Abstract
Disclosure: T.W. Laetsch: Advanced Microbubbles, AI Therapeutics, Bayer, Inc., ITM Oncologists, Jazz Pharmaceuticals, MassiveBio. R.H. Alvaro: None. D. Ziegler: Bayer, Inc., Amgen Inc, AstraZeneca, Merck, Novartis Pharmaceuticals, Day One Biopharmaceuticals, Accendatech, FivePhusion, Alexion Pharmaceuticals, Inc., Norgine. H.J. Kang: None. C. Albert: None. T.C. Watt: Ymabs Therapeutics Inc. S.L. Fetzko: None. A. Arakawa: None. K. Nysom: Bayer, Inc., Eli Lilly & Company. C. Rigaud: None. S. Suriyapperuma: Eli Lilly & Company. N. Sharma: Eli Lilly & Company. P. Peterson: Eli Lilly & Company. J. Wright: Eli Lilly & Company. D. Morgenstern: None.
Introduction: Selpercatinib is a highly selective and potent oral RET inhibitor with CNS activity, approved for treatment of RET-altered tumors in patients (pts) aged ≥2 years. Here we report on the safety and efficacy of selpercatinib in pediatric and adolescent pts with RET-altered solid tumors from the LIBRETTO-121 study, with a median follow-up of 30 months. Methods: LIBRETTO-121 (NCT03899792) is a multicenter phase 1/2 trial in pts 0.5-21 yrs of age with advanced, RET-altered solid tumors. To confirm the recommended phase 2 dose (RP2D) for selpercatinib, dosing started at 92 mg/m2 BID, equivalent exposure to 160 mg BID in adults. The primary objectives were to evaluate safety and dose-limiting toxicities (DLTs) in phase 1 and determine the ORR per RECIST 1.1 by independent review in the phase 2 population. The secondary objectives were to determine the RP2D and investigator-assessed ORR, clinical benefit rate (CBR), DOR and PFS. Results: As of November 8, 2024, 36 pts aged 2-20 yrs were treated with selpercatinib. Tumor types included RET-mutant medullary thyroid cancer (MTC, n=15), RET fusion-positive papillary thyroid cancer (PTC, n=15) and other (n=6). The most common RET alterations were a M918T mutation (67% [10/15] of MTC pts) or NCOA4-RET fusion (47% [7/15] of PTC pts). Pts (n=36) treated at 92 mg/m2 (up to 160 mg BID) had a similar exposure as adults (n=667) treated with 160 mg BID at steady state on cycle 1 day 8. Time on selpercatinib ranged from 0.4 to 62.4 mo; 25 pts remained on treatment. There were no DLTs or treatment discontinuations due TEAEs; 8 pts (22%) experienced a dose reduction due to TEAEs. The most common TEAEs observed (≥30% of pts) were diarrhea, nausea, elevated AST, pyrexia, abdominal pain, elevated ALT, headache, cough, and vomiting. The most common TEAEs ≥ G3 included weight gain (11%), elevated ALT (8%), vomiting (8%), and anemia, constipation, hypertension, hypokalemia, and reduced neutrophil count, each occurring in 2 pts (6%). Investigator-assessed ORR among all pts was 36% (13/36) and 50% (18/36) had stable disease (SD), resulting in a CBR of 86% (31/36). Responses were durable, with a 24 mo DOR rate of 100% (95% CI: 100, 100). With a median follow-up of 30 mo, investigator-assessed mPFS among all pts has not yet been reached, and the 24 mo PFS rate was 86% (95% CI: 69%, 94%). Among pts with MTC, the ORR was 40% (6/15) and 53% (8/15) had SD, resulting in a CBR of 93% (14/15); 1 pt was unevaluable. In pts with PTC, the ORR was 33.3% (5/15) and 67% (10/15) had SD, resulting in a CBR of 100% (15/15). No MTC or PTC pts had PD through data cut off.
Conclusions: With a median follow-up of 30 months selpercatinib continues to show durable efficacy in pediatric and adolescent pts with RET-altered thyroid cancer and is well tolerated with easily identifiable and manageable toxicities. These results further support the need to identify and target RET alterations with selpercatinib in pediatric and adolescent pts.
Presentation: Monday, July 14, 2025