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

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

doi:10.1016/j.jtocrr.2022.100382

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

JTO Clin Res Rep. 2022 Jul 20;3(9):100382. doi: 10.1016/j.jtocrr.2022.100382. eCollection 2022 Sep.

Authors

Teresa A Szyszko^{1

2

3}, Joel T Dunn¹, Melissa M Phillips⁴, John Bomalaski⁵, Michael T Sheaff⁶, Steve Ellis⁷, Lucy Pike¹, Vicky Goh⁸, Gary J R Cook^{1

8}, Peter W Szlosarek^{4

9}

Affiliations

¹ King's College London and Guy's and St Thomas' PET Centre, St Thomas' Hospital, London, United Kingdom.
² Department of Nuclear Medicine, Royal Free Hospital NHS Trust, London, United Kingdom.
³ Department of Oncology, University College London, London, United Kingdom.
⁴ Department of Medical Oncology, St. Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom.
⁵ Polaris Pharmaceuticals Inc., San Diego, California.
⁶ Department of Histopathology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.
⁷ Department of Diagnostic Imaging, St. Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom.
⁸ Cancer Imaging, School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom.
⁹ Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

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.

Keywords: ASS1; Arginine; FLT PET-CT; Pegargiminase; Thoracic cancers.

Grants and funding

16463/CRUK_/Cancer Research UK/United Kingdom