HIF-2α Inhibition Warranted for VHL-Associated Clear Cell Renal Cell Carcinoma

December 3, 2020
Nichole Tucker

Nichole Tucker, MA, is the Web Editor for Targeted Oncology. Tucker received her Bachelor of Arts in Mass Communications from Virginia State University and her Master of Arts in Media & International Conflict from University College Dublin.

The novel first-in-class small molecule inhibitor of HIF-2α, PT2385 demonstrated the ability to stabilize disease with tolerable safety in patients with von Hippel-Lindau disease-associated clear cell renal cell carcinoma and non-renal tumors, according to results presented in a poster during the 21st Annual Meeting of the Society of Urologic Oncology.

The novel first-in-class small molecule inhibitor of HIF-2α, PT2385 demonstrated the ability to stabilize disease with tolerable safety in patients with von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC) and non-renal tumors, according to results presented in a poster during the 21st Annual Meeting of the Society of Urologic Oncology (SUO).

The population of patients with VHL disease is 1 that is highly susceptible to the development of ccRCC in addition to other tumors that can be both benign and malignant. In the current treatment landscape, the only options for patients with VHL-associated ccRCC are active surveillance and surgical intervention. Due to the lack of systemic therapies for the treatment of VHL-associated ccRCC, the study of PT2385 was launched. It was hypothesized that the HIF-2α inhibitor would be efficacious in this patient population based on its ability to resolve oncogenesis in renal tumors.

Four patients were enrolled in the small study, then enrollment was stopped due to inconsistencies with the drug. Investigators noted that a second-generation HIF-2α inhibitor may offer the patients more reliable pharmacological characteristics. The 4 patients were still dosed with PT2385 800 mg twice daily and followed on treatment for a median of 19 weeks (range 13-143).

Patients were assessed for the primary end point of ORR) in renal tumors per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). The secondary and exploratory end points were safety, pharmacokinetics, response in VHL-associated non-renal tumors, and modulation of erythropoietin.

Characteristics for the patients enrolled were recorded at baseline. All patients were female and had previously resected tumors. Patient 1 was 69 years of age with an ECOG performance status of 1. The patient presented with renal tumors, pancreatic cysts, spinal cord hemangioblastomas, bilateral retinal hemangioblastomas. The patient had 2 renal tumors and was on therapy for 28 weeks. Her median tumor size at baseline was 2 cm (1.6 cm-2.4 cm). Patient 2 was 60 years old with an ECOG performance of 0. The manifestation of VHL-associated disease in patient 2 included renal tumors, pancreatic cysts, cerebellar and spinal cord hemangioblastomas, bilateral retinal hemangioblastomas. The patient was on treatment for 143 weeks and had 2 renal tumors. At baseline, her median tumor sized measured at 2.1 cm (1.5 cm-2.6 cm).

Patients 3 and 4 were aged 53 and 51, respectively. Both patients had an ECOG performance status of 0 and the same time on treatment of 13 weeks. Patient 3 showed VHL manifestations in renal tumors, pancreatic cysts and neuroendocrine tumor, spinal cord hemangioblastomas, and right retinal hemangioblastomas. There was only 1 renal tumor found in patient 3, and the median tumor size was 1.7 cm. Patient 4 presented with VHL-associated renal tumors, pancreatic cysts, a neuroendocrine tumor, and cerebellar hemangioblastoma. Patient 4 had one renal tumor with a median tumor size of 2.1 cm.

All 4 patients enrolled had at least 1 measurable VHL-associated ccRCC tumor in their kidneys. No patient had a tumor size greater than 3.0 cm, per the study’s inclusion criteria.

The results showed that all patients achieved stable disease (SD) as their best response to treatment with PT2385. Notably, 1 of the patients remained on treatment for 2.7 years. Further demonstration of SD in the study population was shown with the median growth rate of individual tumors while patients were on therapy. The median growth rate was -1 mm per year (range, -3 to +4), which was good when compared with the median growth rate on prior therapy of 3mm each year (range, 1-7). The median growth rate on PT2385 was also better than what was observed after therapy ended, which was 3 mm per year (range, 2-7).

Stabilization and improvement were observed with all VHL manifestations in the study patients. Specifically, ocular issues had improvement in retinal hemangioblastomas for 2 out of 3 patients, and all 3 patients with spine hemangioblastomas had SD. The patient who presented with 2 pancreatic solid lesions achieved a 44% decrease in the size of each lesion.

Safety was evaluated in the whole study population and all patients experienced grade 1 and 2 adverse events (AEs). The most common AEs of any grade were nausea (100%), dysphasia (75%), fatigue (75%), and insomnia (50%). Three patients required dose interruptions during the study. No grade 3 or 4 AEs experienced were related to PT2385.

Overall, these efficacy and safety findings for PT2385 warrant further research around HIF-2α inhibitors, including the second-generation agents like MK 6482, which is currently being investigated in a phase 2 clinical trial of patients with VHL-associated ccRCC.

Reference:

Chaflin H, Yerram N, Gautam R, et al. An Open-Label phase II study to evaluate PT2385 for the treatment of Von Vippel-Lindau disease-associated clear cell renal cell carcinoma. Presented at: 2020 SUO Annual Meeting; December 2-5, 2020; Virtual. Abstract 108.