2796 - Longitudinal T-Cell Receptor Analysis of Patients with Locally Advanced NSCLC Treated with Hypofractionated Chemoradiation and SABR Boost

I. N. Goronzy¹, J. E. Juarez Casillas², T. C. Wu³, B. K. Neilsen³, J. Hack², A. S. Chumpitaz Lavalle², C. Felix², J. Goldman⁴, E. Garon⁴, A. Lee³, J. M. Lee⁵, J. Yanagawa⁵, D. Moghanaki², A. Raldow³, M. L. Steinberg³, D. Schaue², P. Lee⁶, and J. Deng³; ¹David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, ²Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, ³Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, ⁴Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, ⁵Department of Surgery, Division of Thoracic Surgery, University of California, Los Angeles, Los Angeles, CA, ⁶Department of Radiation Oncology, Lennar Foundation Comprehensive Cancer Center, City of Hope National Medical Center, Irvine, CA

Purpose/Objective(s): Conventionally fractionated chemoradiation (CRT) is key in the treatment of locally advanced, unresectable non-small cell lung cancer (LA-NSCLC). Consolidation with durvalumab significantly improves survival, underscoring T cell importance. Hypofractionated radiation can also enhance systemic immunity, suggesting benefits beyond local control, though this has not been explored in LA-NSCLC. In an early-phase trial, patients with LA-NSCLC were treated with hypofractionated CRT with a PET-adapted stereotactic ablative radiotherapy boost (HyCRT-SABR). We investigated the longitudinal evolution of T-cell receptor (TCR) signatures with hypofractionation and its relationships to outcomes. Materials/

Methods: Data from a single-institution, nonrandomized, dose-escalated HyCRT-SABR with concurrent carboplatin/paclitaxel (pre-PACIFIC) trial for LA-NSCLC were analyzed (NCT01345851). Patients received an initial 40 Gy in 10 fractions followed by a PET-adapted SABR boost of 25 Gy (low), 30 Gy (int), or 35 Gy (high) in 5 fractions to residual PET-avid disease. Blood was collected at baseline, after 40 Gy, and 3-months after treatment for T cell receptor (TCR) beta chain sequencing (from a technology company). Associations between clinical features (stage, histology, mutations, smoking history, SABR boost) and TCR diversity metrics (Simpson’s D, max productive frequency, Pielou evenness) with overall survival (OS), regional, or distant control were modeled using mutual information (MI), a quantitative measure of dependence in which higher relative rank indicates more predictive features.
Results: 28 patients (median [range] age, 70 (51-88) years; 57% male; 14% with stage II, 86% with stage III) were enrolled. There were no significant differences in toxicity, OS, PFS, or LC between SABR cohorts. TCR analysis was done for 17 patients (low, n= 6; int, n=9; high, n=1). For known prognostic clinical features, MI confirmed N/group stage and histology as the high scoring features for regional or distant control and N stage as the highest scoring for OS. SABR cohort was the low ranking, consistent with similar group outcomes. For exploratory features, MI identified TCR metrics at all timepoints as predictive. For regional or distant control, TCR metrics post 3-months outranked clinical features and metrics at baseline were of similar predictive rank as T stage, mutation status, and smoking history. For OS, TCR metrics after 40 Gy outranked all clinical features except N stage.
Conclusion: Our findings illustrate that TCR metrics of patients with LA-NSCLC from baseline to 3-months after hypofractionated CRT are potential predictors for overall survival and tumor control, equivalent to known prognostic clinical features. These findings may have implications for applying a hypofractionated CRT approach in the era of adjuvant durvalumab to amplify T-cell function.