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Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase

Research output: Contribution to journalArticlepeer-review

Teresa A. Szyszko, Joel T. Dunn, Melissa M. Phillips, John Bomalaski, Michael T. Sheaff, Steve Ellis, Lucy Pike, Vicky Goh, Gary J.R. Cook, Peter W. Szlosarek

Original languageEnglish
Article number100382
JournalJTO Clinical and Research Reports
Volume3
Issue number9
DOIs
PublishedSep 2022

Bibliographical note

Funding Information: Disclosures: Dr. Szlosarek received support from the Higher Education Funding Council for England and research support from Polaris Group. Dr. Bomalaski is a paid employee of Polaris Pharmaceuticals. The remaining authors declare no conflict of interest. Funding Information: This work was funded and supported by Polaris Pharmaceuticals, Inc., and supported by the Barts Experimental Cancer Medicine Centres, Cancer Research UK , and The Department of Health , England; Wellcome / EPSRC Centre for Medical Engineering [ WT 203148/Z/16/Z]; the National Institute for Health Research Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London; and Cancer Research UK National Cancer Imaging Translational Accelerator Award (C4278/A27066). The authors are very grateful to all the participants and families who took part in the ADIPemCis (TRAP) dose-expansion MPM and nonsquamous NSCLC cohort 3'-deoxy-3'-[ 18 F] fluorothymidine positron emission tomography-computed tomography substudy. The authors also thank all the staff at the Barts Experimental Cancer Medicine Centre, King’s College London and Guy’s and St Thomas’ PET Centre, St Thomas’ Hospital and Bor-Wen Wu from Polaris Pharmaceuticals, Inc., the study sponsor. Funding Information: This work was funded and supported by Polaris Pharmaceuticals, Inc. and supported by the Barts Experimental Cancer Medicine Centres, Cancer Research UK, and The Department of Health, England; Wellcome/EPSRC Centre for Medical Engineering [WT 203148/Z/16/Z]; the National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas’ NHS Foundation Trust and King's College London; and Cancer Research UK National Cancer Imaging Translational Accelerator Award (C4278/A27066). The authors are very grateful to all the participants and families who took part in the ADIPemCis (TRAP) dose-expansion MPM and nonsquamous NSCLC cohort 3'-deoxy-3'-[18F] fluorothymidine positron emission tomography-computed tomography substudy. The authors also thank all the staff at the Barts Experimental Cancer Medicine Centre, King's College London and Guy's and St Thomas’ PET Centre, St Thomas’ Hospital and Bor-Wen Wu from Polaris Pharmaceuticals, Inc. the study sponsor. Disclosures: Dr. Szlosarek received support from the Higher Education Funding Council for England and research support from Polaris Group. Dr. Bomalaski is a paid employee of Polaris Pharmaceuticals. The remaining authors declare no conflict of interest. Publisher Copyright: © 2022 The Authors

King's Authors

Abstract

Introduction: Pegargiminase (ADI-PEG 20I) degrades arginine in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma (MPM) and NSCLC. Imaging with proliferation biomarker 3'-deoxy-3'-[18F] fluorothymidine (18F-FLT) positron emission tomography (PET)-computed tomography (CT) was performed in a phase 1 study of pegargiminase with pemetrexed and cisplatin (ADIPemCis). The aim was to determine whether FLT PET-CT predicts treatment response earlier than CT. Methods: A total of 18 patients with thoracic malignancies (10 MPM; eight NSCLC) underwent imaging. FLT PET-CT was performed at baseline (PET1), 24 hours post-pegargiminase monotherapy (PET2), post one cycle of ADIPemCis (PET3), and at end of treatment (EOT, PET4). CT was performed at baseline (CT1) and EOT (CT4). CT4 (modified) Response Evaluation Criteria in Solid Tumors (RECIST) response was compared with treatment response on PET (changes in maximum standardized uptake value [SUVmax] on European Organisation for Research and Treatment of Cancer–based criteria). Categorical responses (progression, partial response, and stable disease) for PET2, PET3, and PET4 were compared against CT using Cohen's kappa. Results: ADIPemCis treatment response resulted in 22% mean decrease in size between CT1 and CT4 and 37% mean decrease in SUVmax between PET1 and PET4. PET2 agreed with CT4 response in 62% (8 of 13) of patients (p = 0.043), although decrease in proliferation (SUVmax) did not precede decrease in size (RECIST). Partial responses on FLT PET-CT were detected in 20% (3 of 15) of participants at PET2 and 69% (9 of 13) at PET4 with good agreement between modalities in MPM at EOT. Conclusions: Early FLT imaging (PET2) agrees with EOT CT results in nearly two-thirds of patients. Both early and late FLT PET-CT provide evidence of response to ADIPemCis therapy in MPM and NSCLC. We provide first-in-human FLT PET-CT data in MPM, indicating it is comparable with modified RECIST.

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