HIF-2 Targeting Is Set to Transform Kidney Cancer Management: With Chandler Park, MD; and Katy Beckermann, MD

In this episode of Oncology Unplugged, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, was joined by Katy Beckermann, MD, to discuss kidney cancer highlights from the 2026 Genitourinary Cancers Symposium. Dr Beckermann is director of Genitourinary Cancer Research at Tennessee Oncology in Franklin.

Their conversation focused on the clinical evolution of HIF-2 targeting, specifically the integration of belzutifan (Welireg) into earlier lines of therapy and novel combinations. Drs. Park and Beckerman examined the phase 3 LITESPARK-022 trial (NCT05239728), which evaluated adjuvant pembrolizumab (Keytruda) plus belzutifan in patients with clear cell renal cell carcinoma (ccRCC). Although the disease-free survival curves showed early and sustained separation, the experts noted that overall survival data remain immature and expressed concern regarding the rate of grade 3 adverse effects with the investigational combination, which may lead to overtreatment in the absence of enrichment biomarkers. However, they noted that a particularly strong efficacy signal was highlighted in the sarcomatoid patient population.

In the refractory setting, the phase 3 LITESPARK-011 trial (NCT04586231) comparing lenvatinib (Lenvima) plus belzutifan vs cabozantinib (Cabometyx) in patients with RCC was identified as practice-changing. This investigational combination was shown to increase the median progression-free survival (PFS) and generate durable responses.

The discussion also touched on frontline triplet regimens from the phase 1/2 KEYMAKER-U03 umbrella platform. Early data with pembrolizumab plus lenvatinib and belzutifan showed a median PFS that may influence future first-line clinical practice for patients with ccRCC.

The experts also emphasized proactive management of unique HIF-2 inhibitor–associated toxicities. They explained that anemia, driven by erythropoietin inhibition, is nearly universal and should be managed with aggressive erythropoietin or darbepoetin supplementation once hemoglobin levels drop below 10 g/dL. Furthermore, they recommended home pulse oximetry to monitor for hypoxia and baseline echocardiograms for TKI combinations to screen for reduced ejection fraction and volume overload.

Drs Park and Beckermann concluded by spotlighting the need for familiarity with these new agents to optimize patient outcomes.