Abstract PR011: Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: Updated data from the iMATRIX Alectinib phase I/II open-label, multi-center study
Bibliographic record
Abstract
Abstract Background Alectinib is a central nervous system (CNS)-penetrant, oral, inhibitor of ALK-fusion proteins that has demonstrated durable responses in adults with ALK-positive non-small cell lung cancer and children with Anaplastic Large Cell Lymphoma. In children and adolescents there remains a significant unmet clinical need for patients with tumors harboring ALK-fusions, including infantile high-grade gliomas and inflammatory myofibroblastic tumors at diagnosis or relapse. Here we present updated safety and efficacy data from the iMATRIX Alectinib phase I-II study (NCT04774718). Methods Patients with ALK fusion-positive solid or CNS tumors for whom prior treatment has proven to be ineffective or for whom there is no satisfactory treatment available, less than 18 years of age, were eligible. Patients were recruited to the Part 1, safety run-in to confirm the recommended phase 2 dose (RP2D) and monitor drug pharmacokinetics. Investigators reported Best Overall Response according to RANO (CNS tumors), RECIST (solid tumors) or INRC (neuroblastoma) criteria with a data cut off of January 2024. Results In total 16 patients with a median age of 10 years (range 0 months - 17 years), diagnosed with inflammatory myofibroblastic tumor (n=5), high grade glioma (n=5), renal cell carcinoma (n=2), mesothelioma (n=1), nephroblastoma (n=1), ALK-fusion histiocytosis (n=1, protocol deviation) and anaplastic large cell lymphoma (n=1, protocol deviation) were enrolled. Among 16 patients, 10 had not received prior systemic therapy. ALK fusion partners were EML4 in 3 patients, CLTC and KIF5C in 2 patients each, and FN1, KIF5B, NPM, PPP1CB, STRN, TPM3, PLEKHA7, DCTN1 and HNRNPA3 in 1 patient each. Only 1 Dose Limiting Toxicity of Grade 3 increased alanine aminotransferase, in the context of multiple intercurrent viral infections, was reported in an 8 year old with nephroblastoma. The DLT resolved after treatment interruption and alectinib was restarted at a reduced dose level. Thirteen patients experienced an Adverse Event (AE) reported as related to alectinib, including 5 patients with Grade ≥ 3 related AE. There were no AE-related deaths, and no new safety signals detected. Investigator reported Best Overall Response rate in 12 patients was 91.7%; (1 CR, 10 PR) and 1 patient was reported to have Stable Disease. Four patients were excluded from the efficacy analysis due to protocol deviations related to the inclusion criteria (n=2 had an ineligible tumour type, n=1 was not dosed, n=1 had no measurable disease according to RANO criteria). Conclusions Alectinib continues to be well tolerated in pediatric patients with ALK-fusion positive solid or CNS tumors. In this hard-to-treat population, efficacy results are very promising with the majority of patients experiencing a tumour response, indicating a positive benefit-risk profile. AcknowledgmentsWe acknowledge Thorsten Ruf’s contribution to the study design and implementation. Citation Format: Francois Doz, Michela Casanova, Kyung-Nam Koh, Karsten Nysom, Adela Canete, Hyoung Jin Kang, Matthias Karajannis, Darren Hargrave, Nadege Corradini, Yeming Wu, #Huanmin Wang, Carolina Sturm, Johannes Noe, Tao Xu, Nastya Kassir, Yachun Tai, Francis Mussai, Clare Devlin, Amar Gajjar. Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: Updated data from the iMATRIX Alectinib phase I/II open-label, multi-center study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr PR011.
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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".