MK-6482, is a first-in-class oral HIF-2α inhibitor that targets a key oncogenic driver of clear cell renal cell carcinoma (ccRCC) and is currently undergoing clinical trials. Findings from a phase 1/2 trial involving advanced ccRCC patients with at least 1 prior line of therapy, were recently presented by Dr. Toni Choueiri of the Dana-Farber Cancer Institute, at the Genitourinary Cancers Symposium (GUCS) 2020.1 The study demonstrated that MK-6842 was well tolerated with a favorable safety profile and an encouraging control rate, and has progressed to an upcoming phase 3 trial.1,2
ccRCC is the most common histologic variant of RCC, accounting for 70-80% of all kidney cancers.3 It has been shown to be more common in males, and increases with age.4 An unmet clinical need in patients with metastatic ccRCC who have progressed beyond immunotherapy and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors has led to the investigation of alternative therapeutic strategies, such as targeting of the transcription factor, hypoxia-inducible factor (HIF)-2α.5 The rationale for HIF-2α inhibition stems from 90% of ccRCC harboring a von Hippel-Lindau mutation which results in the activation of hypoxia-inducing genes, as key drivers of the disease.5 Therefore, inhibiting HIF-2α may lead to the suppression of multiple oncogenic pathways in ccRCC.5
At the GUCS 2020, Dr. Choueiri presented results of the first-in-class oral once-daily HIF-2α inhibitor, MK-6842, developed by Merck.1 A total of 55 patients with advanced ccRCC were enrolled in an expansion cohort where the median number of prior therapies was 3 (range 1-9).1 67% of patients received anti-programmed cell death 1 (PD-1) and anti-VEGF agents.1 Patients were further stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria with 5 patients (9%) at favorable risk, 40 patients (73%) at intermediate risk and 10 patients (18%) at poor risk.1
At a median follow-up of 14 months, the overall response rate was 24% with 13 confirmed partial responses. 56% of patients had stable disease and an 80% disease control rate was achieved.1 Partial responses occurred in 2/5 patients with favorable disease, 10/40 patients with intermediate risk and 1/10 patients in poor risk. The most common adverse events (AEs) were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), and cough (31%). Anemia and hypoxia, which are ‘on target’ toxicities, were the most common grade 3 AEs. Approximately one third of patients had grade 3-5 treatment-related AEs which led to the treatment discontinuation of 2 patients. 16 patients (29%) continued treatment beyond 12 months.
Based on these positive preliminary findings, MK-6482 will now progress to phase 3 trials. One of the trials will include 736 randomized metastatic ccRCC patients with no more than 3 prior systemic therapies, and MK-6482 will be compared to everolimus with respect to the progression-free and overall survival.2
1. Choueiri TK 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). JCO. 2020;38(6_suppl):611-611. doi:10.1200/JCO.2020.38.6_suppl.611
2. A Study of MK-6482 Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005) – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04195750. Accessed March 9, 2020.
3. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373(9669):1119-1132. doi:10.1016/S0140-6736(09)60229-4
4. Wu J et al. Renal cell carcinoma histological subtype distribution differs by age, gender, and tumor size in coastal Chinese patients. Oncotarget. 2017;8(42):71797-71804. doi:10.18632/oncotarget.17894
5. Martínez-Sáez O et al. Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy. Crit Rev Oncol Hematol. 2017;111:117-123. doi:10.1016/j.critrevonc.2017.01.013