2136 - NRG LU008: Phase III Prospective Randomized Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed by Concurrent Mediastinal Chemoradiation for Locally-Advanced Non-Small Cell

C. B. Simone II^1,2, C. Hu^3,4, J. H. Heinzerling II⁵, K. Mileham⁶, K. A. Higgins⁷, L. Lin⁸, M. Abazeed⁹, N. Ohri¹⁰, and J. D. Bradley¹¹; ¹New York Proton Center, New York, NY, ²Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ³Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, ⁴NRG Oncology, Philadelphia, PA, ⁵Levine Cancer Institute, Atrium Health and Southeast Radiation Oncology Group, Charlotte, NC, ⁶Levine Cancer Institute, Atrium Health/Wake Forest School of Medicine, Charlotte, NC, ⁷City of Hope, Atlanta, GA, ⁸Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, ⁹Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, ¹⁰Department of Radiation Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, ¹¹Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Purpose/Objective(s): Outcomes remain poor for unresectable LA-NSCLC treated with concurrent chemoradiation followed by immunotherapy. The primary tumor is the most common site of non-metastatic failure, and local failure (LF) is associated with overall survival (OS). While local control (LC) and OS have improved by increasing the biological effective dose with SBRT in early-stage NSCLC, SBRT use in LA-NSCLC has largely been limited to primary tumor boost after chemoradiation, which has high morbidity. A recent phase II trial of SBRT to the primary tumor and chemoradiation to involved lymph nodes demonstrated lower rates of pulmonary and cardiac toxicities relative to historical controls, while improving LC, progression-free survival (PFS), and OS. We hypothesize that replacing conventionally fractionated radiotherapy with SBRT to the primary tumor followed by concurrent chemoradiation to the mediastinum will be associated with lower rates of toxicity and improved QOL, while also improving LC, PFS, and OS. Materials/

Methods: LU008 is a phase III randomized trial in stage II-III NSCLC conducted by NRG Oncology (NCT05624996). Inclusion criteria include node-positive stage II-III NSCLC, medically inoperable or surgery declined, identified primary tumor =7 cm, ECOG performance status (PS) 0-2, and =4 cycles of systemic therapy prior to registration. Key exclusion includes central primary tumor location that is <2cm from involved nodal disease. Patients are randomized to chemoradiation to all disease (60/2 Gy) (control arm) or SBRT to the primary (BED =100 Gy in 3-5 fractions) followed by chemoradiation to nodal disease (60/2 Gy) (experimental arm). Standard concurrent chemotherapy regimens are allowed in both arms. Maintenance therapy is pragmatic, with most patients expected to receive durvalumab for up to 12 months. The primary objectives are to compare OS and PFS. Secondary objectives are to compare response rate, LC, patterns of failure, pulmonary function changes, QOL, and toxicity. Exploratory objectives include biospecimen analyses, regional lung ventilation, and proton vs. photon differences. Real-time pre-treatment reviews are conducted.
Results: LU008 was activated nationally on 5/10/23. As of 3/1/24, 30 patients have been accrued, and 266 sites have the trial open to accrual. Final target accrual is 474 subjects, with an expected 9.5 accruals per month after a 6-month ramp up.
Conclusion: LU008 is a thoracic NCI National Clinical Trial Network (NCTN) trial with highly pragmatic eligibility criteria, with no lab/PFT cutoffs, no CT chest/MRI brain/lab time windows, no exclusions for actionable mutations, and allowing ECOG PS 2. LU008 is the only phase III NCTN trial accruing for inoperable LA-NSCLC and may change the standard of care in inoperable LA-NSCLC by improving LC, PFS, and OS.

Funding: Grants U10CA180868 (NRG Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA196067 (NRG Specimen Bank), U24CA180803 (IROC) from the National Cancer Institute (NCI).