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

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.

Figure 1

Timing of PET-CT and CT imaging and therapy. The postcycle 4 CT was only done for the MPM participants, and there is a slight difference in the timing of PET 4 in the two groups (at day 120 for MPM and at day 80 for NSCLC). ADI-PEG 20, pegargiminase; ADIPemCis, pegargiminase with pemetrexed and cisplatin; CT, computed tomography; FLT, 3'-deoxy-3'-fluorothymidine; MPM, malignant pleural mesothelioma; PET, positron emission tomography.

Figure 2

MPM response on (A) FLT PET-CT and (B) CT. Most MPM cases (71%) had PR at EOT and the remainder (29%) had StD, whereas there is a mixed picture on CT with 33% revealing PR, StD, and PD, respectively. CT, computed tomography; EOT, end of treatment; FLT, 3'-deoxy-3'-fluorothymidine; MPM, malignant pleural mesothelioma; PD, progressive disease; PET, positron emission tomography; PR, partial response; StD, stable disease; SUVmax, maximum standardized uptake value.

Figure 3

NSCLC response on (A) FLT PET-CT and (B) CT. Most NSCLC cases (67%) had PR at EOT and the remainder (33%) had StD, whereas CT had PR in 57% and StD in 43%. CT, computed tomography; EOT, end of treatment; FLT, 3'-deoxy-3'-fluorothymidine; PET, positron emission tomography; PR, partial response; StD, stable disease; SUVmax, maximum standardized uptake value.

Figure 4

FLT PET-CT in MPM (case 4). (A) Baseline SUVmax equals 6.4 (red arrow). (B) Post ADI-PEG20 at 24 hours, the SUVmax decreased to 5.9 (8% reduction hence StD). (C) Postcycle 1 of combined therapy, the SUVmax increased slightly to 6.2 (maintained StD); however, at (D) end of treatment, the SUVmax decreased significantly to 1.0 (84% reduction from baseline hence PR). CT also had response, but StD at EOT and earlier time points. ADI-PEG20, pegargiminase; CT, computed tomography; EOT, end of treatment; FLT, 3'-deoxy-3'-fluorothymidine; MPM, malignant pleural mesothelioma; PET, positron emission tomography; PR, partial response; StD, stable disease; SUVmax, maximum standardized uptake value.

Figure 5

FLT PET-CT in NSCLC (case 11). (A) Baseline where primary lesion has SUVmax equals to 6.4 (red arrow). (B) Post–ADI-PEG20 at 24 hours, the SUVmax reduced to 4.8 (25% reduction hence PR). (C) Postcycle 1 of combined therapy, the SUVmax increased slightly to 5.4; however, at (D) end of treatment, the SUVmax decreased further to 4.1 (35% reduction from baseline) and hence PR was maintained. CT similarly had PR at end of treatment with a 33% reduction in size and StD at earlier time points. ADI-PEG20, pegargiminase; CT, computed tomography; EOT, end of treatment; FLT, 3'-deoxy-3'-fluorothymidine; MPM, malignant pleural mesothelioma; PET, positron emission tomography; PR, partial response; StD, stable disease; SUVmax, maximum standardized uptake value.