Oral selpercatinib in pediatric patients (pts) with advanced <i>RET</i>-altered solid or primary CNS tumors: Preliminary results from the phase 1/2 LIBRETTO-121 trial.
Bibliographic record
Abstract
10009 Background: Activating RET alterations are oncogenic drivers of select pediatric and adult cancers. Selpercatinib is a first-in-class, highly selective and potent, CNS active RET kinase inhibitor. The manageable toxicity profile and durable anti-tumor activity in RET-altered cancers demonstrated in the LIBRETTO-001 phase 1/2 trial led to global approvals of selpercatinib in adults and adolescents with thyroid cancer and adults with NSCLC. Methods: LIBRETTO-121 (JZJJ) is a multicenter phase 1/2 trial in pts 0.5-21 years (yrs) of age with advanced, RET-altered solid or CNS tumors. Enrollment began in June 2019 and is ongoing. Selpercatinib is administered orally as capsule or liquid suspension BID continuously. Dosing started at the adult recommended phase 2 dose (RP2D) equivalent, 92mg/m2 BID, to confirm RP2D in pts ≤2 yrs and > 2 yrs. The phase 1 primary objective is to evaluate safety and dose limiting toxicities (DLTs). The phase 2 primary objective is to determine overall response rate by RECIST 1.1 or RANO by independent review. Results: As of 2-Oct-2020, 11 pts (6 male) aged 2–20 yrs (medullary thyroid cancer, n = 8; papillary thyroid cancer, n = 2; osteosarcoma, n = 1) had been treated (phase 1, n = 4; phase 2, n = 7). At baseline, 7 pts had measurable disease. RET alterations included fusions (n = 2), activating mutations (n = 8) and mutation with unknown clinical significance (n = 1). Prior therapies included surgery (n = 8), chemotherapy (n = 1), vandetanib (n = 1) and radiotherapy (n = 3), while 3 pts were previously untreated. Time on selpercatinib ranged from 0.9-13.4 months and 9 pts remain on treatment. One pt experienced a dose reduction and 2 pts experienced dose interruptions due to treatment-emergent adverse events (TEAEs) (elevated alanine aminotransferase [ALT] and bilirubin). There were no DLTs and no TEAEs that led to discontinuation of selpercatinib. TEAEs in > 15% of pts included elevated alkaline phosphatase (ALP), constipation, headache, elevated aspartate aminotransferase (AST), diarrhea, hyperphosphatemia, hypoalbuminemia, hypothyroidism, nausea, pyrexia, urinary tract infection, vomiting and weight gain. Drug-related TEAEs in > 15% of pts included elevated AST, elevated ALP, hyperphosphatemia and hypothyroidism. One pt reported TEAEs ≥ grade (G) 3 (elevated ALT, G3 and AST, G3) related to selpercatinib. Best response was unconfirmed partial responses in 4 pts, stable disease in 6 pts (two lasting ≥16 weeks) and progressive disease in 1 pt. Conclusions: These findings appear consistent with the adult trial results, showing preliminary evidence of safety and efficacy of selpercatinib in pediatric pts with RET-altered solid tumors. The phase 1 portion in pts ≤2 yrs and phase 2 portion at RP2D of 92mg/m2 BID for pts > 2 yrs are ongoing. Clinical trial information: NCT03899792.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".