Early FDG PET imaging and circulating T-cell repertoire biomarkers of response to chemotherapy and PD-1 checkpoint inhibitors in patients with stage IV NSCLC.
Authors: Yaseen Faisal , Santana-Davila Rafael , Grassberger Clemens , Chen Delphine L. , Baik Christina , Eaton Keith D. , Tseng Diane , Menon Smitha Patiyil , Deng Lei , Lee Sylvia , Jimenez Ariana D , Lampe Paul D. , Houghton A. McGarry , Kinahan Paul E , Zeng Jing , Bowen Stephen R. 
Published: June 2024

8622

Background: Chemotherapy and immune checkpoint inhibitors (chemoICI) for stage IV NSCLC without driver mutations produce variable response patterns and outcomes. Early assessment could establish selective benefit from treatment (de)escalation, consolidation, or adaptation. We evaluated FDG PET imaging and circulating T cell repertoire biomarkers of chemoICI response for clinical decision support. Methods: 35 patients with stage IV NSCLC prospectively enrolled on PET BRIGHT (NCT04151940) from 2019-2023 and received first-line carboplatin-pemetrexed-pembrolizumab. Synchronous FDG PET/CT and peripheral blood draws were performed prior to and after first dose of chemoICI at week 3. Imaging biomarkers included standardized uptake value (SUV) and total lesion glycolysis (TLG) metrics within the primary metabolic tumor volume and across lung lesions. Immunophenotyping included T cell receptor (TCR) sequencing from which TCR diversity metrics were extracted. Spearman correlation of FDG PET and TCR biomarkers with bi-dimensional size reduction after initial chemoICI was estimated. ROC analysis of PET and TCR biomarkers to discriminate chemoICI response status was benchmarked against PD-L1 testing, along with Mann-Whitney testing of groupwise differences. Results: The majority tested negative for PD-L1 (58% TPS<1%). Most patients (63%) had partial response (PR) to initial chemoICI versus 33% with stable disease (SD) and 4% with progressive disease (PD). FDG PET primary tumor peak SUV decreased by a median of 15% [-82%, 63%] at week 3, while TLG decreased by 36% [-55%, 83%]. Higher baseline peak SUV and TLG, along with greater decline after first dose, were correlated with post-chemoICI size reduction (R 0.43-0.64, p=0.001-0.036). PR patients had higher baseline peak SUV (12 vs 6 g/mL, p=0.014) and greater week 3 decline in TLG (39% vs 7%, p=0.032) relative to SD/PD patients. Across lung lesions, PR-patient maximum SUV decreased while SD/PD-patient maximum SUV increased at week 3 (20% vs -19%, p=0.010). FDG PET biomarkers were stronger discriminators of chemoICI response status (AUC 0.75-0.82, p=0.009-0.046) than PD-L1 (AUC 0.60, p=0.42). Higher baseline blood TCR Simpson clonality was positively correlated with size reduction (R 0.70, p=0.004), whereas TCR Pielou evenness was negatively correlated (R -0.68, p=0.006). Higher baseline TCR clonality / lower TCR evenness discriminated chemoICI response status (AUC 0.80-0.84, p=0.028-0.049). TCR diversity changes were uncorrelated with response. Conclusions: FDG PET imaging prior to and after first dose chemoICI, along with baseline circulating T cell repertoire biomarkers, predict future response. Further investigation of these patient- and lesion-level biomarkers to guide personalized (de)escalation, consolidation, or adaptation of regimens for stage IV NSCLC is warranted. Clinical trial information: NCT04151940 .