ASCO GU 2020: Phase I/II Study of the Oral HIF-2 α Inhibitor MK-6482 in Patients with Advanced Clear Cell Renal Cell Carcinoma

San Francisco, CA ( The therapeutic landscape of metastatic clear cell renal cell carcinoma has changed significantly in recent years, with the emergence of checkpoint inhibitor (CPI) immunotherapy and CPI/tyrosine kinase inhibitor (TKI) combinations becoming standard 1st- and 2nd-line treatment options. An outstanding need, however, is an effective therapy for patients who have progressed beyond immunotherapy and VEGF TKIs.
In the first of four abstracts of the Renal Cell Carcinoma Oral Abstract Session, Prof Toni Choueiri, Medical Oncologist at Data-Farber Cancer Institute, presented the findings of a Phase I/II study of the oral HIF-2a inhibitor MK-6482 in patients with pre-treated metastatic RCC. 

Prof Choueiri first highlighted the biology of clear cell RCC (ccRCC) as a clear rationale for HIF-2a inhibition. 90% of ccRCC harbors VHL mutation resulting in defective VHL protein and activation of hypoxia-inducible genes as key oncogenic drivers of the disease. The HIF-2a transcription factor activates the expression of genes associated with tumor progression, including VEGFA. Therefore, inhibiting HIF-2a and VEGF may result in the suppression of multiple oncogenic pathways in ccRCC. MK-6482 is a potent, oral, selective small molecular inhibitor of HIF-2a. 

The study population included patients with advanced ccRCC who have received at least 1 prior line of therapy in an expansion cohort of MK-6482 at 120 mg daily, following a dose escalation cohort in solid tumors. A total of 55 patients with advanced ccRCC were enrolled, where most patients had received both prior anti-PD1 and anti-VEGF agents (67%). The median number of prior therapies was 3, suggesting a heavily pre-treated population. Most (73%) patients had intermediate-risk disease per the IMDC risk criteria, however, all riks groups were represented. 

At a median follow-up of 13 months, most adverse events were low-grade in nature. The most common events being anemia (75%) and fatigue (67%). Anemia and hypoxia (15%) were the most common grade 3 adverse events and both represent on-target effects. Prof Choueiri noted that hypoxia occurred in the setting of a trigger (such as pneumonia or pleural effusion) and that patient condition improved with supplemental oxygen and appropriate management of the underlying cause. No drug-related related grade 4/5 events were observed. 

With respect to efficacy, the confirmed overall response rate was 24% and disease control rate was 80%. By risk category, partial responses were seen in favorable, intermediate and poor-risk groups. The median progression-free survival for the whole cohort was 11 months, and 16.5, 11 and 6.9 months for favorable, intermediate and poor-risk groups, respectively. Prof Choueiri further highlighted responses with the median duration of duration of response not reached. A high proportion of patients had durable responses beyond 6 months with several ongoing responses. 

In summary, this Phase I/II trial of a novel oral HIF-2a inhibitor in pre-treated advanced ccRCC showed very promising activity with an encouraging response/disease control rate and evidence of activity across IMDC risk groups, in patient population that has mostly been treated with prior CPI and VEGF TKI.  
Presented by: Toni K. Choueiri, MD, Chief of Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute,  Boston, Massachusetts  
Written by: Anis Hamid, MBBS, Medical Oncology Research Fellow at Dana-Farber Cancer Institute and Medical Oncologist, PhD candidate, University of Melbourne, Australia (Twitter: @anis_a_hamid) at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California
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