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

Szyszko, Teresa; Dunn, Joel; Phillips, Melissa; Bomalaski, John S.; Sheaff, Michael; Ellis, Steve; Pike, Lucy; Goh, Vicky; Cook, Gary; Szlosarek, Peter W.

doi:10.1016/j.jtocrr.2022.100382

Cited by 3 publications

(2 citation statements)

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“…Moreover, twice as many patients enrolled with nonepithelioid than epithelioid disease, despite the former representing approximately one-third of mesothelioma cases . Mechanistically, we identified reduced 18-FLT uptake by 24 hours of pegargiminase monotherapy and robust metabolic responses on completion of chemotherapy using positron emission tomography, corroborating the thymidine salvage pathway as a downstream target of pegargiminase . Based on these findings, the ATOMIC-Meso phase 2-3 trial evaluated the primary efficacy and safety of adding pegargiminase or placebo to standard chemotherapy with pemetrexed and platinum (cisplatin or carboplatin) in patients with chemotherapy-naive nonresectable nonepithelioid pleural mesothelioma …”

Section: Introductionmentioning

confidence: 56%

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma

Szlosarek,

Creelan,

Sarkodie

et al. 2024

JAMA Oncol

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ImportanceArginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma.ObjectiveTo determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor.Design, Setting, and ParticipantsThis was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months’ follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023.InterventionPatients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months.Main Outcomes and MeasuresThe primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only.ResultsAmong 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo).Conclusions and RelevanceIn this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology.Trial RegistrationClinicalTrials.gov Identifier: NCT02709512

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Section: Introductionmentioning

confidence: 56%

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma

Szlosarek,

Creelan,

Sarkodie

et al. 2024

JAMA Oncol

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“…Numerous studies confirm that [ 18 F]FLT uptake reflects tumor proliferation in most human cancers, especially for brain, lung and breast tumors [ 5 , 6 , 7 , 8 , 9 ]. This radiolabeled nucleoside has been particularly useful as a prognostic tool for the treatment response in standard chemotherapy and radiotherapy [ 10 ] as well as the early assessment of the therapy response in cases of new therapeutics [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Automated Optimized Synthesis of [18F]FLT Using Non-Basic Phase-Transfer Catalyst with Reduced Precursor Amount

2022

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3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a positron emission tomography (PET) tracer useful for tumor proliferation assessment for a number of cancers, particularly in the cases of brain, lung, and breast tumors. At present [18F], FLT is commonly prepared by means of the nucleophilic radiofluorination of 3-N-Boc-5′-O-DMT-3′-O-nosyl thymidine precursor in the presence of a phase-transfer catalyst, followed by an acidic hydrolysis. To achieve high radiochemical yield, relatively large amounts of precursor (20–40 mg) are commonly used, leading to difficulties during purification steps, especially if a solid-phase extraction (SPE) approach is attempted. The present study describes an efficient method for [18F]FLT synthesis, employing tetrabutyl ammonium tosylate as a non-basic phase-transfer catalyst, with a greatly reduced amount of precursor employed. With a reduction of the precursor amount contributing to lower amounts of synthesis by-products in the reaction mixture, an SPE purification procedure using only two commercially available cartridges—OASIS HLB 6cc and Sep-Pak Alumina N Plus Light—has been developed for use on the GE TRACERlab FX N Pro synthesis module. [18F]FLT was obtained in radiochemical yield of 16 ± 2% (decay-corrected) and radiochemical purity >99% with synthesis time not exceeding 55 min. The product was formulated in 16 mL of normal saline with 5% ethanol (v/v). The amounts of chemical impurities and residual solvents were within the limits established by European Pharmacopoeia. The procedure described compares favorably with previously reported methods due to simplified automation, cheaper and more accessible consumables, and a significant reduction in the consumption of an expensive precursor.

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Emerging Radiopharmaceuticals in Pet Imaging for Mesothelioma: A Review of [18F]FDG Alternatives

Guglielmo,

Crivellaro,

Castello

et al. 2024

Mol Diagn Ther

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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

Cited by 3 publications

References 36 publications

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma

Automated Optimized Synthesis of [18F]FLT Using Non-Basic Phase-Transfer Catalyst with Reduced Precursor Amount

Emerging Radiopharmaceuticals in Pet Imaging for Mesothelioma: A Review of [18F]FDG Alternatives

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