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Prognostic value and peripheral immunologic correlates of early FDG PET response imaging in a phase II trial of risk-adaptive chemoradiation for unresectable non-small cell lung cancer

Introduction: We hypothesized that FDG PET imaging during chemoradiation for unresectable non-small cell lung cancer (NSCLC) is prognostic for survival, and that tumor PET response is correlated with peripheral T-cell function. Methods: 45 patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the phase II FLARE-RT trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). FDG PET imaging was performed prior to treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while non-responders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor (TCR) sequencing, and plasma cytokines analysis were performed. Results: Median follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival (PFS) 53%, and 1-year locoregional control (LRC) 88%. Higher mid-treatment PET total lesion glycolysis was detrimental to OS (1-yr 87% vs. 63%, p<0.001), PFS (1-yr 60% vs. 26%, p=0.044) and LRC (1-yr 94% vs. 65%, p=0.012), even after adjustment for clinical/treatment factors. Higher PD-L1 tumor proportion score (TPS) was correlated with PET response (p=0.017): 6/6 patients with high PD-L1 (TPS>50%) were classified as PET responders, while 4/5 patients classified as PET non-responders had negative PD-L1 (TPS<1%). Higher TCR richness and clone distribution slope was associated with improved OS (p=0.018-0.035); clone distribution slope was correlated with PET response (p=0.031). Germline DNA alterations in immunologic pathways had an outsized effect on OS and PET response; of the top 30 SNPs ranked by association with PET response status (p<0.016), a plurality (13/30) came from immunologic pathways. Conclusions: Mid-chemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.