Belzutifan a ray of hope for VHL-associated renal cancer?

In a phase II study, the novel oral HIF*-2α inhibitor belzutifan showed promise for individuals with renal cell carcinoma (RCC) associated with von Hippel-Lindau (VHL) disease, a rare autosomal dominant hereditary disease associated with benign and malignant neoplasms, including clear-cell RCC, pancreatic neuroendocrine tumours, and CNS** and retinal hemangioblastomas.

“Since patients with VHL disease have a lifelong risk of tumours in affected organs, most patients undergo several surgical procedures during their lives, with considerable attendant complications,” said the researchers. “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.”

Belzutifan, a second-generation small-molecule HIF-2α inhibitor that offers better pharmacologic properties than the first-generation compound, has shown benefit for patients with advanced clear-cell RCC. [Nat Med 2021;27:802-805; Clin Cancer Res 2020;26:793-803]

Sixty-one participants (median age 41 years, 52 percent male) were on daily belzutifan 120 mg until the occurrence of disease progression or unacceptable adverse events (AEs). All patients had localized RCC and pancreatic lesions (22 with pancreatic neuroendocrine tumours), 50 had CNS hemangioblastomas, while 12 had evaluable retinal hemangioblastomas at baseline. [N Engl J Med 2021;385:2036-2046]

After a median follow-up of 21.8 months, 49 percent of participants had a confirmed objective response***. “[M]ost patients had a reduction in renal tumour size. These indicate that belzutifan has activity against RCC associated with VHL disease,” said the researchers.

Two patients had disease progression as per review committee. “[However,] a mechanism of possible resistance to belzutifan is unknown,” the researchers noted. Evidence shows that resistance may have sprung from prolonged HIF-2α inhibitor use, or HIF-2α G323E gatekeeper mutation preventing HIF-2 dissociation. [Nature 2016;539:112-117; Clin Cancer Res 2020;26:793-803]

Almost all (n=20) patients with pancreatic neuroendocrine tumours had a confirmed response. Reponses were also seen in 30 percent of participants with CNS hemangioblastomas. All 16 evaluable eyes among those with retinal hemangioblastomas were graded as improved. “[These] indicate clear signs of activity in VHL disease-associated neoplasms,” the researchers noted.

AEs were mostly low-grade, with anaemia being the most common (90 percent). “[The drop in haemoglobin levels] was consistent with expectations for a HIF-2α inhibitor given the integral role of HIF-2α in erythropoietin production and erythropoiesis,” they explained. “[Also,] the number of patients who received transfusion or growth factor support was low. Haemoglobin levels also stabilized typically without intervention after an initial decrease in levels.”

“HIF-2α inhibition may offer a more favourable safety profile than antiangiogenic agents,” the researchers added, given the treatment-related AEs reported with other agents (ie, TKIs^#, pazopanib). [Oncotarget 2018;9:23390-23395; Oncotarget 2016;7:85306-85317; Lancet Oncol 2018;19:1351-1359] In the pazopanib study, only a third were able to receive the full dose without unacceptable AEs. In the current trial, despite treatment interruptions in 26 patients, only seven discontinued treatment while nine had dose reductions owing to AEs.

“[Our findings] suggest that belzutifan might serve as an alternative treatment or a complement to surgical treatment in these patients. Therefore, belzutifan might play an integral role in the treatment of patients with VHL disease by delaying or obviating the need for serial surgeries that are associated with substantial complications,” said the researchers.

A major step in oncology

Belzutifan may also reduce the risk of loss of organ function, as well as death from metastatic RCC or CNS hemangioblastomas, added Dr Manuela Schmidinger from the Medical University of Vienna, Austria, in an editorial. “[B]locking HIF-2α at the most proximal point in the pathway may represent another major step in oncology beyond the treatment of VHL-associated tumours, since HIF-2α, the target of belzutifan, controls multiple genes involved in cancer progression.” [N Engl J Med 2021;385:2090-2091]

“[The current data also] stand out for the major differences shown (ie, less serious AEs, greater treatment adherence) … Treatment adherence appears particularly important in the context of a chronic disease, in which young patients may need lifelong, regular medical intervention,” she added.