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

Our plain-English summary of 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, by T.A. Szyszko, J.T. Dunn, M.M. Phillips, et al (JTO Clinical and Research Reports, 2022).

The study

• Authors: T.A. Szyszko, J.T. Dunn, M.M. Phillips, J. Bomalaski, M.T. Sheaff, S. Ellis, L. Pike, V. Goh, G.J.R. Cook, P.W. Szlosarek
• Journal: JTO Clinical and Research Reports
• Published: 2022;3(9):100382
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2022 The Authors.

In plain English

This was an imaging substudy of a phase 1 trial (TRAP) of pegargiminase (ADI-PEG 20) with the chemotherapy drugs pemetrexed and cisplatin. It included 18 patients enrolled from May 2015 to May 2017: 10 with malignant pleural mesothelioma (MPM) and 8 with nonsquamous non-small cell lung cancer. Patients had FLT PET-CT scans, which use a tracer as a marker of tumor cell proliferation. Scans before treatment, about 24 hours after the first pegargiminase dose, after one cycle and at end of treatment were compared with end-of-treatment CT measurements of tumor size. The 24-hour scan agreed with end-of-treatment CT in 8 of 13 patients (62%), which the authors called fair, marginally significant agreement. However, there was no significant evidence that the fall in FLT uptake preceded the fall in size. At end of treatment, in MPM, FLT showed partial response in 5 of 7 patients, compared with 3 of 9 on CT. Response was not significantly linked to survival. The authors called the end-of-treatment scan a promising alternative for MPM, noting the small numbers and missed scans.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Imaging substudy within the dose-expansion part of a phase 1 clinical trial (TRAP), with repeated (longitudinal) FLT PET-CT and CT scans
• Who was studied: 18 chemotherapy-naive adults with ASS1-deficient thoracic cancers, enrolled May 2015 to May 2017 at London centres. 10 had advanced malignant pleural mesothelioma (5 biphasic, 4 sarcomatoid, 1 epithelioid). 8 had stage IV nonsquamous NSCLC.
• Exposure: This study did not examine asbestos exposure. The exposure studied was drug treatment: weekly intramuscular pegargiminase (ADI-PEG 20, 36 mg/m2) with pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) every 21 days. MPM patients received up to six cycles and NSCLC patients up to four.
• Main results:
  • Across all patients, tumor uptake on FLT PET (SUVmax) fell by a mean of 37% plus or minus 16% from baseline to end of treatment (13 patients with data). Tumor size on CT fell by a mean of 22% plus or minus 14% (16 patients).
  • The changes on the earlier scans were small: a mean 2% decrease at 24 hours and a 3% increase after one cycle. The authors said these were within test-retest repeatability. Only the end-of-treatment scan differed significantly from baseline (p = 0.002).
  • The 24-hour FLT scan agreed with the end-of-treatment CT response in 62% (8 of 13) of patients overall: 71% (5 of 7) in MPM and 50% (3 of 6) in NSCLC. Cohen's kappa was 0.38, with marginal significance (p = 0.043).
  • The scans after one cycle and at end of treatment showed no statistically significant agreement with CT.
  • There was no statistically significant evidence that the fall in tumor proliferation (FLT uptake) preceded the fall in tumor size on CT.
  • Partial response on FLT PET-CT was seen in 20% (3 of 15) of patients at 24 hours and 69% (9 of 13) at end of treatment. On end-of-treatment CT the rate was 44% (7 of 16).
  • In MPM, partial response on FLT PET-CT was 25% (2 of 8) at 24 hours, 30% (3 of 10) after one cycle and 71% (5 of 7) at end of treatment. On end-of-treatment CT it was 33% (3 of 9).
  • In NSCLC, partial response on FLT PET-CT was 14% (1 of 7) at 24 hours and after one cycle, and 67% (4 of 6) at end of treatment. On end-of-treatment CT it was 57% (4 of 7).
  • No end-of-treatment FLT scan showed progressive disease. On the final CT, 33% (3 of 9) of MPM patients had progressive disease; no NSCLC patient did. The authors said the reason for this difference in MPM was unclear.
  • Scan response was not significantly correlated with overall survival or progression-free survival, in the whole group or within either group.
• The authors' conclusion: The authors concluded that early FLT imaging agreed with end-of-treatment CT in nearly two-thirds of patients, and that FLT uptake was strongly suppressed at end of treatment. They described this as the first-in-human use of FLT PET-CT in MPM. They stated that, on the basis of a limited number of participants, the end-of-treatment scan is a promising alternative to mRECIST for MPM.
• Limitations the authors state:
  • The study had no FLT test-retest data of its own.
  • The EORTC-based response criteria used have not been validated for FLT imaging, and there are no data on FLT measurements specifically in MPM.
  • The comparison relied on RECIST measurements on CT because no better surrogate marker of response was available.
  • The number of participants was too small to compare reliably with survival outcomes, and several participants could not complete all planned scans because of illness.
  • FLT evaluates only the exogenous thymidine pathway and may be affected by a 'flare' after antifolate therapy.
  • The authors said the small sample size, high dropout, wide confidence intervals and barely significant p values mean further evaluation is needed.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pegargiminase (ADI-PEG20), Pleural Mesothelioma, Pemetrexed (Alimta), Cisplatin, PET-CT, Modified RECIST (mRECIST).

Related studies

• Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms — P.W. Szlosarek, M.M. Phillips, et al. (2020)
• 18F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography fused imaging in malignant mesothelioma patients: looking from outside is not enough — E. Roca, S. Laroumagne, et al. (2013)
• Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers — E. Beddowes, J. Spicer, et al. (2017)
• Loss of Argininosuccinate Synthetase-1 (ASS1) Occurs in Esophageal Adenocarcinoma and Represents a Promising Biomarker for Therapy with Pegargiminase — K. Knipper, S.I. Lyu, et al. (2025)
• Prognostic and predictive role of [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unresectable malignant pleural mesothelioma (MPM) treated with up-front pemetrexed-based chemotherapy — P.A. Zucali, E. Lopci, et al. (2017)
• Fluorodeoxyglucose versus Choline Positron Emission Tomography/Computed Tomography Response Evaluation in Two Malignant Pleural Mesothelioma Patients Treated with Talc Pleurodesis and Neoadjuvant Chemotherapy — K. Kitajima, T. Nakamichi, et al. (2018)

Browse more research in JTO Clinical and Research Reports, or return to medical research.