Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

Abstract

BACKGROUNDAntibodies targeting the programmed death‐ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy.METHODSPatients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti–PD‐L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment‐related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune‐related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion‐related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms.RESULTSOf the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%).CONCLUSIONSAvelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010‐7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma

“…In the initial dose‐escalation part (phase Ia), patients with various tumors received avelumab at 1, 3, 10, or 20 mg/kg q2w via a 1‐hour intravenous infusion . In the dose‐expansion part (phase Ib), patients were enrolled into tumor‐specific cohorts and received avelumab at 10 mg/kg q2w …”

“…12 In the dose-expansion part (phase Ib), patients were enrolled into tumor-specific cohorts and received avelumab at 10 mg/kg q2w. 11,31 JAVELIN Solid Tumor JPN is a phase I, open-label, multicenter trial of avelumab in Japanese patients with various advanced or metastatic solid tumors. In the initial dose-escalation part, patients received avelumab at 3, 10, or 20 mg/kg q2w.…”

Management of Immunotherapy-Related Toxicities, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology

“…Pooled safety data on avelumab reported that 25% of patients experienced anygrade infusion reactions (439/1,738) with high-grade events in 0.7% (12/1,738); most occurred during the first infusion, with nearly all reactions occurring within the first 4 treatment cycles. 128,129 Premedication appeared to decrease the rate of severe infusion-related reactions. 128 The U.S. prescribing instructions for avelumab include acetaminophen and diphenhydramine before infusion during the first 4 treatment cycles.…”

“…128,129 Premedication appeared to decrease the rate of severe infusion-related reactions. 128 The U.S. prescribing instructions for avelumab include acetaminophen and diphenhydramine before infusion during the first 4 treatment cycles. 129 Most infusion reactions associated with ICIs are mild and associated with low-grade fever, chills, headache, or nausea.…”

Immune-Related Adverse Events: Pneumonitis

“…Recent studies suggest that pneumonitis after PD-L1 inhibitor therapy may occur less frequently than after PD-1 inhibitor therapy. For example, in a pooled analysis of data from phase 1 and phase II trials, the overall incidence of anygrade pneumonitis for avelumab in patients with advanced solid tumors was around 1.2% [131]. Similarly, Pillai et al and Khunger et al both reported that the incidence of any-grade pneumonitis was higher in NSCLC patients treated with PD-1 inhibitors as compared to PD-L1 inhibitors (PD-1 vs PD-L1: around 4% vs around 2%) [83,127].…”