ASCO GU 2021: Phase 2 Study of the Oral Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor MK-6482 in Combination with Cabozantinib in Patients with Advanced Clear Cell Renal Cell Carcinoma (ccRCC)

( 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 phase I study of patients with ccRCC, MK-6482 monotherapy was associated with antitumor activity. In a plenary abstract presentation in the Oral Abstract Session: Renal Cell Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Toni Choueiri presented results of the combination of MK-6482 (belzutifan) and cabozantinib in patients with advanced ccRCC who had previously received treatment, including immunotherapy and TKIs, among a larger study (NCT03634540) which also included treatment naïve patients.

In this cohort of the overall study, enrolled patients had metastatic ccRCC and had received no more than 2 prior systemic treatment regimens. Initially, six patients who were either treatment naïve (cohort 1) or had previously received therapy (cohort 2) received treatment with belzutifan 120 mg and cabozantinib 60 mg orally once daily for 21 days followed by initial evaluation by a safety review committee.


In this preliminary analysis, efficacy was evaluated among patients who received at least one dose of treatment and had an opportunity for at least 6 months of follow-up. The authors assessed the primary endpoint of objective response rate (ORR), as defined based on RECIST v1.1 by investigator review. Secondarily the authors considered progression-free survival (PFS), overall survival (OS), and duration of response (DOR) with safety evaluated among all cohort participants.

Initial safety evaluation of the combination of belzutifan 120 mg plus cabozantinib 60 mg was performed in the first six accrued patients with only 1 participant experiencing dose-limiting toxicity of hand-foot syndrome. As a result, belzutifan 120 mg plus cabozantinib 60 mg was determined to be the recommended phase 2 dose.

In the safety analysis population, the authors included 52 patients with a median age of 64 years of whom 73.6% were male and 54.7% had ECOG PS 1. Twenty-eight (52.8%) received prior first-line and 24 (45.2%) prior second-line therapies.


The median (range) duration of follow-up from enrollment to data cut-off was 11.3 months (5.6-24.0) among the 41 patients with at least 6 months of follow-up. Over this time frame, the confirmed ORR was 22.0% (with 9 patients experiencing PR) and 90% of patients had any tumor shrinkage. The aggregate disease control rate (CR+PR+SD) was 92.7% with a median (range) duration of response which was not reached (3.7+ to 14.8+ months) with all responses ongoing.


The median PFS was 16.8 months (95% confidence interval 9.2-not reached) with a 6- and 12-month PFS of 78%, and 65%, respectively. Further, the 6- and 12-month overall survival rate was 95.0% and 81%, respectively.

While treatment-related adverse events (TRAE) were common with 52 of 53 (98.1%) patients experiencing at least one TRAE, 92% of events were grade 1 and 2. The most common TRAEs experienced by at least 30% of patients were anemia (75.5%), fatigue (67.9%), hand-foot syndrome (52.8%), diarrhea (45.3%), hypertension (43.4%), nausea (35.8%), and ALT/AST increase (32-34%). Grade 3 TRAEs which were experienced by more than 5% of patients included hypertension (22.4%), anemia (11.3%), fatigue (11.3%), and ALT increase (5.7%). While 2 patients (3.8%) experienced grade 3 hypoxia, there were no grade 4 TRAEs or deaths. Discontinuations due to TRAEs occurred in 6 patients (11.3%) for belzutifan and 8 patients (15.1%) for cabozantinib.

As a result, Dr. Choueiri concluded that this preliminary analysis demonstrates that belzutifan in combination with cabozantinib has promising antitumor activity in previously treated pts with metastatic ccRCC.

Presented by: Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute 

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