Introduction:

Patients with von Hippel-Lindau (VHL) disease have an increased risk for developing clear cell renal cell carcinoma (ccRCC) as well as other benign and malignant tumors in multiple organs. Current treatment of VHL associated ccRCC is based on a program of surveillance and surgical intervention to minimize the risk of metastasis, as no systemic therapies are currently approved for use in the localized setting. PT2385 is a first-in-class small molecule inhibitor of HIF-2α which has shown efficacy in advanced sporadic ccRCC. Specifically, HIF-2α is believed to be the primary mediator of oncogenesis in renal tumors with VHL alterations. Here we report on the safety and efficacy of oral PT2385 in VHL patients with localized ccRCC.

Methods:

Eligible patients were required to have at least 1 measurable VHL associated ccRCC tumor confined to the kidney and no solid ccRCC tumor greater than 3.0 cm. PT2385 was administered orally at a dose of 800 mg twice daily. The primary endpoint of the study was overall response rate (ORR) in renal tumors, based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). Secondary and exploratory endpoints included evaluation of the safety profile, pharmacokinetic data, response in VHL-associated non renal tumors, and modulation of erythropoietin (EPO). The study was halted after enrolment of four patients owing to the inconsistent pharmacokinetic characteristics of the drug, in favor of a second-generation HIF-2α inhibitor with more reliable pharmacologic properties.

Results:

Four patients were enrolled on study with median follow-up of 19 weeks (range 13-143). All patients had stable disease (SD) as their best response at latest assessment, including 1 patient who has remained on study for 2.7 years. Median growth rate of individual tumors on therapy was -1 mm/yr (range -3-4), compared to a median of 3(1-7) prior to therapy, and 3(2-7) after termination of therapy. VHL manifestations in other organ systems (hemangioblastoma, pancreatic neuroendocrine tumor) remained stable or improved. 2/3 patients with ocular manifestations had improvement in retinal hemangioblastomas and one had SD as the best response. 3/3 patients with spine hemangioblastomas had SD. 1 patient with 2 pancreatic solid lesions exhibited a 44% decrease in size of both lesions. All patients had at least one grade 1-2 AE, most commonly a mild impairment in concentration manifested as word-finding difficulties. There were no grade 3-4 AEs related to PT2385.

Conclusion:

In the first study of a novel HIF2a inhibitor in patients with VHL, PT2385 demonstrated stabilization of disease in VHL-associated clear cell RCC and other tumors, and showed an acceptable safety profile. Further evaluation of this class of agents in VHL is warranted, and a second-generation HIF-2α inhibitor is currently the subject of a phase 2 trial in this population.

Funding: This research was supported by the Intramural Research Program of the NIH, Urologic Oncology Branch. Author LM was funded by NCI Contract No. HHSN26120080001E, 75N910D00024, Task Order No. 75N91019F000129.