Afatinib in paediatric patients with recurrent/refractory ErbB-dysregulated tumours: Results of a phase I/expansion trial

Aim: This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer. Methods: The dose-finding part enroled patients (2- < 18 years) with recurrent/refractory tumours. Patients received 18 or 23 mg/m2/d afatinib orally (tablet or solution) in 28-d cycles. In the maximum tolerated dose (MTD) expansion, eligible patients (1- < 18 years) had tumours fulfilling >= 2 of the following criteria in the pre-screening: EGFR amplification; HER2 amplification; EGFR membrane staining (H-score > 150); HER2 membrane staining (H-score > 0). The primary end-points were dose-limiting toxicities (DLTs), afatinib exposure, and objective response. Results: Of 564 patients pre-screened, 536 patients had biomarker data and 63 (12%) fulfilled >= 2 EGFR/HER2 criteria required for inclusion in the expansion part. A total of 56 patients were treated (17 in the dose-finding and 39 in the expansion part). DLTs were observed in one of six MTD-evaluable patients receiving 18 mg/m(2)/d and in two of five MTD-evaluable patients receiving 23 mg/m(2)/d; 18 mg/m(2)/d was defined as the MTD. There were no new safety signals. Pharmacokinetics confirmed exposure consistent with the approved dose in adults. One partial response (-81% per Response Assessment in Neuro-Oncology) was observed in a patient with a glioneuronal tumour harbouring a CLIP2::EGFR fusion; unconfirmed partial responses were observed in two patients. In total, 25% of patients experienced objective response or stable disease (95% confidence interval: 14-38). Conclusion: Targetable EGFR/HER2 drivers are rare in paediatric cancers. Treatment with afatinib led to a durable response (> 3 years) in one patient with a glioneuronal tumour with CLIP2::EGFR fusion. (c) 2023 The Authors. Published by Elsevier Ltd.

Automated summary

This study assessed the safety, pharmacokinetics, and preliminary antitumor activity of afatinib in pediatric patients with cancer. Results showed that afatinib had limited efficacy in pediatric tumors, but it may be effective in patients with specific mutations.