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/m ² /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/m²/d and in two of five MTD-evaluable patients receiving 23 mg/m²/d; 18 mg/m²/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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Birgit Geoerger reports being paid for a consulting/advisory role by Boehringer Ingelheim, AstraZeneca, and Novartis. Lynley Marshall reports being paid for a consulting/advisory role, honoraria, and participating in a speakers’ bureau by Bayer; and a consulting/advisory role by Illumina, BMS and Tesaro, and participation in independent data monitoring committees for studies run by Eisai and Merck. Karsten Nysom reports being paid for a consulting or advisory role and honoraria by Y-mAbs and Bayer; being paid for a consulting/advisory role by EUSA Pharma and for participation in independent data monitoring committee for a study run by Lilly; and has received travel/accommodation/expenses from Bayer. Eric Bouffet reports being paid for a consulting or advisory role by Novartis, Bayer, and Roche, and has received institutional research funding grants from Roche and BMS. Isabelle Aerts reports being paid for a consulting/advisory role by AstraZeneca. Kim Van Vlerken reports being an employee of Boehringer Ingelheim and has been compensated for a leadership role on clinical trials for Boehringer Ingelheim. Eric Fu and Flavio Solca report being employees of Boehringer Ingelheim. Robert M. Lorence reports both being an employee of Boehringer Ingelheim and being paid for a consulting/advisory role by Boehringer Ingelheim. David S. Ziegler reports being paid for a consulting/advisory role by Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Amgen, Alexion and Norgine. Guy Makin, Anne-Sophie Defachelles, Loredana Amoroso, Pierre Leblond and Paulette Barahona report no conflicts of interest.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)