Abstract Introduction: Selpercatinib, approved by FDA in May 2020 is a highly selective and potent RET inhibitor which has demonstrated antitumor activity in patients (pts) with RET-altered non-small-cell lung cancer and thyroid cancer. To further characterize clinical safety, we analyzed the timing of selected treatment-emergent adverse events (TEAEs) as well as long-term use of selpercatinib. Methods: Pts with RET-fusion positive or RET-mutant tumors who received at least 1 dose of selpercatinib, as part of the LIBRETTO-001 study, were included in this analysis (data-cut off 19 Dec 2019; NCT 03157128). Median time to onset, dose reduction, and discontinuation due to TEAEs were evaluated for relevant common TEAEs (≥25% of pts) and TEAEs of special interest. TEAE data were also analyzed according to time exposed to treatment at cutoff (<12 or ≥12 months). Results: A total of 702 pts were included in the analysis and 99% experienced ≥1 TEAE (any grade). At cutoff, median time on treatment was 8.7 mo, with 78% continuing to receive selpercatinib. Common TEAEs and TEAEs of interest are summarized (median time to onset, dose reduction, and discontinuation due to TEAEs) in the table. 466 (66.4%) pts received treatment for <12 months, whereas 236 (33.6%) pts received treatment for ≥12 months. Similar rates of grade ≥3 TEAEs were observed across the two exposure groups, 271 (58.2%) pts and 145 (61.4%) pts on treatment for <12 months and ≥12 months, respectively. 138 (29.6%) pts on treatment <12 months and 81 (34.3%) pts on treatment ≥12 months underwent dose reductions due to TEAEs. 32 (6.9%) pts on treatment <12 months and 5 (2.1%) pts on treatment ≥12 months discontinued treatment due to TEAEs. Conclusion: Most TEAEs had a median onset within the first month of treatment, with TEAEs minimally impacting a patient's ability to receive selpercatinib. In these analyses, no new safety concerns were identified in patients on treatment for <12 months or ≥12 months. Relevant TEAEs of interest by decreasing frequency in any grade in ≥25% of patients and TEAEs of interest (N = 702)TEAE(consolidated terms)Any Grade TEAEn (%)Median time (weeks) to first occurrence (range)Leading to dose reductionn (%)Leading to drug discontinuationn (%)Dry Mouth273 (38.9)2.9 (0.1-107.9)5 (0.7)0 (0.0)Diarrhea257 (36.6)8.0 (0.1-99.9)11 (1.6)0 (0.0)Hypertension252 (35.9)History of hypertension114 (39.4)2.5 (0.1-83.0)5 (1.7)0 (0.0)No history of hypertension138 (33.4)2.2 (0.1-60.0)4 (1.0)0 (0.0)AST increased210 (29.9)4.1 (0.1-111.1)39 (5.6)2 (0.3)ALT increased201 (28.6)4.1 (0.1-79.7)45 (6.4)3 (0.4)Constipation178 (25.4)4.4 (0.1-90.4)2 (0.3)0 (0.0)QTc Prolongation118 (16.8)3.5 (0.1-92.0)16 (2.3)0 (0.0)Hypersensitivity30 (4.3)1.7 (0.9-77.0)20 (2.8)3 (0.4)Rash191 (27.2)9.3 (0.1-110.4)15 (2.1)1 (0.1)Edema242 (34.5)9.8 (0.1-109.9)7 (1.0)0 (0.0)Fatigue246 (35.0)5.4 (0.1-9918 (2.6)2 (0.3)N, number of subjects in the population; n, number of subjects in the specified category; TEAE, treatment-emergent adverse event. AST, aspartate transaminase; ALT, alanine aminotransferase; QTc, corrected QT. Citation Format: Todd M Bauer, Benjamin Besse, Herbert H F Loong, Bruce Robinson, Victoria Soldatenkova, Catherine Elizabeth Muehlenbein, Bente Frimodt-Moller, Caroline E McCoach. Safety of selpercatinib for RET-altered advanced solid tumors: a post hoc analysis of LIBRETTO-001 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT160.