Prognostic Value and Peripheral Immunologic Correlates of Early FDG PET Response Imaging in a Phase II Trial of Risk-Adaptive Chemoradiation for Unresectable NSCLC

Abstract

<h3>Purpose/Objective(s)</h3> We hypothesized that FDG PET imaging during chemoradiation for unresectable non-small cell lung cancer (NSCLC) is prognostic for survival, and that PET response is correlated with systemic immune response to treatment, as characterized by peripheral immunologic correlates and tumor PD-L1 status. A prognostic test that could predict patient outcome would help better select patients who need additional therapies, and spare toxicity in patients who do not. <h3>Materials/Methods</h3> A total of 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 multifactor radiomics. PET responders received 60 Gy in 30 fractions, while non-responders received concomitant boosts to 74 Gy in 30 fractions. 22/45 patients received durvalumab post-chemoradiation. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor (TCR) sequencing, and plasma cytokines analysis were performed. Overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were estimated by Kaplan-Meier. Unsupervised learning of germline DNA sequencing SNP genotypes was performed with hierarchical clustering and summarized with cumulative frequency distributions of rank ordered SNPs. Genotype associations to OS, PFS, and PET response status were characterized by logistic regression with Firth penalization for estimating odds ratios (OR). TCR diversity metric trends were estimated by Spearman rank correlation and pairwise changes by Wilcoxon signed rank testing. TCR diversity metric associations to OS and PFS were assessed by Permutation testing of Harrell's c-index. <h3>Results</h3> Median follow-up was 18.8 months, 1-year OS 82%, 1-year PFS 53%, and 1-year LRC 88%. Higher mid-treatment PET total lesion glycolysis was detrimental to OS (1-yr 87% vs. 63%, <i>P</i> < 0.001), PFS (1-yr 60% vs. 26%, <i>P</i> = 0.044) and LRC (1-yr 94% vs. 65%, <i>P</i> = 0.012), even after adjustment for clinical/treatment factors. Tumor PD-L1 expression was correlated with PET response (<i>P</i> = 0.017), with 6/6 patients with high PD-L1 TPS (> 50%) classified as PET responders and 4/5 patients with negative PD-L1 TPS (< 1%) classified as PET non-responders. 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 (<i>P</i> < 0.016), a plurality (13/30) came from immunologic pathways. Higher TCR richness, higher clone distribution slope, and smaller decline in clone distribution slope was associated with improved OS (<i>P</i> = 0.018-0.05); clone distribution slope was correlated with PET response (<i>P</i> = 0.031). <h3>Conclusion</h3> Mid-chemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral immunologic biomarkers.