For patients with von Hippel-Lindau disease (VHL), the discovery of a drug that could limit the incidence of tumor growth is life-changing. The disease, a rare autosomal dominant hereditary disorder occurring in approximately one in every 27,300 to 39,000 live births, is associated with benign and malignant neoplasms, including clear cell renal cell carcinoma, pancreatic neuroendocrine tumors, and hemangioblastomas in the central nervous system and retina. Approximately 70 percent of patients with VHL disease develop renal cell carcinomas in their lifetime.
A recently published study offers a ray of hope for these patients. For those treated with belzutifan, the percentage of patients with renal cell carcinoma who had an objective response was 49 percent after a median follow-up of 21.8 months. Additional positive results, to the delight of researchers, hold a promising future for treatment of the disease.
Groundbreaking Study
When the study began, researchers had one clear goal: help patients who have suffered for so long.
"I've been treating individuals with VHL for 20 years and, in that time, I've always looked for ways to improve the outcomes of the patient population," noted Eric Jonasch, MD, Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center and lead study researcher. "These individuals have a tendency to develop tumors across organ systems and the treatments up to this point are interventional, requiring dozens of surgeries in their lifetimes. We knew that finding a therapy that could shrink the tumors and decrease the number of interventions in their lifetimes would be life-changing."
As mentioned by Jonasch, neoplasms associated with VHL disease are currently managed with surgical resection or ablation with the goal of reducing the risk of metastatic disease and controlling local or systemic sequelae. Most patients undergo many surgical procedures over the course of their lives, often with considerable complications.
In current practice, clinical judgment informs the risk-benefit assessment for surgery, but surgical intervention is typically recommended to decrease the risk of metastatic disease in the case of renal tumors that grow beyond a 3 cm diameter threshold and for those that grow rapidly, according to the study. Systemic therapy, such as that evidenced in the belzutifan study, could provide similar benefits for patients with renal tumors and other neoplasms associated with VHL disease.
The Phase II, open-label, single-group trial investigated the safety and efficacy of the HIF-2[alpha] inhibitor belzutifan administered orally at a dose of 120 mg daily in patients 18 years of age or older with renal cell carcinoma-associated VHL disease and at least one measurable tumor. A total of 61 patients with a median age of 41 were enrolled in the U.S., Denmark, France, and the United Kingdom. A total of 59 patients had undergone at least one previous tumor reduction procedure, such as a partial nephrectomy, craniotomy, or cryoablation; 46 patients with renal tumors had undergone tumor reduction procedures, including 40 patients who had undergone a partial or radical nephrectomy; and at baseline, patients had a median of 2.0 renal cell carcinoma target tumors, 1.0 pancreatic target lesions, and 1.5 central nervous system hemangioblastomas. At baseline, all 61 patients had localized renal cell carcinoma and pancreatic lesions, 50 patients had central nervous system hemangioblastomas, and 12 patients had retinal hemangioblastomas.
Per the study, imaging of renal tumors with CT or MRI was performed at baseline and every 12 weeks thereafter. Assessments of target tumors in VHL-disease associated renal cell carcinoma were obtained and evaluated by independent central radiology reviewers two or more times before screening imaging was performed to estimate growth kinetics before treatment, when available. For those patients in the trial with non-renal cell carcinoma neoplasms, radiologic imaging and ophthalmic evaluations were performed at baseline and during the trial treatment period. A maximum of five target lesions and five nontarget lesions identified for assessment in each affected organ system were also assessed.
Trial Results
"A great and very welcomed surprise of the trial was that we saw very robust shrinkage in the patients' pancreatic and central nervous system lesions," Jonasch said. "We found that treatment with belzutifan not only benefited individuals with renal cell carcinoma, but also other lesions."
A total of 30 patients had confirmed partial responses, for an objective response in renal cell carcinoma of 49 percent. An additional 30 patients had a best response of stable disease, a reduction in the sum of all target lesion diameters was observed in 56 patients, and patients who had growing tumors before treatment saw a reduction in the sum of the largest tumor diameters after treatment began. At 24 months, the percentage of patients with progression-free survival was 96 percent.
In terms of tumor growth, treatment with belzutifan resulted in a median linear growth rate of -3.7 mm per year, compared to 3.6 mm per year prior to treatment. Among patients with a partial response, the median linear growth rate was 4.1 mm per year before treatment, compared with -5.6 mm per year during the on-treatment period. Among those patients with stable disease, the median linear growth rate was 3.4 mm per year before treatment and -1.6 mm per year during treatment.
All 61 patients enrolled in the trial had pancreatic lesions, and a confirmed response was observed in 47 individuals, including six patients who had a complete response. Among 22 patients with pancreatic neuroendocrine tumors, 20 patients had a confirmed response, including three patients who had a complete response. For those patients with central nervous system hemangioblastomas, 15 of 50 patients had a confirmed response, including three who had a complete response, according to the study.
"When we started this study, we worked very hard to collect information on other organ sites in the hopes that maybe we could broaden the label, and the data we collected was very compelling," Jonasch said. "It really was an incredible moment to see the data and receive approval. By far, these were the best results we could have hoped for from an efficacy perspective in regards to tumor shrinkage."
In terms of next steps, Jonasch hopes that the use of this therapy will decrease the number of interventional procedures patients living with VHL will have to endure.
"Before treatment, the 61 patients involved in this trial were averaging 20 procedures per year. After initiating treatment, the net number of procedures per individual was reduced to three across all patients," he said. "This journey of discovery from a compound that was turned into a drug, investigated, and used as a very effective therapy shows the importance of supporting science-based development. For communities who have rare diseases, working together can help support this type of research and advocate for patients. We must work together for the common cause."
Kelly Wolfgang is a contributing writer.
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