Abstract A017-PR013: Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: An update from the iMATRIX alectinib phase I/II open-label, multi-center study

Background: Alectinib is a next generation, oral, ALK inhibitor being investigated in children and adolescents with ALK-fusion bearing tumors. Here we present updated safety and efficacy data from iMATRIX Alectinib phase I-II study (NCT04774718). Methods: Patients, less than 18 years of age, with ALK fusion-positive CNS and non-CNS tumors for whom prior treatment had proven to be ineffective or for whom there was no satisfactory treatment available were eligible. Patients were recruited to Part 1 to confirm the recommended phase 2 dose (RP2D) and to study drug pharmacokinetics. Alectinib was administered as an oral tablet or suspension twice a day according to initial weight. Investigators reported Best Overall Response according to RANO (CNS tumors) or RECIST v1.1 (solid tumors) criteria (data cut off February 2025). Results: In total 25 patients with a median age of 7.5 years (range 0-17 years) were enrolled. Fifteen patients were diagnosed with solid tumors: inflammatory myofibroblastic tumor (n = 10), renal cell carcinoma (n = 2), mesothelioma (n = 1), nephroblastoma (n = 1), and atypical melanocytic tumor (n = 1). Eight patients were diagnosed with CNS tumors: high grade glioma (n = 7) and pleomorphic xanthoastrocytoma (n = 1). Two patients had ineligible conditions: histiocytosis (n = 1) and anaplastic large cell lymphoma (n = 1). Ten of 25 patients had received prior systemic therapy. ALK fusion partners were EML4 and CLTC in 3 patients, TPM3, KIF5C, PPP1CB and FN1 in 2 patients, and DCTN1, KIF5B, NPM, STRN, CLIP1, RANBP2, ZEB2, PLEKHA7, CDC42BPB, HNRNPA3, and ZNF397 in 1 patient each. In the 24 safety evaluable patients, only 1 Dose Limiting Toxicity (DLT) of Grade 3 increased alanine aminotransferase, during multiple viral infections, was reported. The DLT resolved after treatment interruption and Alectinib was successfully tolerated at a reduced dose level. Twenty patients (83%) experienced at least one Adverse Event (AE) reported as related to Alectinib, mostly Grade 1 or 2. Grade ≥ 3 AEs assessed as related to alectinib by the investigator were reported for 6 patients (25%) and consisted of increases in CPK,AST, ALT, bilirubin; neutropenia, optic neuropathy, encephalopathy and weight gain. Of these the increased ALT (DLT) and optic neuropathy/ encephalopathy in 2 patients were serious AEs. No new safety signals were detected. Investigator reported Best Overall Response rate in 19 patients was 89.5%; (3 CRs, 14 PRs) and 2 patients were reported to have confirmed stable disease. One complete response and 5 partial responses were observed in 6/6 evaluable patients with CNS tumors. Two complete responses and 9 partial responses were seen in 11 evaluable patients with solid tumours. Four patients were excluded from the efficacy analysis due to ineligible tumor type (n = 2), not dosed (n = 1), no measurable disease according to RANO criteria (n = 1). Conclusions: Alectinib continues to have a favourable safety profile in pediatric patients. Clinical efficacy results are highly encouraging with most patients experiencing a tumor response. 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, David Ziegler, Nicolas Prud'homme, Carla Manzitti, Quentin Campbell-Hewson, Carolina Sturm-Pellanda, Tao Xu, Dhruvitkumar S. Sutaria, Livingstone Fultang, Clare Devlin, Francis Mussai, Amar J Gajjar. Alectinib in children and adolescents with solid or CNS tumors harboring ALK-fusions: An update from the iMATRIX alectinib phase I/II open-label, multi-center study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A017-PR013.