The hypoxia-inducible factor (HIF)-2α inhibitor belzutifan significantly reduced the risk of progression of clear cell renal cell carcinoma in patients previously treated with immune checkpoint inhibitors and antiangiogenic therapies compared with everolimus. The phase III LITESPARK-005 trial, led by Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Cancer at Dana-Farber Cancer Institute, showed the risk of disease progression was reduced by 25% to 26% among patients receiving belzutifan.
The results were presented at the European Society for Medical Oncology (ESMO) Congress 2023 (Abstract LBA88).
Toni K. Choueiri, MD
“This is real progress for patients and could lead to approval of this drug for this patient group,” said Dr. Choueiri.
More on Belzutifan and HIF-2α
Belzutifan is currently approved for patients with von Hippel-Landau disease–associated renal cell carcinoma. The drug was originally investigated and approved for patients with kidney cancer with von Hippel-Landau disease because they have inherited a mutation that inactivates the VHL gene, which results in an overabundance of HIF-2α in cells.
When overabundant in cells, HIF-2α is associated with increased cancer-driving activity, such as cell proliferation, immune evasion, hypoxia, and angiogenesis. William G. Kaelin, Jr, MD, also of Dana-Farber Cancer Institute, was awarded the Nobel Prize in Physiology or Medicine in 2019 for the discovery of the role HIF-2α in cancer and other diseases.
“The knowledge we have about hypoxia and angiogenesis in kidney cancer stemmed from this essential preclinical research at Dana-Farber,” noted Dr. Choueiri. “Bringing this knowledge forward to benefit patients is very gratifying.”
While the mutation that causes von Hippel-Landau disease is inherited, spontaneous mutations that inactivate VHL occur in over 90% of clear cell renal cell carcinoma tumors, suggesting that a HIF-2α inhibitor might also benefit these patients.
LITESPARK-005
LITESPARK-005 enrolled 746 patients with metastatic clear cell renal cell carcinoma whose disease progressed after treatment with both an immune checkpoint inhibitor, such as a PD-1 or PD-L1 inhibitor, and an antiangiogenic therapy. Immune checkpoint inhibitors and antiangiogenic agents have become a standard part of first- and second-line therapies for metastatic clear cell renal cell carcinoma, though most patients eventually experience disease progression and need additional treatment options.
Patients were randomly assigned to receive treatment with either belzutifan or everolimus. At the second interim analysis, after a median of 25.7 months, patients taking belzutifan were 26% less likely to have progressive disease compared with those taking everolimus.
The overall response rate was also higher with belzutifan, at 22% vs 3.5%, and 13 patients experienced a complete response with belzutifan compared to none with everolimus. Patients taking belzutifan were also less likely to discontinue therapy due to side effects.
“Importantly, quality of life favored belzutifan,” said Dr. Choueiri. There was also an improvement in overall survival with belzutifan, though it was not statistically significant.
Further Research
This investigation of monotherapy with belzutifan is part of a broader strategy to learn more about the efficacy and safety of HIF-2α inhibition in renal cell carcinoma. The strategy involves multiple LITESPARK trials examining belzutifan alone and in combination with other therapies in treatment-naive and pretreated patients.
Dr. Choueiri also presented updated findings from the phase II LITESPARK-003 at the ESMO Congress 2023 (Abstract LBA87) that showed belzutifan plus cabozantinib resulted in durable antitumor activity in patients with advanced clear cell renal cell carcinoma, with a safety profile consistent with prior observation previously published in The Lancet Oncology.
Disclosure: Both trials were sponsored by Merck Sharp & Dohme LLC. For full disclosures of the study authors, visit cslide.ctimeetingtech.com/esmo2023.
