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

<jats:p>&lt;div&gt;Abstract Purpose:&lt;p&gt;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[&lt;sup&gt;18&lt;/sup&gt;F]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.&lt;/p&gt; Patients and Methods:&lt;p&gt;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.&lt;/p&gt; Results:&lt;p&gt;The median patient age was 63.2 years, with predominantly adenocarcinoma histology (&lt;i&gt;n&lt;/i&gt; = 30, 61.2%), N2 nodal disease (&lt;i&gt;n&lt;/i&gt; = 31, 63.3%), smoking history (&lt;i&gt;n&lt;/i&gt; = 41, 83.6%), and carboplatin–paclitaxel chemotherapy regimen (&lt;i&gt;n&lt;/i&gt; = 31, 63.3%). Target volumes and normal tissue dosimetry were similar between PET responders (&lt;i&gt;n&lt;/i&gt; = 33, 67.3%) and PET nonresponders (&lt;i&gt;n&lt;/i&gt; = 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), &lt;i&gt;P&lt;/i&gt; &lt; 0.001], whereas higher mid-RT TLG correlated with DM [HR = 1.52 (95% CI, 1.05–2.21), &lt;i&gt;P&lt;/i&gt; = 0.03]. Of 49 patients, 25 received durvalumab and exhibited lower 1-year DM (20% vs. 54.2%, &lt;i&gt;P&lt;/i&gt; = 0.04) with no difference in 1-year LRP (20% vs. 4.2%, &lt;i&gt;P&lt;/i&gt; = 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.&lt;/p&gt; Conclusions:&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;</jats:p>