Mature Outcomes and Patterns of Failure in the Phase II FLARE-RT Trial of Biological Image-guided and Risk-Adaptive Chemoradiation for Unresectable NSCLC

PURPOSE: FLARE-RT tested personalized functional-lung-avoidance and response-adaptive radiotherapy intensification for unresectable non-small cell lung cancer (NSCLC) using FDG-PET/CT and SPECT/CT. We report mature outcomes and failure patterns. METHODS: 49 patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on FLARE-RT (NCT02773238) from 2016-2021 and initiated chemoradiation. Patients with Week 3 FDG-PET response received 60Gy in 30 fractions. Patients with non-response received concomitant boosts Weeks 4-6 to residual metabolic disease of 74-90Gy total guided by FDG uptake. Overall survival (OS, primary endpoint) and progression free survival (PFS) were estimated via Kaplan-Meier. Locoregional progression (LRP) and distant metastasis (DM) cumulative incidence were estimated via Aalen-Johansen, with death and alternative progression pattern as competing risks. Predictors of treatment failure modes were identified through Fine-Gray regression. RESULTS: At 52.3 months median follow-up, 1-year and 2-year OS were 81.6% (95%CI:71.5-93.2%) and 54.2% (CI:41.8-70.4%), respectively; 1-year and 2-year PFS were 53.1% (CI:40.9-69.0%) and 40.5% (CI:28.8-57.0%), respectively. Cumulative incidence for 1-year and 2-year LRP was 12.2% (CI:4.9-23.2%) and 18.5% (CI:9.0-30.6%), respectively; 1-year and 2-year DM were 34.7% (CI:21.7-48.1%) and 43.1% (CI:28.9-56.5%), respectively. Higher pre-RT FDG-PET total lesion glycolysis (TLG) correlated with increased LRP (HR=1.87 [CI:1.41-2.49], p<0.001), whereas higher mid-RT TLG correlated with DM (HR=1.52 [CI:1.05-2.21], p=0.03). 25 of 49 patients received durvalumab and exhibited lower 1-year DM (20.0% vs. 54.2%, p=0.04) with equivocal 1-year LRP (20.0% vs. 4.2%, p=0.27). CONCLUSION: Biological image-guided FLARE-RT achieved durable locoregional control with consistent survival outcomes relative to RTOG0616 (60Gy arm) and RTOG1106 (adaptive arm). This informs biomarker-guided and risk-adaptive therapy for unresectable NSCLC.