ASCO GU 2021: The Oral HIF-2 α Inhibitor MK-6482 in Patients with Advanced Clear Cell Renal Cell Carcinoma (RCC): Updated Follow-up of a Phase I/II Study

(UroToday.com) The treatment landscape for first-line therapy among patients with metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 2 years. In 2018, the publication of the CheckMate214 data demonstrated a survival benefit for patients treated with nivolumab and ipilimumab compared with sunitinib in intermediate and poor-risk mRCC, ushering in the immunotherapy era for mRCC. The subsequent publication of the JAVELIN Renal 101, KEYNOTE-426, and CheckMate-9ER studies demonstrated the superiority of avelumab and axitinib, pembrolizumab, and axitinib, and nivolumab and cabozantinib compared to sunitinib in this disease space. However, few patients respond completely and most will progress within the year.


In addition to comprising the focus of studies to date, clear cell RCC (ccRCC) accounts for approximately 70% of kidney cancer cases in the US. Molecular work over the past few decades has identified that a key oncogenic driver in RCC is the transcription factor hypoxia-inducible factor 2α (HIF-2α). MK-6482 is a small molecule HIF-2α inhibitor that blocks the heterodimerization of HIF-2α with HIF-1β, inducing tumor regression in mouse xenograft RCC models. In a plenary abstract presentation in the Oral Abstract Session: Renal Cell Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Todd Michael Bauer presented updated data from the first-in-human phase 1/2 study of MK-6482 in advanced solid tumors (NCT02974738).

The authors accrued patients aged 18 years and older with advanced ccRCC who had received at least 1 prior therapy, and who had evidence of measurable disease based on RECIST v1.1 criteria. Further, patients were required to have ECOG status 0 or 1, adequate organ function, and life expectancy ≥6 mo. Once accrued, patients received 120 mg of MK-6482 orally once daily, based on results from the dose-escalation cohorts.

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While the primary endpoint was safety, patients were assessed at baseline, within 7 days before week 9, and then every 8 weeks with response assessed using RECIST v1.1 with key secondary end points included ORR, duration of response (DOR), and PFS.

Fifty-five patients with ccRCC were treated with MK-6482 120 mg (52 in expansion and 3 in dose-escalation cohorts). Patients had received a median number of 3 (range 1-9) prior lines of therapy. Forty-two patients (81%) previously received PD-1/L1 inhibitors and 48 (92%) previously received VEGF inhibitors. According to IMDC criteria, 13 patients (24%) had favorable risk and 42 (76%) had intermediate or poor-risk disease.

Over a median follow-up of 28 months, the most common all-grade, all-cause adverse events which were experiences in at least 30% of patients were anemia (76%), fatigue (71%), dyspnea (49%), nausea (36%), cough (31%), and hypoxia (31%). In terms of grade 3 adverse events, anemia (27%) and hypoxia (16%) were the most common. Grade 4 adverse events were experienced by two patients (4%) while 4 patients (7%) experienced grade 5 adverse events; however, no grade 4 or 5 AEs were related to treatment.

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The objective response rate (ORR) was 25%, with 14 patients having confirmed PRs, and 30 patients (55%) having stable disease. Thus, the disease control rate (CR+PR+SD) was 80% with a median DOR that was not reached (77% had a response of at least 6 months).

Stratified by IMDC risk, 4 of 13 patients with favorable risk had PR (ORR = 31%) and 10 of 42 with intermediate or poor risk had PR (ORR = 24%) with corresponding disease control rates of 92% and 76%, respectively.

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In the overall population, median PFS was 14.5 months with 1-year progression-free survival of 51%.

As of June 1, 2020, 33 patients (60%) discontinued because of PD and 2 (4%) because of AEs while 11 patients (20%) had ongoing treatment.

Dr. Bauer thus concluded that MK-6482 demonstrates promising single-agent activity in patients with ccRCC and warrants assessment in a phase III trial which is underway. 

Presented by: Todd Michael Bauer, MD, Medical Oncology, Tennessee Oncology

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
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