favorable-risk patients receiving ipilimumab (Yervoy) and nivolumab (Opdivo), longer-term follow up has since revealed a curve flip demonstrating a survival advantage.²

Despite this, his approach is nuanced and patient specific. “If I see someone with good-risk disease, the way I stratify them is I consider their volume of disease,” he explained. For patients with indolent, lung-only or lymph node-only metastases, he tends to favor an immuno-oncology (IO/IO) combination such as ipilimumab and nivolumab, citing the durable survival benefit. However, for a patient with bone metastases or rapidly progressive disease where a swift response is critical, he leans toward an IO/VEGF tyrosine kinase inhibitor (TKI) combination.

“I know that these patients need rapid reduction in their tumor burden,” Kilari said, pointing to the lower rates of primary progressive disease with IO/TKI regimens, which are often less than 10%, compared with upwards of 20% with ipilimumab and nivolumab.

Kilari emphasized that VEGF TKI monotherapy still has a role in select patients. He referenced data from a study (NCT01684397) looking at pazopanib (Votrient) alternating with bevacizumab (Avastin), where the progression-free survival approached 24 months in a predominantly favorable-risk population.³

“I do believe that in patients with good-risk disease, there is a subset of patients that VEGF therapy, monotherapy with VEGF TKIs is probably adequate,” he said, emphasizing the importance of a shared decision-making discussion.

Biomarkers and the Future of Personalization

When asked about the use of molecular markers to guide therapy, Kilari tends to use next-generation sequencing for all his patients with advanced disease and that it has not yet changed his treatment selection. “I do not look at PD -1 status to help stratify my patients,” he stated. He noted that while PBRM1 loss may indicate a more angiogenic signature, and BAP1 mutations are linked to aggressive disease, these haven’t been actionable in the clinic.

He did, however, highlight an ongoing trial that represents a step toward personalization: the BIONIKK trial (NCT02960906) is a phase 2, biomarker-driven study investigating personalized treatment for naïve metastatic clear cell renal cell carcinoma (mccRCC).⁴

This study uses tumor RNA sequencing to classify patients into angiogenic or immunogenic clusters and then randomly assigns them to receive either ipilimumab and nivolumab or a VEGF TKI. “I think that’s probably the farthest we’ve advanced in RCC in terms of looking at biomarkers,” Kilari noted.

Later-Line Data: The LITESPARK-011 Trial

Finally, Kilari pointed to the phase 3 LITESPARK-011 trial (NCT04586231)⁵ as a standout presentation from the 2026 ASCO GU Cancers Symposium for its implications in the second-line setting. This trial enrolled patients with metastatic RCC who had progressed on prior immune checkpoint inhibitors and had not received cabozantinib (Cabometyx), lenvatinib (Lenvima), or belzutifan (Welireg). Patients were randomly assigned to 60 mg cabozantinib or the combination of 20 mg lenvatinib plus 120 mg belzutifan daily.

The study met its primary end point, with progression-free survival of 14.8 months in the combination arm versus 10.7 months with cabozantinib alone, and a hazard ratio of 0.70. The objective response rate was also higher with the combination at 52% vs 40%, including a complete response rate of 5.4% compared with 1.1% with cabozantinib.⁵

Although overall survival data are trending in favor of the combination, they have not yet reached statistical significance. Kilari noted that the toxicity profiles were similar, though he was intrigued by a higher rate of cardiac dysfunction in the combination arm, 7% vs 1.1%, and expressed interest in seeing further granularity on those events. He concluded that while the data are compelling, a key question remains whether the combination is synergistic or simply additive, and whether sequential therapy might achieve the same outcome with less toxicity.

As the field continues to advance, Kilari emphasized the importance of ongoing studies, including trials looking at shorter durations of therapy and triplet combinations, which he hopes will yield results before upcoming major meetings. For now, these data reinforce the need for a tailored, risk-adapted approach to upfront therapy selection in renal cell carcinoma.

REFERENCES

1. 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

2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi:10.1056/NEJMoa1712126. Epub 2018 Mar 21.

3. George S, Vaishampayan U, Hutson A, et al. A phase I/ II trial of pazopanib (Paz) alternating (alt) with bevacizumab (Bev) in treatment-naïve metastatic clear cell renal cell carcinoma (mccRCC) patients (pts): Phase II results. Ann Oncol. 2024;35(suppl 2):S1016-S1017. doi:10.1016/j.annonc.2024.08.1789

4. Vano YA, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial. Lancet Oncol. 2022;23(5):612-624. doi:10.1016/S1470-2045(22)00128-0

5. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti-PD-(L)1 therapy: open-label phase 3 LITESPARK-011 study. J Clin Oncol. 2026;44(suppl 7):417. doi:10.1200/JCO.2026.44.7_supplLBA417