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

10004 Background: Alectinib is a next generation oral inhibitor of ALK-fusion proteins, being investigated in children and adolescents with ALK-fusion bearing tumors at diagnosis or relapse. Here we present updated safety and efficacy data from the iMATRIX Alectinib phase I-II study (NCT04774718). Methods: Patients, less than 18 years of age, with ALK fusion-positive solid or 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 monitor drug pharmacokinetics. Investigators reported Best Overall Response according to RANO (CNS tumors) or RECIST v1.1 (solid tumors) criteria with a data cut off of July 2024. Results: In total 22 patients with a median age of 8 years were enrolled. Fourteen patients were diagnosed with solid tumors: inflammatory myofibroblastic tumor (n = 9), renal cell carcinoma (n = 2), mesothelioma (n = 1), nephroblastoma (n = 1), and atypical melanocytic tumor (n = 1). Six patients were diagnosed with CNS tumors: high grade glioma (n = 5) and pleomorphic xanthoastrocytoma (n = 1). Two patients had ineligible conditions: histiocytosis (n = 1) and anaplastic large cell lymphoma (n = 1). Among the 22 patients, 14 had not received prior systemic therapy. ALK fusion partners were EML4 and CLTC in 3 patients, TPM3 and KIF5C in 2 patients, and DCTN1, FN1, KIF5B, NPM, PPP1CB, STRN, CLIP1, RANBP2, ZEB2, PLEKHA7, CDC42BPB and HNRNPA3 in 1 patient each. In the 21 safety evaluable patients, only 1 DLT of Grade 3 increased alanine aminotransferase, in the context of multiple viral infections, was reported. The DLT resolved after treatment interruption and Alectinib was restarted at a reduced dose level, and then tolerated well. Eighteen patients (86%) experienced at least one Adverse Event (AE) reported as related to Alectinib, the majority being of Grade 1 and 2 severity. Grade ≥ 3 AEs related to alectinib were reported for 5 patients (23.8%) and there were 2 patients with serious AEs related to Alectinib. There were no new safety signals detected. Investigator reported Best Overall Response rate in 16 patients was 87.5%; (14 PRs) and 2 patients were reported to have stable disease. A partial response was observed in 5/5 evaluable patients with CNS tumors and in 9/11 evaluable patients with solid tumours. Six 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) or lack of response assessment by the analysis cut-off date (n = 2). Conclusions: Alectinib continues to have a favourable safety profile in pediatric patients. Despite this being a very challenging population to treat, clinical efficacy results are transformational with the majority of patients experiencing a tumor response. Clinical trial information: NCT04774718 .