Mature Outcomes and Patterns of Failure in the Phase II FLARE-RT Trial of Biological Image-Guided and Risk-Adaptive...

The nonrandomized phase II trial Functional Lung Avoidance and Response-adaptive Escalation Radiation Therapy (FLARE-RT) tested personalized risk-adaptive radiotherapy for unresectable non-small cell lung cancer (NSCLC) using 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT and single-photon emission computed tomography/CT. We report radiation dosimetry, mature outcomes, adverse events, failure patterns, and risk stratification models.

Forty-nine patients with American Joint Committee on Cancer version 7 stage IIB-IIIB NSCLC enrolled in FLARE-RT (NCT02773238) from 2016 to 2021 and initiated chemoradiation. Patients with week 3 FDG-PET response received 60 Gy in 30 fractions. Patients with nonresponse received concomitant boosts from weeks 4 to 6 to residual metabolic disease of 74 to 90 Gy 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 patterns as competing risks. Predictors of treatment failure modes were identified through Fine-Gray regression.

The median patient age was 63.2 years, with predominantly adenocarcinoma histology (n = 30, 61.2%), N2 nodal disease (n = 31, 63.3%), smoking history (n = 41, 83.6%), and carboplatin-paclitaxel chemotherapy regimen (n = 31, 63.3%). Target volumes and normal tissue dosimetry were similar between PET responders (n = 33, 67.3%) and PET nonresponders (n = 16, 32.7%); PET-guided radiation boosts in select nonresponders did not increase the risk of adverse events except for grade 2 esophagitis. At 52.3 months median follow-up, 1- and 2-year OS was 81.6% [95% confidence interval (CI), 71.5%-93.2%] and 54.2% (95% CI, 41.8%-70.4%), respectively; median OS was 29.1 months (95% CI, 17.3-NA). One- and two-year PFS was 53.1% (95% CI, 40.9%-69%) and 40.5% (95% CI, 28.8%-57.0%), respectively; median PFS was 12.3 months (95% CI, 9.2-not reached). DM occurred in 18 of 31 cases and was the primary mode of failure. Cumulative incidence for 1- and 2-year LRP was 12.2% (95% CI, 4.9%-23.2%) and 18.5% (95% CI, 9.0%-30.6%), respectively; 1- and 2-year DM was 34.7% (95% CI, 21.7%-48.1%) and 43.1% (95% CI, 28.9%-56.5%), respectively. Higher pre-RT FDG-PET total lesion glycolysis (TLG) correlated with increased LRP [hazard ratio (HR) = 1.87 (95% CI, 1.41-2.49), P < 0.001], whereas higher mid-RT TLG correlated with DM [HR = 1.52 (95% CI, 1.05-2.21), P = 0.03]. Of 49 patients, 25 received durvalumab and exhibited lower 1-year DM (20% vs. 54.2%, P = 0.04) with no difference in 1-year LRP (20% vs. 4.2%, P = 0.27). Of 49 patients, 26 were treated with proton radiotherapy, yielding outcomes and failure patterns that were not different compared to those treated with photon therapy.

Biological image-guided FLARE-RT achieved durable locoregional control with OS similar to RTOG 0617 (60 Gy arm)/RTOG 1106 (adaptive arm) and comparable with PACIFIC (durvalumab arm). Risk-adaptive radiation boosts in select patients were well tolerated with potential for improved disease control. Elevated TLG on baseline FDG-PET and residually on mid-treatment FDG-PET was associated with a greater risk of LRP and DM, respectively, which may refine selective radiotherapy and systemic therapy intensification. Validation of these findings is warranted in next-generation trials of imaging biomarker-guided and risk-adaptive therapy for unresectable NSCLC.