Abstract P4-01-09: 18F-FLT-PET/CT for the prediction of response to ANG-1005 therapy in patients with brain metastases from breast cancer

Abstract

Abstract Background: ANG1005 (formerly called GRN1005) is a peptide-drug conjugate being developed for targeted treatment of brain metastases. It consists of 3 molecules of paclitaxel covalently linked to Angiopep-2 designed to cross the blood brain barrier (BBB) via the low density lipoprotein (LDL) receptor-related protein-1 (LRP1)-mediated trancytosis. This drug was evaluated in a multi-center, open-label single-arm study (GRABMB study). An interim analysis determined that the agent met the futility endpoint based on MRI assessment (SABC 2012). However, centrally confirmed responses were achieved in the study, and a biomarker substudy enrolling patients (pts) to evaluate the utility of FLT-PET in assessing response to treatment with ANG1005 suggested sufficient activity of the agent to allow continuation of the study. 18F-FLT (3’-Fluoro-3’ deoxythymidine)-PET imaging is a novel imaging modality which provides a tool for measuring in vivo tumor cell proliferation. FLT is an analog of thymidine; cellular retention of FLT reflects DNA synthesis. Methods: Adult pts with measurable BMBC were eligible with or without history of prior WBRT. We compared 18F-FLT-PET/CT with MRI-gadolinium contrast images for brain metastases detection and for assessment of whether treatment with ANG1005 was associated with significant change in intracranial tumor uptake of 18F-FLT. ANG1005 therapy was administered intravenously at 550 mg/m2 q 21d until progression of intra-cranial disease or unacceptable toxicity. All pts underwent 18F-FLT PET/CT imaging before and after 1 cycle of therapy with ANG1005. Pts were scanned dynamically over 30 min followed by a static whole body PET image at 1 hour post-injection. We calculated the% of change before and after therapy, with change > 20% considered significant. Results: 5/10 planned pts have been accrued to the substudy to date, and 12 metastatic brain lesions have been analyzed. The maximum standard uptake value (SUVmax) ranged from 0.8 to 4.0, mean 1.8 for baseline scans. Tumor to normal brain background ratios ranged from 3.2 to 22.3, mean 9.4. 7/12 lesions showed >20% change between pre and post therapy. The average% change was (-) 42.39% ± 12.77, range: 29.2 to 66.8% (using SUVmax), and (-) 38.7% ± 14.3, range: 20.12 to 57.10% (using tumor to normal ratios). Based on brain MRI evaluation per RECIST 1.1 criteria, 1 pt had intra-cranial partial response (PR) and 3 patients had stable disease (SD). These pts remained on therapy for an average of 7 cycles, range: 5 to 9 cycles. 1 pt withdrew consent after 2 cycles of therapy and opted to receive whole brain radiation therapy. 5/42 pts achieved a confirmed investigator-assessed PR by MRI at 550 mg/m2, and 4/13 pts achieved a PR at 650 mg/m2, a dose not progressed due to toxicity. Conclusion: This pilot study using 18F-FLT-PET imaging of brain metastases suggests that it is a promising tool for detection and measurement of CNS disease. Given that contrast-enhanced MRI detection of brain metastases represent gadolinium leakage through the BBB rather than actual tumor volume measurements, better approaches are needed to assess efficacy of therapies. Accrual to this study is ongoing. Updated results with ANG1005 will be presented during the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-09.