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.

Pembrolizumab Versus High-Dose Interferon-α2b as Adjuvant Therapy for Pediatric Melanoma: A Retrospective Study

“…Most studies have investigated immunotherapy in pediatric patients with advanced tumors. To date, nivolumab (NCT0230445848 [ 12 ]), pembrolizumab (NCT0233266849 [ 4 ]), atezolizumab (NCT0254160450 [ 13 ]), and avelumab (NCT0345182551 [ 14 ]) have been investigated as monotherapies for recurrent and refractory pediatric tumors, but only 3% of patients with solid tumors experienced an objective response across all four trials. Compared with adult cancers, most pediatric cancers have lower mutational burdens and fewer infiltrating T cells, which may account for this lack of efficacy [ 15 ].…”

Pediatric Solid Cancers: Dissecting the Tumor Microenvironment to Improve the Results of Clinical Immunotherapy

“…Regarding anti-PD-L1 agents, a phase I/II study of atezolizumab in pediatric patients and young adults with refractory or relapsed solid tumors showed partial remission in 1/75 patients treated for ST, with a good toxicity profile [ 148 ]. Likewise, a phase I study of avelumab described four stabilizations of disease in 21 patients treated for R/R ST, without grade 4–5 adverse events [ 158 ].…”

Checkpoint Immunotherapy in Pediatrics: Here, Gone, and Back Again

“…50 Avelumab produced no objective responses. 51 Outside of a single partial response using pembrolizumab against a high-grade glioma, no responses were seen in the most common pediatric solid tumors, including central nervous system tumors, neuroblastoma, osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. In total, across all four trials, only 3% of patients with solid tumors experienced an objective response.…”

“…48 Similarly, in the trial evaluating avelumab, only one patient with an atypical teratoid/rhabdoid tumor was included; again, there was no response. 51 The responses that did occur were extremely limited and could correspond to atypical cases. However, three responses among 15 patients with a SMARCB1-deficient tumor type represents a preliminary signal of efficacy for a single agent, especially compared with the 3% efficacy rate observed in solid tumors overall.…”