VHL inactivation results in aberrant stabilization and accumulation of HIF-2α (Figure 1). This leads to subsequent constitutive activation of genes that drive tumor growth. MK-6482 is a potent, selective, small molecule, which is a HIF-2α inhibitor and has shown favorable safety and antitumor activity in advanced RCC.1
Figure 1 – HIF-2α drives tumor growth in VHL-RCC:
In the presented study (figure 2), patients with a confirmed diagnosis of VHL disease, with at least one RCC non-metastatic tumor and no previous systemic or anticancer treatments, were treated with 120 mg once daily of MK-6482 for a duration of at least 12 weeks. Tumor evaluation was performed 12 weeks thereafter. The primary objective was to evaluate the efficacy of MK-6482 for the treatment of VHL disease-associated RCC, and the primary endpoint included objective response rates (ORR).
Figure 2 – Study design:
A total of 61 patients were accrued to the study with their baseline characteristics shown in figure 3. Out of the 61 patients, 56 (91.8%) patients are still undergoing treatment with a minimum of 60 weeks’ follow-up.
Figure 3 – Patient baseline characteristics:
The overall response rate in target RCC lesions was 36.1% (95% CI 24.2-49.4), with 91.8% of patients demonstrating a decrease in the size of the target lesion (Figure 4).
Figure 4 – Response in target RCC lesions by independent central review:
The responses were durable with a median time to response of 31.1 weeks (range 11.9-62.3 weeks). The median duration of response has not been reached up until the time of this presentation. The progression-free survival (PFS) rate at 52 weeks was 98.3% (figure 5).
Figure 5 – Duration of treatment:
Response rates were also seen in pancreatic lesions (63.9%, 95% CI 50.6-75.8), and CNS hemangioblastoma (30.2%, 95% CI 17.2-46.1). Improvement in retinal lesions was also evident by the central committee, with 93.8% (15 patients) showing improved and stable retinal lesions.
The adverse events profile is shown in figure 6, with 60 patients (98.4%) having a treatment-related adverse event (TRAEs). A total of 8 patients (13.1%) had a grade 3 TRAE, and no grade 4 or 5 events were reported. One patient (1.6%) discontinued treatment due to a treatment-related adverse event (grade 1 dizziness). Anemia was the most common adverse effect (83.6% grade 1 or 2) but was amenable to medical management.
Figure 6 – Treatment-related adverse events:
Concluding his presentation, Dr. Ramaprasad stated that promising clinical activity was observed with MK-6482 in treatment-naïve patients with VHL-associated RCC. Importantly, clinical activity was also observed in non-RCC lesions. MK-6482 was shown to be well-tolerated and had a favorable safety profile. MK-6482 had demonstrated durable efficacy in patients with VHL disease-associated with RCC and non-RCC lesions.
Presented by: Ramaprasad Srinivasan MD, PhD, Head, Molecular Cancer Therapeutics Section, National Cancer Institute, Center for Cancer Research, Bethesda, MD
Written by: Hanan Goldberg, MD, MSc., Assistant Professor of Urology, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.
References:
- Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). Journal of Clinical Oncology 2020; 38(6_suppl): 611-.
ASCO 2020: Phase II Study of the Oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau Disease–Associated Renal Cell Carcinoma