TPS8594 Background: Despite definitive surgery and perioperative chemotherapy, many patients with locoregional non-small cell lung cancer (NSCLC) continue to experience recurrent disease and limited survival. Although targeted therapies are standard treatment for metastatic NSCLC with genomic alterations, their use in the early-stage setting is still being characterized. Initial studies examining targeted therapy in neoadjuvant setting for early-stage epidermal growth factor receptor positive NSCLC has shown promise. Selpercatinib is a highly selective, potent, and central nervous system active rearranged during transfection (RET) inhibitor with demonstrated robust and sustained antitumor activity and manageable toxicity in patients with RET fusion-positive advanced NSCLC. Cohort 7 of the Phase 2, open-label, single arm LIBRETTO-001 study evaluates efficacy and safety of neoadjuvant selpercatinib in patients with resectable stage IB-IIIA RET fusion-positive NSCLC (NCT03157128). Methods: Key eligibility criteria include age ≥18 years; histologically confirmed stage IB–IIIA NSCLC (AJCC, version 8); presence of RET fusion in tumor (by PCR or NGS) or blood (by NGS) (pre-treatment biopsy confirmed); resectable and operable tumor; measurable disease (RECIST 1.1); and ECOG performance status 0-1. Key exclusion criteria include presence of other known oncogenic drivers; and concurrent investigational anticancer therapy. Eligible patients will undergo full staging including radiographic tumor measurements using CT, PET, and brain MRI at baseline and after two 28-day cycles of neoadjuvant selpercatinib, followed by surgery. Dosing regimen is 160 mg twice daily. Resected tumor specimens will be sent to an Independent Pathology Review Committee (IPRC) for evaluation. Patients may then be treated with stage-appropriate adjuvant therapy/surveillance, based on the treating physician’s decision, followed by selpercatinib until disease recurrence, unacceptable toxicity, withdrawal, or death, for a maximum treatment duration of 3 years. The primary endpoint is to determine the rate of major pathologic response (MPR) by IPRC, defined as ≤ 10% residual viable tumor cells in the surgically resected specimen. Efficacy based on the MPR will be assessed using the Simon's 2-stage design. In Stage I, 9 patients will be enrolled; if ≤1 patient achieves an MPR, the study will be stopped. Otherwise, at least 10 additional patients will be enrolled, with a total of 19 patients undergoing surgery. The rate of pathologic complete response (pCR) by IPRC, disease-free survival, and overall survival will be assessed as secondary endpoints. pCR rate will be determined at the time of surgery, indicating no remaining viable tumor cells. Safety of peri-operative treatment will be assessed, including 30- and 90-day post-operative readmission and mortality rates. Clinical trial information: NCT03157128.