Belzotevan significantly reduced the risk of developing clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, in patients previously treated with immune checkpoint inhibitors and antiangiogenic therapies, compared with everolimus.
The phase III clinical trial, led by Tony K. Choueiri, of the Dana-Farber Cancer Institute, said that the risk of developing the disease was reduced by 25 to 26%. The findings were presented at the European Society for Medical Oncology (ESMO) Annual Congress on October 21, 2023, in Madrid, Spain.
“This is a real advance for patients and could lead to the approval of this drug for this group of patients,” said Tony Choueiri, who gave the presentation at ESMO in Madrid.
Action of the drug
Belzotevan, an HIF-2α inhibitor, is currently approved for patients with von Hippel-Landau (VHL)-associated renal cell carcinoma, a form of kidney cancer. The drug was originally approved for kidney cancer patients with VHL disease because patients inherit a mutation that inactivates the VHL gene, leading to an excess abundance of HIF-2α in the cells.
The abundance of HIF-2α in cells is associated with increased carcinogenic activity such as cell proliferation, immune evasion, decreased oxygen levels (called hypoxia) and formation of blood vessels (called angiogenesis). William J. got Kaelin Jr., of Dana-Farber Cancer Institute, received the 2019 Nobel Prize in Physiology or Medicine for his discovery of the role of HIF-2α in cancer and other diseases.
Tony K said: Choueiri: “The knowledge we have about hypoxia and angiogenesis in kidney cancer resulted from this basic preclinical research at Dana-Farber.” “Advancing this knowledge for the benefit of patients is very rewarding.”
Although the mutation that causes VHL disease is inherited, spontaneous mutations that inactivate VHL activity also occur in more than 90% of ccRCC tumors, suggesting that an HIF-2α inhibitor may also benefit patients with ccRCC.
Clinical trial
The trial, called LITESPARK-005, enrolled 746 patients with metastatic ccRCC who progressed after treatment with an immune checkpoint inhibitor (ICI), such as a PD-1 or PD-L1 inhibitor, and antiangiogenic therapy. ICIs and antiangiogenic drugs have become part of the standard first- and second-line treatment for metastatic ccRCC, although the majority of patients eventually experience disease progression and require additional treatment options.
Results in the second interim analysis, after a median of 25.7 months, showed that patients who took belizotevan were 26% less likely to progress compared to those who took everolimus.
Clinical results
The overall response rate was also higher with belizotevan, 22% versus 3.5%, and 13 patients had a complete response with belizotevan compared with none with everolimus. Patients taking belzotevan were also less likely to stop treatment due to side effects.
There was an improvement in overall survival with belzutivan, although it was not statistically significant, but “it is important to highlight that quality of life was in favor of belzutivan,” said Tony K. Choueiri.
For the researchers, this investigation into plazotiphan monotherapy is part of a broader strategy to learn more about the efficacy and safety of HIF-2α inhibition in RCC. The strategy includes multiple LITESPARK trials examining belozotevan alone and in combination with other therapies in disease-naïve and pretreatment settings.
Tony K. also presented Choueiri updated phase 2 results of LITESPARK-003 at the ESMO conference showing that belzotevan plus cabozantinib have robust antitumor activity and a safety profile consistent with previous observations published in the journal “Lancet Oncology“.
“Wannabe internet buff. Future teen idol. Hardcore zombie guru. Gamer. Avid creator. Entrepreneur. Bacon ninja.”