Updated entrectinib data in children and adolescents with recurrent or refractory solid tumors, including primary CNS tumors.
Bibliographic record
Abstract
107 Background: The phase 1/2 STARTRK-NG trial (NCT02650401) is evaluating entrectinib, a CNS-penetrant oral inhibitor of TRK, ROS1 and ALK tyrosine kinases, in children and adolescents < 21 years old with recurrent/refractory solid tumors, including primary CNS tumors. Methods: After determining the recommended dose as 550mg/m 2 /day in all-comers, expansion cohorts with gene-fusion-positive CNS/solid tumors ( NTRK1/2/3 and ROS1) are being enrolled. Results: As of 1 July 2019 (data cut-off), 34 patients (4.9 months to 20 years old; median age 7 years) have been evaluated for response to treatment with entrectinib. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) using RANO for CNS tumors, RECISTv1.1 for solid tumors, or Curie score for neuroblastomas. Responses in fusion-positive patients were assessed by blinded independent central review (BICR), and occurred at doses ≥400mg/m 2 . Best responses in patients with fusion-positive CNS tumors (n = 8) were four CR ( ETV6-NTRK3, EML1-NTRK2, GOPC-ROS1, and TPR-NTRK1), two PR ( KANK1-NTRK2 and EEF1G-ROS1), and two PD ( EML4-ALK and PARP6-NTRK3). In patients with fusion-positive solid tumors (n = 6) best responses were three CR ( DCTN1-ALK, ETV6-NTRK3, and ETV6-NTRK3), and three PR ( TFG-ROS1, EML4-NTRK3, and KIF5B-ALK). Responses (Investigator-assessed) in patients with non-fusion tumors (n = 20) were one CR ( ALK F1174L mutation), four SD, ten PD, and five patients were unevaluable or had no data. The objective response rate (defined as the total number of CR and PR) in fusion-positive patients was 86% (12/14) versus 5% (1/20) in non-fusion patients. Similarly, PFS was 17.5 months (95% CI 7.4–NE) in fusion-positive patients versus 1.9 months (1.8–5.7; p = 0.0002) in non-fusion patients. Most commonly reported treatment-related adverse events included weight gain (n = 14 [5 Grade 3/4]), elevated creatinine (n = 13), anemia (n = 13), nausea (n = 11), increased ALT (n = 10 [1 Grade 3/4]), increased AST (n = 10 [1 Grade 3/4]), decreased neutrophils (n = 9 [6 Grade 3/4]), and bone fractures (n = 7, of which 4 were treatment related). Conclusions: In children and adolescents < 21 years old, entrectinib has produced striking, rapid, and durable responses in solid tumors with target gene fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".