Background: Durvalumab following chemoradiation (CRT) is a standard of care for unresectable stage III NSCLC, but there remains an unmet need for improved therapeutic options among patients with driver-mutated tumors that are unresponsive to immunotherapy. As targeting of specific driver mutations (e.g. ALK, RET, ROS1) has proven effective in the metastatic setting, it is hypothesized that outcomes could also be improved for patients with driver-mutated stage III NSCLC. Methods: BO42777 (NCT05170204) is a phase I–III platform study evaluating the safety and efficacy of multiple targeted therapies versus durvalumab following CRT in patients with locally advanced, unresectable stage III NSCLC. Biomarker eligibility is determined via local tissue testing or central testing within the BX43361 master screening study (NCT05419375). Biomarker-eligible patients are enrolled into the relevant cohort and randomized 1:1 to receive durvalumab or targeted therapy (alectinib [ALK+], entrectinib [ROS1+], or pralsetinib [RET fusion+]). New cohorts may be added in the future. Key inclusion criteria: locally advanced, unresectable stage III NSCLC, age ≥18 years, ≥2 prior cycles of concurrent or sequential CRT (cCRT or sCRT), and ECOG PS 0–2. Patients are stratified based on staging (IIIA vs IIIB or IIIC), CRT type (cCRT vs sCRT), and PD-L1 status (tumor cell score < 1% vs ≥1% vs unknown) and will receive investigational treatment for three years or durvalumab for one year, until progression or maximum duration of treatment, unacceptable toxicity, consent withdrawal, or death. Primary endpoint: progression-free survival (RECIST v1.1) by blinded independent central review. Key secondary endpoints: distant metastasis-free survival, time to CNS progression, objective response rate, duration of response, overall survival, and safety (adverse events). Time to confirmed deterioration and patient-reported outcomes will be assessed through questionnaires. Tumor response will be assessed by CT/MRI imaging at regular intervals. Enrolment is ongoing (target of 320 patients) across 200 sites in 11 countries. As of 7 February 2023, five patients have been randomized. This trial in progress was previously presented at ELCC, Luis Paz-Ares et al. (#744), and reused with permission. Clinical trial information: NCT05170204.