Belzutifan (MK-6482), a novel oral agent that targets germline pathogenic variants in the von Hippel-Lindau (VHL) gene that gives rise to VHL disease, demonstrated robust clinical activity and a very mild adverse event (AE) profile in VHL patients with renal cell carcinoma, a phase II, open-label, single-group study indicated.
Belzutifan specifically targets hypoxia-inducible factor 2α (HIF-2α), a transcription factor that drives the progression of clear-cell renal cell carcinoma.
In a group of 61 VHL patients with renal cell carcinoma, almost half (49%, 95% CI, 36-62%) achieved an objective response to treatment, Eric Jonasch, MD, University of Texas M.D. Anderson Cancer Center, Houston, and colleagues reported in The New England Journal of Medicine.
Another 49% had a best response of stable disease and only 3% of patients experienced disease progression while receiving therapy.
All 61 patients in the study also had pancreatic lesions and a confirmed response was also observed in over three-quarters of them, with 10% of patients achieving a complete response (CR), investigators added.
Approximately one-third of patients had pancreatic neuroendocrine tumors and in this group of patients, 91% achieved a confirmed response to belzutifan.
Additionally, the majority of patients also had central nervous system hemangioblastomas and here again, 30% had a confirmed response to treatment, including 6% who also achieved a CR.
Adverse events were generally grade 1 or 2, the most common of which were anemia, fatigue, headache, and dizziness.
“As observed in the current trial, patients often underwent multiple surgical or ablative procedures before treatment with belzutifan,” Jonasch and colleagues explained.
“After treatment initiation, only three patients underwent an intervention directed at a neoplasm associated with VHL disease [so]… data from the current trial suggest that belzutifan might serve as an alternative treatment or a complement to surgical treatment in these patients,” the authors suggested.
Patients received belzutifan, given orally at a dose of 120 mg once a day administered in three 40 mg tablets, which was continued beyond study endpoint baring AEs or disease progression.
The median age of the cohort was 41 years (range, 19-66 years), approximately half of participants were men and almost all patients (97%) had undergone at least one previous tumor reduction procedure.
At baseline, patients had a median of 2 (range, 1-5) renal cell carcinoma target tumors; 1 (range 1-3) pancreatic target lesions, and 1.5 (range, 1-5) central nervous system target hemangioblastomas, as investigators pointed out.
At a median follow-up of 21.8 months (range 20.2-30.1 months), almost all patients at 89% continued to receive treatment with belzutifan.
“A reduction in the sum of all target lesion diameters was observed in 56 patients (92%),” the authors reported.
In fact, before treatment, tumors were growing with a median linear growth rate of 3.6 mm per year (range, −3.1 to 18.6 mm) in most patients. This compared with a median linear growth rate of −3.7 mm (range, −9.5 to 10.1 mm) during the on-treatment period, researchers noted.
However, median linear growth rates varied depending on whether patients achieved a partial response (PR) or had stable disease in response to treatment.
Among those with a PR, the median linear growth rate was 4.1 mm per year (−3.1 to 18.6) prior to initiation of belzutifan compared to −5.6 mm per year (range, −9.5 to −1.3 mm) during the treatment internal.
Among patients with stable disease, the median linear growth rate was 3.4 mm per year (range, −0.5 to 8.9 mm) before treatment compared to −1.6 mm per year (range, −7.2 to 10.1 mm) per year during the on-treatment period.
The median time to response was 8.2 months (range, 2.7-19.1 months) and at 24 months, 96% (95% CI, 87-00%) of patients were still alive and free of disease progression, as investigators also noted.
Treatment was interrupted in 43% of patients due to AEs while the dose was reduced in 15% for the same reason.
However, only seven patients out of the original cohort of 61 patients discontinued treatment after a median duration of 8.1 months (range, 1.9-19.3 months).
“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 sequel,” the authors observed.
“An effective systemic alternative might reduce the surgical burden in patients with VHL disease and represents a new approach to the management of VHL-disease-associated neoplasms that are confined to organs,” they suggested.
Commenting on the findings, Manuela Schmidinger, MD, Medical University of Vienna, Vienna, Austria. noted that extrarenal manifestations of VHL typically occur earlier than renal cell carcinoma and are associated with substantial morbidity and mortality.
“[T]he therapeutic inhibition of HIF-2α may represent a major advance in the overall management of VHL disease, which represents an enormous burden [to patients] even before the occurrence of clear-cell renal cell carcinoma,” as she points out.
Indeed, extrarenal manifestations of the disease occur early at a mean age of onset of only 26 years and when these tumors and cysts reach a critical volume, “they cause severe neurologic symptoms, blindness or death if not treated appropriately,” Schmidinger observed.
Because current treatment options are limited to surgery, radiation therapy or microwave ablation, VHL patients often undergo multiple procedures over many years which in and of themselves can cause a number of disabilities related mostly to damage caused by these interventions to the central nervous system.
“Considering both the efficacy of the treatment in all VHL-associated tumors and the acceptable adverse-event profile of this HIF-2α inhibitor, early and possibly even intermittent use of belzutifan may spare patients with VHL disease multiple surgeries, decrease their risk of loss of organ function (such as renal failure and blindness) and reduce their risk of death from metastatic renal cell carcinoma or CNS hemangioblastomas,” Schmidinger suggested.
Belzutifan, a novel oral agent that targets germline pathogenic variants in the von Hippel-Lindau (VHL) gene that gives rise to VHL disease, had robust clinical activity and was well tolerated in VHL patients with renal cell carcinoma.
This novel oral agent might represent an alternative to surgery or a complement to it by dramatically reducing the need for multiple surgical or ablative procedures in VHL patients who harbor a variety of neoplasms.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded by Merck Sharp & Dohme.
Jonasch reported consulting for Aravive, Aveo, Calithera, Eisai, Exelixis Inc., Ipsen Biopharmaceuticals Inc., Merck, NiKang, Novartis Pharma, and Pfizer.
Schmidinger reported consulting for Bristol-Myers Squibb, Eisai Inc., EUSA Pharma (US) LLC, Merck, Merck Sharp & Dohme, and Pfizer Pharma GMBH, and serving on advisory boards for Ipsen Biopharmaceuticals Inc.
Cat ID: 127
Topic ID: 81,127,730,120,935,127,192,925