Background: Concurrent chemoradiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC) can cause significant toxicities, and disease recurrence after treatment is common. We previously demonstrated that a dose-painted radiotherapy approach provides excellent local disease control and has a favorable toxicity profile. Consolidation immunotherapy was recently shown to improve outcomes after chemoradiotherapy for LA-NSCLC, and pembrolizumab monotherapy is now a standard of care for patients with advanced high PD-L1-positive NSCLC. We hypothesize that dose-painted thoracic radiotherapy and immunotherapy without chemotherapy will be safe and effective for the treatment of biomarker-selected patients with LA-NSCLC. Methods: Patients with a new diagnosis of unresectable stage II or stage III NSCLC and performance status 0-1 will be enrolled on this phase II trial at one of three participating institutions. Twenty-five subjects with PD-L1 Tumor Proportion Score (TPS) of at least 50% will receive three cycles of induction pembrolizumab (200 mg every 3 weeks). Subjects then receive 20 fractions of dose-painted radiotherapy, where lesions with metabolic tumor volume exceeding 20 cc on FDG-PET receive a dose of 55 Gy, while smaller lesions receive a dose of 48 Gy. Subjects then receive 12 additional cycles of pembrolizumab. The primary endpoint is progression-free survival one year following study enrollment, which we hypothesize will be achieved for at least 65% of study subjects. Other endpoints include overall survival, distant metastasis-free survival, freedom from intrathoracic disease progression, adverse events, patient-reported outcomes, and physical activity metrics captured using wearable devices. In addition, we will explore markers of immune activation as prognostic factors. Approximately 38 patients with PD-L1 TPS below 50% will receive standard chemoradiotherapy and adjuvant therapy to serve as a contemporary comparison cohort. SPRINT is an innovative biomarker-driven study that explores a paradigm shift in the local and systemic therapy used to treat LA-NSCLC. This trial opened in August of 2018, and 5 subjects have been enrolled to date. Clinical trial information: NCT03523702