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Von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC) has always been difficult to treat. However, a group of researchers led by Dr William G. Kaelin Jr from the Dana-Faber Cancer Institute and Harvard Medical School in America have discovered treatments including immunotherapy, HIF-2α inhibitors, and potentially CDK4/6 inhibitors for the treatment of VHL-associated RCC. He was speaking at the virtual International Kidney Cancer Symposium over the weekend.
However, these treatments do not generate responses in all patients, and may need to be combined with a growth factor inhibitor called MET or other drugs, such as immunotherapy or CDK4/6 to avoid resistance.
“We think HIF-2 is the driver, or oncoprotein, in VHL–associated renal cell carcinoma cells and, if anything, HIF-1 seems to act as a tumour suppressor and is frequently lost in such tumours,” Kaelin said.
In a recent phase 2 study, the efficacy of MK-6482, a HIF-2α inhibitor was assessed in patients with VHL disease with at least one RCC tumour. These patients were untreated and did not have metastases. There were 61 patients in the study, 27.9% of whom responded. 43 patients (70.5%) achieved stable disease with the MK-6482 HIF-2α inhibitor. Additionally, the median duration of response had not yet been reached. Notably, most of the patients on the trial (86.9%) experienced a reduction in the size of their tumours. At 52 weeks, the progression-free survival (PFS) rate was 98.3%.
Most patients (96.7%) experienced an adverse event, mostly mild or moderate (83.6%). Severe adverse events were reported in 9.8% of patients and were primarily fatigue (4.9%) and anaemia (3.3%).
The HIF-2α inhibitor also showed promising activity in patients with heavily pretreated clear cell RCC, with responses of 24% and disease control rates of 80% in the 55 patients. Additionally, the the length of time before the cancer progressed (progression-free survival) was 11.0 months and at 12 months, 49% of patients remained progression free.