HIF-2α Inhibitor Shows First-Line Promise For VHL-Associated RCC, Related Lesions

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Patients with Von Hippel-Lindau disease (VHL) may benefit from first-line treatment with the hypoxia-inducible factor (HIF)-2α small molecule inhibitor MK-6482 for renal cell carcinoma (RCC) and other lesions, suggest research presented at the ESMO Virtual Congress 2020. 

Ramaprasad Srinivasan, from the National Cancer Institute in Bethesda, Maryland, USA, explained that the oral agent combats the aberrant stabilisation and accumulation of HIF-2α in patients with VHL, and has previously been shown to have favourable safety and activity in patients with advanced RCC. 

The current phase II trial recruited 61 VHL-diagnosed patients with one or more measurable RCC lesions who were free from metastatic disease and had not previously received systemic anticancer therapy.  

The patients were aged a median 41 years and all had VHL-associated pancreatic lesions, 70.5% had central nervous system (CNS) haemangioblastoma and 26.2% had retinal lesions.  

At the time of reporting, 91.8% of patients were continuing treatment with MK-6482 at a dose of 120 mg/day and median follow-up was 68.7 weeks, the investigator said.  

The primary endpoint of RECIST objective response rate (ORR) by independent central review was achieved by 36.1% of the cohort; all responses were partial and a further 62.3% had stable disease, with one patient unevaluable. 

In addition, 91.8% of patients showed a decrease in target lesion size and 11.5% of patients with stable disease had an unconfirmed partial response, commented Ramaprasad Srinivasan. 

Patients responded to MK-6482 after a median 31.1 weeks and the median duration of response has not been reached, he said, noting that 98.3% of patients had achieved progression-free survival at week 52. 

Ramaprasad Srinivasan also reported an ORR by independent central review of 63.9% of 61 patients with pancreatic lesions, including a complete response in 6.6%, with corresponding rates for the 43 patients with CNS haemangioblastoma of 30.2% and 11.6%.  

Among 16 patients with retinal lesions, 68.8% had improved and 25.0% had stable disease, and none had progressive disease (one patient was not evaluated), he added. 

Safety analysis showed that the most common adverse event (AE) at any grade was anaemia (90.2%), followed by fatigue (60.7%), headache (37.7%), dizziness (36.1%), nausea (31.1%), dyspnoea (19.7%), arthralgia (18.0%), upper respiratory tract infection (18.0%), elevated alanine aminotransferase (16.4%) and myalgia (16.4%). 

But just 13.1% of patients experienced grade 3 treatment-related AEs, of anaemia (6.6%), fatigue (4.9%) and dyspnoea (1.6%), and there were no grade 4 or 5 treatment-related AEs. One patient discontinued treatment because of grade 1 dizziness. 

“Anaemia was an expected on-target side effect of this agent and was amenable to medical management”, the presenter remarked. 

“In conclusion, promising clinical activity was observed with MK-6482 in the study of treatment-naïve patients with VHL-associated RCC”, said Ramaprasad Srinivasan. 

He continued: “MK-6482 has a favourable safety profile and has demonstrated durable efficacy in patients with VHL disease-associated renal cell carcinoma, as well as non-renal tumours.” 

Reference 

Srinivasan R, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC): Update on RCC and non-RCC disease. Ann Oncol 2020; 31 (Suppl_4): S1142–S1215. DOI: 10.1016/annonc/annonc325.