| Summary: | 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′-[<sup>18</sup>F]fluorothymidine positron emission tomography (<sup>18</sup>F-FLT PET). We determined the magnitude of the <sup>18</sup>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 <sup>18</sup>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 <sup>18</sup>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 <sup>18</sup>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 <sup>18</sup>F-FLT flare occurred in all lesions in 1 patient, while another patient had an <sup>18</sup>F-FLT reduction in all lesions; 17 patients showed varied lesion uptake. All patients showed global TS inhibition reflected in plasma dUrd levels (<i>p</i> < 0.001) and <sup>18</sup>F-FLT flares of TS-responsive normal tissues including small bowel and bone marrow (<i>p</i> = 0.004 each). Notably, 83% (5/6) of patients who exhibited <sup>18</sup>F-FLT flares were also RECIST responders with a median OS of 31 m, unlike patients who did not exhibit <sup>18</sup>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 <sup>18</sup>F-FLT flare suggest the efficacy of the tracer as an indicator of the early therapeutic response to pemetrexed in NSCLC.
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