A Subset of Non-Small Cell Lung Cancer Patients Treated with Pemetrexed Show (18)F-Fluorothymidine “Flare” on Positron Emission Tomography

SIMPLE SUMMARY: Thymidylate synthase (TS) inhibitors have remained among the most effective chemotherapies used in the treatment of various cancer types. Imaging of tumour proliferative activity while on antifolates has been studied with 3′-deoxy-3′-[(18)F]fluorothymidine positron emission tomography ((18)F-FLT PET) imaging. The aim of this study was to use (18)F-FLT PET/CT imaging to understand the basis of early drug action with the antifolate drug pemetrexed on TS inhibition. While every patient showed a global change in the plasma marker of TS inhibition after drug administration, tumour TS inhibition was selective and patients who showed a tumour change in the imaging biomarker had a greater therapy response and longer overall survival following a combination treatment including pemetrexed. The study findings implicate the potential use of (18)F-FLT PET/CT to understand the basis of drug action in other studies involving TS inhibitors. ABSTRACT: Thymidylate synthase (TS) remains a major target for cancer therapy. TS inhibition elicits increases in DNA salvage pathway activity, detected as a transient compensatory “flare” in 3′-deoxy-3′-[(18)F]fluorothymidine positron emission tomography ((18)F-FLT PET). We determined the magnitude of the (18)F-FLT flare in non-small cell lung cancer (NSCLC) patients treated with the antifolate pemetrexed in relation to clinical outcome. Method: Twenty-one patients with advanced/metastatic non-small cell lung cancer (NSCLC) scheduled to receive palliative pemetrexed ± platinum-based chemotherapy underwent (18)F-FLT PET at baseline and 4 h after initiating single-agent pemetrexed. Plasma deoxyuridine (dUrd) levels and thymidine kinase 1 (TK1) activity were measured before each scan. Patients were then treated with the combination therapy. The (18)F-FLT PET variables were compared to RECIST 1.1 and overall survival (OS). Results: Nineteen patients had evaluable PET scans at both time points. A total of 32% (6/19) of patients showed (18)F-FLT flares (>20% change in SUVmax-wsum). At the lesion level, only one patient had an FLT flare in all the lesions above (test–retest borders). The remaining had varied uptake. An (18)F-FLT flare occurred in all lesions in 1 patient, while another patient had an (18)F-FLT reduction in all lesions; 17 patients showed varied lesion uptake. All patients showed global TS inhibition reflected in plasma dUrd levels (p < 0.001) and (18)F-FLT flares of TS-responsive normal tissues including small bowel and bone marrow (p = 0.004 each). Notably, 83% (5/6) of patients who exhibited (18)F-FLT flares were also RECIST responders with a median OS of 31 m, unlike patients who did not exhibit (18)F-FLT flares (15 m). Baseline plasma TK1 was prognostic of survival but its activity remained unchanged following treatment. Conclusions: The better radiological response and longer survival observed in patients with an (18)F-FLT flare suggest the efficacy of the tracer as an indicator of the early therapeutic response to pemetrexed in NSCLC.