181 - Risk-Adapted Radiotherapy for Locally Advanced NSCLC: Pooled Analysis of Two Prospective Trials

Purpose/Objective(s): PAINT and REPAINT were prospective phase II trials evaluating risk-adapted, personalized, and de-intensified radiotherapy for locally advanced non–small cell lung cancer (LA-NSCLC). We report long-term clinical outcomes and patterns of failure from both studies.

Materials/Methods: PAINT and REPAINT enrolled patients with stage IIB–III NSCLC and ECOG 0–2 who were suitable for definitive concurrent chemo-radiotherapy. Baseline FDG-PET was utilized to quantify the volume of each pulmonary tumor and involved lymph node. Lesions were categorized as high-risk (>25 cc in PAINT, >20 cc in REPAINT) or low-risk. PAINT delivered 25 daily fractions, with 65 Gy to high-risk and 52–57 Gy to low-risk lesions. The risk-adapted radiotherapy arm of REPAINT delivered 20 daily fractions, with 55 Gy to high-risk and 44–48 Gy to low-risk lesions. Elective nodal irradiation was not permitted. All patients received weekly carboplatin/paclitaxel; adjuvant systemic therapy was allowed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Cumulative incidence of in-field recurrence was analyzed using competing risks methods. Associations between clinical factors and survival were assessed using multivariable Cox proportional hazards models.

Results: Thirty-five patients were enrolled on PAINT (2013-2016), and 23 were enrolled on the risk-adapted radiotherapy arm of REPAINT (2017-2022). Seven PAINT participants (20%) received adjuvant chemotherapy. Eighteen REPAINT participants (78%) received contemporary adjuvant therapy with durvalumab (n=17) or osimertinib (n=1). With a median follow-up duration of 6.5 years, the median PFS duration is 8 months, and the median OS duration is 31 months. Treating progression at other sites and death without progression as competing risks, the 5-year cumulative incidence rate of in-field disease recurrence for study participants is 18%. On a per-lesion basis, the 5-year cumulative incidence rate for tumors and lymph nodes smaller than 20 cc (n=150) is 5%. Multivariable models demonstrated that high disease burden (HR=1.05 per 10 cc, p=0.020) and performance status 2 (HR=3.88, p=0.001) were associated with increased risk of death, while treatment on REPAINT was associated with reduced risk of death (HR=0.41, p=0.021). Thirty-five patients experienced no grade =2 toxicity. Among those with treatment-related adverse events, esophagitis was the most common toxicity. Grade 3 esophagitis occurred in 5% of patients. Analysis showed that mean esophageal dose predicted esophagitis risk; RT course length did not.

Conclusion: Risk-adapted radiotherapy with modest dose de-intensification for small-volume disease yields a low toxicity profile and achieves durable disease control for patients with LA-NSCLC, particularly when effective adjuvant therapy is available. Further studies testing this approach are ongoing.