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Tumor Response to Stroma-Modifying Therapy: Magnetic Resonance Imaging Findings in Early-Phase Clinical Trials of
Andrés M Arias-Lorza1, James R Costello1, Sunil R Hingorani2
1Moffitt Cancer Center.
Abstract:
Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20, HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values that were predictive of pharmacodynamic responses were: ADC > 1.46×10-3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans<0.07min-1 (BA = 72%, p = 0.2), ve<0.17 (BA = 68%, p < 0.01), and vp<0.02 (BA = 60%, p < 0.01). Further, ve<0.39 at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies.
Insights
PEGPH20 depletes tumor hyaluronic acid, reducing interstitial fluid pressure and improving chemotherapy distribution. Quantitative MRI biomarkers identified baseline parameters predictive of treatment response, aiding patient selection for PEGPH20 therapy.
Area of Science:
- Oncology
- Radiology
- Pharmacology
Background:
- PEGPH20 targets intratumoral hyaluronic acid (HA), a component linked to elevated interstitial fluid pressure and poor drug delivery in solid tumors.
- High HA levels impede the efficacy of chemotherapies by creating a physical barrier and increasing tumor pressure.
- Quantitative magnetic resonance imaging (qMRI) offers a non-invasive method to assess tumor microenvironment changes.
Approach:
- Prospective clinical trials (HALO-109-101, -102, -201) involving 29 patients with metastatic advanced solid tumors treated with PEGPH20.
- Acquisition of qMRI data at baseline and post-treatment to generate maps of Apparent Diffusion Coefficient (ADC), T1, k, v, v, and iAUC.
- Analysis of changes in qMRI parameters post-PEGPH20 administration and identification of baseline parameters predictive of these pharmacodynamic responses.
Key Points:
- PEGPH20 treatment led to decreased tumor ADC and T1, and increased iAUC, k, v, and v on day 1 post-treatment, indicating HA depletion.
- HA depletion resulted in reduced tumor water content and increased tumor perfusion, permeability, extracellular matrix space, and vascularity.
- Specific baseline qMRI parameter thresholds (e.g., ADC > 1.46×10-3 mm2/s, T1 > 0.54s, iAUC < 9.2 mM-s) were predictive of pharmacodynamic responses.
Conclusions:
- qMRI-derived biomarkers demonstrate the impact of PEGPH20 on tumor stroma.
- Baseline qMRI parameters can predict pharmacodynamic changes following PEGPH20 treatment.
- These qMRI biomarkers hold potential for guiding patient selection and monitoring treatment response in clinical studies involving PEGPH20 and similar tumor stroma-modulating therapies.
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