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MADRID -- Treatment with the hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (Welireg) in advanced, heavily pretreated kidney cancer led to superior outcomes when compared with an older kinase inhibitor, a phase III trial demonstrated.

Final progression-free survival (PFS) analysis showed a 26% reduction in disease progression or death with belzutifan versus everolimus (Afinitor), despite an identical median PFS of 5.6 months in both arms (HR 0.74, 95% CI 0.63-0.88). All subgroups derived benefit, and rates of response increased by an absolute 18% with the HIF-2α inhibitor, reported Laurence Albiges, MD, PhD, of Gustave Roussy Institute in Villejuif, France.

Median overall survival (OS) favored belzutifan, at 21.4 months versus 18.1 months with everolimus, but the difference was not significant, according to the late-breaking presentation at the European Society for Medical Oncology (ESMO) congress.

Still, the findings from the so-called LITESPARK-005 study represent the first positive phase III trial involving advanced renal cell carcinoma (RCC) patients who have failed on an immune checkpoint inhibitor and VEGF tyrosine kinase inhibitor (TKI), now standard first-line agents, said Albiges.

She noted that belzutifan was well-tolerated, and that quality of life (QOL) assessments clearly and quickly favored the drug, a first-in-class oral HIF-2α inhibitor that gained FDA approval in 2021 for cancers associated with von Hippel-Lindau (VHL) disease, including VHL-associated RCC.

HIF-2α is a key driver of VHL and clear cell RCC, and inhibition of the protein blocks downstream oncogenic signaling pathways, explained Lisa Pickering, MD, PhD, of the Royal Marsden Hospital in London, who served as ESMO's designated discussant for the study.

"HIF-2α inhibition is a novel and exciting strategy, and belzutifan is the first agent of this class to demonstrate activity in advanced renal cancer," said Pickering. "On the back of this practice-changing data, I hope it will soon be available to patients."

LITESPARK-005 is part of a large clinical program evaluating belzutifan in RCC, and multiple phase III trials are either planned or ongoing, including studies in first-line, second-line, and in the adjuvant setting, noted Albiges.

In the same session at ESMO, findings presented on belzutifan plus cabozantinib (Cabometyx) from cohort 1 of the single-arm LITESPARK-003 study, which involved patients with previously untreated advanced RCC, showed response rates of 70% with the combination, including complete responses in 8% and disease control in 98% (responses plus stable disease). Median investigator-assessed PFS reached 30.3 months, with an OS rate of 86% at 3 years.

These phase II findings prove the concept that belzutifan is combinable with another active agent in RCC, said Pickering.

Phase III LITESPARK-005 Trial

Data analysis for included 746 patients with unresectable locally advanced or metastatic clear cell RCC, who were randomized 1:1 to treatment with either of the oral drugs. Eligibility criteria required that patients had progressed on up to three prior systemic regimens, including treatment with both an anti-PD-1/L1 checkpoint inhibitor and prior anti-VEGF therapy.

Dual primary endpoints were PFS per blinded independent central review (BICR) and OS, and Albiges presented data on the first and second interim analyses. Investigators measured QOL via the Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS) questionnaire and the EORTC QLQ-C30 global health status and QOL scale.

Patients had a median age of 62-63 years, and more than three-fourths were men. About two-thirds of patients had International Metastatic RCC Database Consortium (IMDC) intermediate-risk disease, with 12% considered high risk and roughly 20% favorable risk. Half had received two or three prior TKIs and over 85% had two or three prior lines of therapy.

Belzutifan induced responses in 21.9% of patients (including complete responses in 2.7%), as compared with just 3.5% with everolimus (P<0.0001). However, the HIF-2α inhibitor was associated with higher rates of progressive disease as best response (33.7% vs 21.5%) on BICR.

Data on PFS proved significant, and the drug produced superior PFS rates at 12 and 18 months compared with everolimus:

• 12 months: 34% vs 18%
• 18 months: 23% vs 9%

On OS, Pickering pointed out that the hazard ratio for the two interim analyses remained relatively stable, with an HR of 0.88 (95% CI 0.73-1.07) at the most recent analysis. At 18 months, OS rates were 55% with belzutifan versus 51% with everolimus.

"I thought it might be positive at this point, and therefore, possibly a little disappointing," she said. Final analysis is pending, though most events had been recorded already (441 of 483).

In terms of safety, nearly all study participants in both arms experienced toxicity. Belzutifan was associated with higher rates of anemia (83% any grade) and hypoxia (15%) by virtue of its mechanism of action, noted Pickering. Adverse events (AEs) of any cause led to treatment discontinuation in 6% of patients on belzutifan and 15% of those on everolimus.

In each arm, grade ≥3 treatment-related AEs occurred in 39% and serious treatment-related AEs in 13%. Deaths due to treatment were recorded in one patient on belzutifan and two on everolimus.

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