Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial

Abstract

Background: We report dose-escalation results from an open-label, phase 1/2 trial evaluating avelumab (anti-PD-L1) in paediatric patients with refractory/relapsed solid tumours.

Methods: In phase 1, patients aged < 18 years with solid (including central nervous system [CNS]) tumours for which standard therapy did not exist or had failed were enrolled in sequential cohorts of 3-6 patients. Patients received avelumab 10 or 20 mg/kg intravenously every 2 weeks. Primary endpoints were dose-limiting toxicities (DLTs) and grade ≥ 3 treatment-emergent adverse events (AEs).

Results: At data cut-off (27 July 2021), 21 patients aged 3-17 years had received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15). One patient had three events that were classified as a DLT (fatigue with hemiparesis and muscular weakness associated with pseudoprogression; 20 mg/kg cohort). Grade ≥ 3 AEs occurred in five (83%) and 11 (73%) patients in the 10 and 20 mg/kg cohorts, respectively, and were treatment-related in one patient (7%; grade 3 [DLT]) in the 20 mg/kg cohort. Avelumab exposure in paediatric patients receiving 20 mg/kg dosing, but not 10 mg/kg, was comparable or higher compared with approved adult dosing (10 mg/kg or 800 mg flat dose). No objective responses were observed. Four patients with CNS tumours (20 mg/kg cohort) achieved stable disease, which was ongoing in two patients with astrocytoma at cut-off (for 24.7 and 30.3 months).

Conclusion: In paediatric patients with refractory/relapsed solid tumours, avelumab monotherapy showed a safety profile consistent with previous adult studies, but clinical benefits were limited.

Trial registration: ClinicalTrials.gov NCT03451825.

Keywords: Avelumab; Immune checkpoint inhibitor; Immunotherapy; Paediatrics; Phase 1.

Conflict of interest statement

DAM reports serving as a consultant or advisor for Bayer, Boehringer Ingelheim, Clarity Pharmaceuticals, Roche, and Y-mAbs Therapeutics; is a member of a speakers bureau for EUSA Pharma; has received institutional research funding from Bristol Myers Squibb; and has received reimbursement for travel and accommodation expenses from EUSA Pharma and Y-mAbs Therapeutics. KN has received honoraria from and reports serving as a consultant or advisor for Bayer and Y-mAbs Therapeutics. MEM reports serving as a consultant or advisor for Ventana Medical Systems; has received institutional research funding from Bayer, Ignyta, Lilly, MSD, and Roche; holds stock in GE Healthcare, Johnson & Johnson, Teva Pharmaceuticals, and Varian Medical Systems; and has a patent for non-invasive methods of leukaemia cell detection with magnetic resonance imaging/magnetic resonance spectroscopy (US patent 8,894,975). JX was employed by EMD Serono Research & Development Institute Inc., Billerica, MA, USA, an affiliate of Merck KGaA at the time of manuscript preparation. PP and IJ report employment with Merck Healthcare KGaA, Darmstadt, Germany. YV reports employment with EMD Serono Research & Development Institute Inc., Billerica, MA, USA, an affiliate of Merck KGaA. MR reports employment with EMD Serono Research & Development Institute Inc., Billerica, MA, USA, an affiliate of Merck KGaA at the time of manuscript preparation, and holds stock in Bristol Myers Squibb. All other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Trial profile. DLT, dose-limiting toxicity

Fig. 2

Change in target lesions per RECIST 1.1 from baseline over time in evaluable patients (those with baseline and postbaseline data): A all evaluable patients (n = 18); B patients with central nervous system tumours (n = 7). Increases greater than 200% are shown as 200%. PD, progressive disease; RECIST 1.1, Response Evaluation Criteria in Solid Tumours version 1.1

Fig. 3

Histological images of H&E and PD-L1 (73–10) staining of tumour samples for the two patients with astrocytoma who had prolonged SD (> 24 months) with avelumab. Both patients had tumours with ≥ 80% of tumour cells having membrane staining positive for PD-L1 expression. Patient A (female aged 9 years) had a pilocytic astrocytoma (WHO grade I). The patient presented in 2018 with a mass at the cerebellopontine angle and upper cervical spine showing cystic and contrast-enhancing solid portions via MRI scan. Histopathology showed an astrocytic tumour with increased cellularity, mild pleomorphism, low mitotic activity (2/10 high-power fields), and absent necrosis. Immunophenotype was positive for glial fibrillary acidic protein and strong PD-L1 expression in tumour cells but not tumour vessels (arrow). The tumour was BRAFV600E mutation-positive, but no PTEN deletion or MGMT promoter methylation was present. The patient underwent surgery in April 2018 with residual tumour and received vincristine + carboplatin from May to July 2018 (best overall response of PD) followed by thioguanine + procarbazine + lomustine in August 2018 (best overall response unknown); no radiation was administered. The patient received avelumab treatment from October 2018 until April 2021, and tumour size changed over time from 40 to 45 mm. Lansky performance status improved from 50% at study entry to 70% with avelumab treatment, and the patient discontinued from the study to receive subsequent anticancer therapy (surgery). Patient B (male aged 3 years) had an astrocytoma of spinal cord (WHO grade II; NF1-associated). The patient presented in 2018 with a contrast-enhancing intramedullary mass at the upper thoracic spinal cord (MRI). Microscopy showed a tumour with increased cellularity, mild pleomorphism, low mitotic activity (1/10 high-power field), absent microvascular proliferation, and absent necrosis. Immunophenotype was positive for glial fibrillary acidic protein and synaptophysin, and strong PD-L1 expression was seen in tumour cells but not tumour vessels (arrow). The tumour had an NF1 mutation (p.Gln1577*, c.4729C > T), but no mutations of BRAF (V600E), IDH1, TP53, or PTEN were present. In 2021, the tumour was classified as ganglioglioma, WHO grade I. The patient had surgery with residual tumour in July 2018 and received vincristine + carboplatin from August to November 2018 (best overall response of PD), with no radiation. The patient received avelumab treatment from December 2018 until February 2021, and tumour size changed over time from 12 to 16 mm (not classified as PD according to RECIST 1.1 because the tumour size did not increase by ≥ 5 mm), with Lansky performance status stable at 90%. The patient discontinued the study to receive subsequent anticancer therapy (surgery). H&E, haematoxylin and eosin; MRI, magnetic resonance imaging; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease; and WHO, World Health Organization