Analysis of Multiparametric MR imaging and tumor tissue sampling to identify response and acquired resistance to HIF-2 inhibition in patients with advanced clear cell renal cell carcinoma enrolled in a phase 1, multiple-dose, dose-escalation trial of PT2385, a HIF-2alpha inhibitor

Background: We investigated whether multiparametric magnetic resonance imaging (mpMRI) could identify activity of PT2385, a novel inhibitor of hypoxia inducible factor-2 (HIF-2), in patients with advanced clear cell renal cell carcinoma (ccRCC). Through tumor biopsies, we sought to identify mechanisms of response and resistance to HIF-2 inhibition.
Methods: We enrolled patients treated on a multicenter phase I trial of PT2385 at our institution to a companion study investigating three mpMRI techniques, arterial spin labeling (ASL), dynamic contrast enhancement (DCE), and diffusion-weighted imaging (DWI), as potential markers of HIF-2 inhibition. Eligible subjects undergoing mpMRI had eGFR ≥30 mL/min/1.73m2. Subjects who were not eligible to undergo MRI could still undergo blood collection and optional tumor biopsies. The primary objective was to study mpMRI as a potential pharmacodynamic biomarker of response and resistance to PT2385. Secondary objectives were to identify potential blood and tumor biomarkers of response and resistance to PT2385.
Findings: Between August 31, 2015 and November 30, 2015, we consented 11 patients. 10 were treated on the phase I trial, 7 underwent mpMRI, and 6 underwent tumor biopsies. Decrease in ASL perfusion was observed at 2 weeks on treatment with PT2385 in 14/16 lesions (87.5%) across 7 patients. Proximity ligations assay analysis showed dissociation of HIF-2 and HIF-1ï¢ following PT2385 treatment in 3/3 patients who underwent serial biopsies. In a patient with prolonged disease control and focal tumor growth, we discovered a HIF-2alpha gatekeeper mutation (G323E) resulting in preserved HIF-2 complexes and sustained HIF-2 target gene expression despite ongoing PT2385 treatment.
Interpretation: ASL mpMRI warrants further exploration as an imaging biomarker for HIF-2 inhibition in patients with ccRCC. By combining tumorgraft models and clinical samples, we validated HIF-2 as a target and provide insight into mechanisms of resistance in human subjects.EGA study EGAS00001003506