Overall survival following heterogeneous FDG-guided dose-escalation for locally advanced NSCLC in the international phase III NARLAL2 trial.

LBA8069 Background: The survival and loco-regional control for patients (pts) with locally advanced non-small cell lung cancer (LA_NSCLC) treated with radiotherapy (RT) are dismal despite adjuvant Durvalumab. However, there have been concerns about dose escalation for these pts since the unexpected result of the dose-escalation trial RTOG0617. A novel approach is therefore warranted to escalate the dose to the tumor. A possible approach is to use the principle from stereotactic body radiotherapy (SBRT) with inhomogeneous dose distribution. SBRT has demonstrated excellent local control in early-stage lung cancer. The international multicenter NARLAL2 (novel approach to RT for LA_NSCLC) phase III trial on dose escalation, randomized pts with LA_NSCLC between standard 66 Gy/ 33 fractions (F) versus heterogeneous FDG-PET driven dose escalation, aiming at mean dose to GTV-tumorPET 95 Gy/ 33 F and mean dose to GTV-nodePET 74 Gy/ 33 F while strictly respecting dose to organs at risk. We here present the data on overall survival (OS) 1 year after the end of recruitment. Methods: Pts aged ≥18 years with LA_NSCLC were recruited from seven institutions in Denmark and Norway. Eligibility criteria included ECOG PS 0-1, histological or cytological confirmed NSCLC stage IIB-IIIB, signed informed consent, and a clinically acceptable plan for RT with conventional 66 Gy/ 33 F. PET-CT and brain MR were part of staging. Pts were randomly assigned to either treatment group (1:1, stratified for center and histology). The trial aimed to have iso-lung toxicity within the treatment arms by creating two RT plans (before randomization) for each patient (one for each treatment arm) with matching mean lung dose and lung V20Gy. The follow-up (FU) were scheduled weekly during RT, every 3rd month for 2 years, and every 6th month for another 3 years after randomization. At FU visit a CT-scan and toxicity scoring were performed. All interim analyses were passed without interventions (toxicity and OS). The trial's primary endpoint was time to loco-regional failure from randomization. Secondary endpoints included OS, acute, and late toxicity. The sample size calculations requested 350 pts to be enrolled in the study. Recruitment of the pre-planned number of pts finalized in March 2023. The trial was registered with ClinicalTrials.gov (NCT02354274). Results: From January 2015 to March 2023, 350 pts were randomized: 177 and 173 pts in standard and escalated arms respectively. The two groups were well-balanced regarding age, gender, stage, and PS. The dose to GTV-tumor was 66.5 Gy [66.2, 67.1] (median [IQR]) in the standard arm and 88.1 Gy [84.9, 90.4] in the escalated arm. Median OS were 35.8 months (m) and 51.6 m for pts treated in the standard and escalated arm, respectively ( p = 0.36). Median FU time 50.8 m (reverse Kaplan-Meier). Conclusions: Dose escalation is safe in the NARLAL2 setting with respect to OS. Clinical trial information: NCT02354274 .