Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001).
Authors: Brugarolas James , Beckermann Katy , Rini Brian I. , Vogelzang Nicholas J. , Lam Elaine Tat , Hamilton James C , Schluep Thomas , Yi Min , Wong So , Gamelin Erick , Tannir Nizar M. 
Published: February 2022

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Background: Hypoxia inducible factor-2 alpha (HIF2a) is a transcription factor and key tumorigenic driver of clear cell renal cell carcinoma (ccRCC). Normally, HIF2a is expressed at low levels and targeted for degradation by the von Hippel-Lindau ( VHL) tumor suppressor protein. VHL inactivation, the causative event of ccRCC, induces tumorigenesis through uncontrolled accumulation of HIF2a and constitutive expression of downstream target genes implicated in cell survival, cell proliferation and angiogenesis. ARO-HIF2 is a synthetic double-stranded RNAi trigger with an alpha-v beta3 targeting ligand, designed to silence HIF2a expression. Herein, we present initial results from a phase 1 clinical trial of ARO-HIF2 in advanced ccRCC (NCT04169711). Methods: Advanced ccRCC patients (pts) (ECOG ≤ 1), with progressive disease on prior anti-VEGF and checkpoint inhibitor therapy, were enrolled into three escalating dose cohorts (up to 10 per cohort) to receive 225, 525 or 1,050 mg i.v. weekly of ARO-HIF2 until progression or unacceptable toxicity. The primary endpoint was incidence and severity of AEs. Secondary endpoints included tumor response based on RECIST. All pts underwent tumor biopsy at baseline and post-dose for analysis of changes in HIF2a mRNA (qPCR) and protein expression (IHC). Results: At the time of data cut, twenty-three pts (median age 66.5) were enrolled across 3 cohorts. Seventy four percent of pts received ≥ 3 prior lines of therapy. The most common treatment emergent AE was fatigue (39%). Three SAEs in 3 pts were reported by investigators as possibly drug related including, myocarditis (in a pt with a history of TKI induced cardiomyopathy and NSTEMI requiring stent placement), demyelinating neuropathy (in a pt with autoimmune sequelae secondary to checkpoint inhibitors), and hypoxia (in a pt with a pulmonary infiltrate treated with antibiotics). No cases of drug related anemia were reported. Among pts with adequate biopsy for qPCR (n=7), mean (max) reductions in HIF2a mRNA were 38% (47%), 25% (30%) and 28% (28%) in cohorts 1, 2, and 3, respectively. Among pts with adequate biopsy for IHC (n = 12), 8 showed reductions in HIF2a protein with mean (max) reductions of 45% (82%), 57% (90%) and 63% (63%) in cohorts 1, 2, 3, respectively. Across all 3 cohorts, disease control (CR+PR+SD) was seen in 7 (30%) of pts. One pt (cohort 2, with prior sunitinib, nivolumab, axitinib) experienced a partial response with 66% reduction in sum of longest diameters. Six pts had a best response of stable disease. Three pts remain on drug with stable disease and treatment durations between 20 and 32 weeks. Conclusions: HIF2a is a clinically validated driver of ccRCC which can be targeted with a RNAi therapeutic. This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2a expression as well as a favorable safety profile in response to escalating doses of ARO-HIF2. Clinical trial information: NCT04169711.