P01.01 LIBRETTO-432: A Placebo-Controlled Phase 3 Study of Adjuvant Selpercatinib in Stage IB-IIIA RET Fusion-Positive NSCLC

Abstract

Approximately 30% of patients diagnosed with NSCLC present with early-stage (IB-IIIA) disease. Standard treatment options for these patients are definitive locoregional therapies with/without adjuvant chemotherapy, followed by surveillance until disease recurrence. While targeted therapies are standard treatment for metastatic NSCLC with driver mutations, their use in the early-stage setting is still being characterized. Selpercatinib, a highly selective, potent and CNS active RET inhibitor, demonstrated robust and sustained antitumor activity with manageable toxicity in patients with RET fusion-positive advanced NSCLC. There is a growing evidence demonstrating that oncogene addiction in NSCLC could be actionable regardless of disease stage. LIBRETTO-432 is a Phase 3, global, multicenter, randomized, double-blind, controlled trial evaluating the efficacy and safety of adjuvant selpercatinib versus placebo in patients with RET fusion-positive Stage IB-IIIA NSCLC following completion of definitive radiotherapy or surgery with a curative intent, and other adjuvant therapy if indicated (NCT04819100). Patients (n≈170) will be randomized (1:1) to Arm A (selpercatinib twice daily [160mg ≥50kg; 120mg <50kg]), or B (placebo), in continuous 28-day cycles for a maximum treatment duration of 3 years (Figure 1). Stratification factors include disease stage (Stage IB/II/IIIA) and prior definitive therapy (surgery, radiotherapy). Crossover is allowed for Arm B patients who experience disease recurrence. Treatment will continue until disease recurrence, unacceptable toxicity, withdrawal, or death. Key eligibility criteria include age ≥18 years; histologically confirmed Stage IB/II/IIIA NSCLC; mandatory brain MRI during screening to rule out metastasis; presence of activating RET fusion in tumor by PCR/NGS (local or central testing); received definitive locoregional therapy with curative intent (surgery, radiotherapy) for Stage IB/II/IIIA NSCLC; and ECOG performance status 0-1. Maximum time allowed between definitive therapy completion and randomization must be within 26 weeks. Key exclusion criteria are presence of other known oncogenic drivers; evidence of SCLC; and evidence of disease recurrence following definitive therapy. The primary endpoint is investigator-assessed event-free survival (EFS) in the primary analysis population. EFS is defined as time from randomization until locoregional disease recurrence with histopathological confirmation, distant disease recurrence per RECIST v1.1 or histopathological confirmation, or death. Gated secondary endpoints include investigator-assessed EFS in the overall population and overall survival in both the primary analysis and overall population. Non-gated secondary efficacy endpoints include blinded independent central review (BICR)-assessed EFS, time to distant disease recurrence in the CNS assessed by investigator and BICR, and progression-free survival on the next line of treatment. ▪▪▪ ▪▪▪