LITESPARK-005 Trial Reveals PFS Benefit of Belzutifan in Advanced RCC

In addition to meeting the trial’s primary end point, investigators also reported an improvement in the secondary end point of the objective response rate with belzutifan in the phase 3 LITESPARK-005 trial (NCT04195750).

A statistically significant and meaningful improvement in progression-free survival was observed following treatment belzutifan (Welireg) compared with everolimus (Afinitor) in patients with advanced renal cell carcinoma (RCC) whose disease has progressed after a PD-1/PD-L1 inhibitor and VEGF tyrosine kinase inhibitor.¹

These data read out of the phase 3 LITESPARK-005 trial (NCT04195750). In addition to meeting the trial’s primary end point, investigators also reported an improvement in the secondary end point of the objective response rate. Overall survival was investigated as a dual primary end point, but it did not reach significance. Investigators intend to analyze this further in a subsequent analysis. Additional results will be presented at an upcoming meeting.

“This is the first phase 3 trial to show positive results in advanced RCC following these therapies and the first new mechanism to demonstrate potential in advanced RCC in recent years. We look forward to discussing these results with health authorities,” Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories, said in the press release.

A total of 746 patients enrolled on the trial and received either 120 mg of belzutifan orally each day or 10 mg of everolimus orally each day. Belzutifan is a hypoxia-inducible factor-2 alpha inhibitor.

Significant adverse effects (AEs) highlighted in the press release and previously observed in the phase 2 Study 004 (NCT03401788)—which led to belzutifan being approved for cancers associated with von Hippel-Lindau disease such as RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that don’t need immediate surgery—included anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion occurring in 1 patient each.² Of note, 3.3% of patients discontinued treatment due to AEs because of dizziness and opioid overdose.

Investigators also reported that dose interruptions were necessary in 39% of patients because of AEs including fatigue, hemoglobin decrease, anemia, nausea, abdominal pain, and flu-like illness. Moreover, 13% of patients had dose reductions due to AEs, the most frequent being fatigue (7%).

“Patients with advanced RCC face low survival rates, and for those whose cancer progresses following PD-1/PD-L1 and VEGF-TKI therapies, there is a need for new treatment options that can reduce their risk of disease progression or death,” Green concluded.

Patients were eligible for treatment if they had unresectable, locally advanced, or metastatic clear cell RCC, disease progression during or after systemic therapy, and had received no more than 3 prior systemic regimens. Male patients were eligible to enroll if they had abstained from heterosexual intercourse and agreed to use contraception during the intervention period and at least 7 days after the last dose. Female patients were able to enroll if they were not pregnant or breastfeeding.

Patients were excluded from treatment if they had a known malignancy that was progressing or required active treatment within the last 3 years, known central nervous system metastases and/or carcinomatous meningitis, and clinically significant cardiac arrest. Additional exclusion criteria included poorly controlled hypertension, moderate to severe hepatic impairment, and a known psychiatric or substance abuse disorder.

References

1. Merck announces WELIREG® (belzutifan) phase 3 LITESPARK-005 trial met primary endpoint of progression-free survival in certain previously treated patients with advanced renal cell carcinoma. News release. Merck. August 18, 2023. Accessed August 18, 2023. https://bit.ly/3KNgb0Z
2. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. August 13, 2021. Accessed August 18, 2023. https://bit.ly/37DMnzV