As the standard treatment for patients with renal cell carcinoma, the most common type of kidney cancer, related to VHL disease is often surgical procedures, the use of Welireg may reduce surgical burden in patients.
Treatment with Welireg (belzutifan) demonstrated responses in patients with renal cell carcinomas, the most common type of kidney cancer, and non-renal cell carcinoma neoplasms associated with von Hippel-Lindau (VHL) disease, according to findings from a recent trial.
Trial results also demonstrated that responses to Welireg were linked with mild to moderate side effects.
“Until this year, patients with von Hippel-Lindau disease, which is a rare hereditary disorder affecting right around 10,000 people in the U.S., didn’t have any therapeutic treatment options,” said Dr. Eric Jonasch, a professor of medicine in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, in an interview with CURE®.
“Individuals with VHL spend a lifetime undergoing surveillance studies, and when lesions arise — which can occur in their eyes, cerebellum, spinal cord, middle ear, pancreas, adrenal glands, the kidneys, epididymis and round ligaments — … these individuals may need to undergo surgical procedures to prevent either organ damage or the development of metastasis. Having a systemic therapy that can decrease the need for surgical interventions was really very big in the minds of the patients as well as physicians.”
Welireg is a hypoxia-inducible factor 2α (HIF-2α) inhibitor that blocks a particular pathway from inhibiting tumor growth in clear-cell renal cell carcinoma. Researchers assessed the efficacy and safety of this drug in 61 patients (median age, 41 years; 52% men) with renal cell carcinoma or non-renal cell carcinoma neoplasms associated with VHL disease. All patients were treated with 120 mg of Welireg daily. As compared to a randomized-controlled trial, when researchers assign patients a treatment or standard of care, patients in this trial received the same regimen “because (a randomized trial) was not considered to be reasonable or ethical in this patient population,” Jonasch said.
Researchers focused on the objective response to Welireg, defined as a measurable response to the treatment. This included a complete response (the disappearance of all signs of disease) or a partial response (a decrease in tumor size or the extent of disease in the body).
During a median follow-up of 21.8 months, an objective response was observed in 49% of patients with renal cell carcinoma.
“We were hoping to get (objective response) numbers in that range,” Jonasch said. “If you look at the percentage of individuals who had any degree of shrinkage, you see that almost all of the patients — more than 90% of the patients — had some degree of reduction in size, but 49% had a confirmed 30% shrinkage. So it looks like this agent is capable of decreasing the size of these tumors in a fairly consistent manner. … All in all, this 49% objective response rate is impressive.”
Responses to Welireg also occurred in patients with central nervous system hemangioblastomas (30%) and in those with pancreatic lesions (77%). Researchers also assessed 16 eyes in 12 patients with retinal hemangioblastomas at baseline. All patients in this subgroup showed improvement while receiving Welireg.
“I think it's important to mention that we did see a 91% objective response rate in pancreatic neuroendocrine tumors, which is unprecedented,” Jonasch said. “We saw that there was a 30% objective response rate in hemangioblastomas. Once again, this is unprecedented. And amongst those pancreatic neuroendocrine tumors and hemangioblastomas, there were some complete responses as well.”
The most common side effects as a result of Welireg were fatigue (66%) and anemia (90%).
“This drug is relatively well tolerated, which is critical in this patient population, which I would call a well-but-at-risk population,” Jonasch explained. “For a large part, these individuals have excellent performance status and are trying to avoid having the adverse events of undergoing surgery, so you need to have a well-tolerated regimen.”
Throughout the trial, seven patients discontinued treatment. In particular, four patients voluntarily discontinued treatment, one discontinued after disease progression was observed by the investigator, one discontinued for mild dizziness and one patient died from acute toxic effects of fentanyl.
“We now know that by using a targeted HIF-2α inhibitor in individuals with von Hippel-Lindau disease, we are capable of shrinking lesions in the kidney, … pancreatic neuroendocrine tumors, in the central nervous system, hemangioblastomas,” Jonasch explained. “(With) at least a 21.8-month follow up that we have so far in the study, these responses are durable. We've had very few people who have come off-study because of progression, and most people have remained on with continued response.”
Regarding further research, Jonasch added that the data from this phase 2 trial were so strong that there may not be a need for a randomized trial to assess the efficacy and safety of Welireg.
“When it became apparent how strong the data were, the FDA, … the physician and the patient community don't feel that this particular study needs to be turned into a randomized study,” he mentioned. “We have gone beyond the point of saying, we need to do a randomized study to confirm this particular question, which is (whether Welireg is) capable of shrinking VHL-related lesions?”
This doesn’t mean that questions don’t remain about Welireg, Jonasch said. These include how long Welireg will continue to benefit patients and how early should it be given to patients.
“This was a trial that was designed to treat established disease,” he explained. “Can this therapy be used as a prevention strategy, where you treat individuals who have a high probability of developing lesions in the future? In that scenario, you could perform a randomized study, where you randomize between treatment and placebo, testing the hypothesis that this therapy would prevent the development of lesions. I think would be an ethical trial design.”
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