Treatment-related adverse events associated with HER2-Targeted antibody-drug conjugates in clinical trials: a systematic review and meta-analysis

Abstract

Background: Given the increasing use of HER2-targeted antibody-drug conjugates (ADCs) worldwide, the summary of toxicity incidence and profiles of these drugs is crucial to provide reference for clinical application. This meta-analysis aimed to estimate the mean incidences of treatment-related adverse events of HER2-targeted ADCs and to investigate the differences between different drugs and cancer types.

Methods: We performed a systematic search of literature in PubMed, Embase, Web of Science, and Scopus databases from inception to February 1, 2022 and the last search was updated to August 1, 2022. Published prospective clinical trials on single-agent of the US Food and Drug Administration approved HER2-targeted ADCs with available count data regarding treatment-related adverse events were included. The primary outcomes were pooled incidences of treatment-related adverse events and differences between different drugs and cancer types. The data synthesis was performed using a Bayesian hierarchical modelling method and the protocol was registered in PROSPERO (CRD42022331627).

Findings: A total of 39 studies (37 trials) involving 7688 patients across five cancer types were included in the final analysis. On pooling the data using Bayesian hierarchical modelling, the overall mean incidence of all-grade adverse events, high-grade adverse events, serious adverse events, and adverse events that resulted in drug discontinuation were 98.29% (95% CrI, 97.33%-99.07%, τ = 1.49), 47.88% (95% CrI, 42.74%-53.17%, τ = 0.37), 19.45% (95% CrI, 15.70%-23.67%, τ = 0.55), and 10.52% (95% CrI, 8.03%-13.21%, τ = 0.56), respectively. The most common all-grade adverse events were nausea (41.57%; 95% CrI, 40.46%-42.64%, τ = 0.81), fatigue (35.86%; 95% CrI, 34.85%-36.96%, τ = 0.65), and decreased appetite (28.84%; 95% CrI, 22.93%-36.87%, τ = 0.76). The most common high-grade adverse events were thrombocytopenia (8.37%; 95% CrI, 7.75%-9.07%, τ = 0.71), anaemia (6.49%; 95% CrI, 5.86%-7.11%, τ = 1.06), and neutropenia (6.42%; 95% CrI, 5.76%-7.04%, τ = 1.21). We found no difference in the mean incidences of adverse events among different cancer types, as well as different dosing regimens. However, trastuzumab deruxtecan (T-DXd) appeared to have higher mean incidences of adverse events compared with trastuzumab emtansine (T-DM1), especially for the higher dose of T-DXd (6.4 mg/kg Q3W).

Interpretation: The incidences of adverse events between two HER2-targeted ADCs were similar in different cancer types, but different HER2-targeted ADCs appeared to have different mean incidences of adverse events. The comprehensive summary of the adverse events of HER2-targeted ADCs is critical for clinicians caring for patients with cancer receiving HER2-targeted ADCs therapy.

Funding: The National Natural Science Foundation of China (Grant No. 82073402) and Key R&D Plan of Hubei Province, China (No.2020BCA060) funded this study.

Keywords: Adverse events; Bayesian meta-analysis; Clinical trials; HER2-Targeted ADCs; Systematic review.

Fig. 1

Flow diagram of the study selection process. ADC, antibody-drug conjugate.

Fig. 2

Incidences of the most common adverse events associated with HER2-targeted antibody-drug conjugates (ADCs). A, Incidences of the most common all-grade adverse events. B, Incidences of the most common grade 3 or higher adverse events. CrI, Bayesian credible intervals.

Fig. 3

Mean incidences of adverse events by cancer type. A, Mean incidences of all grade adverse events by cancer type. B, Mean incidences of grade 3 or higher adverse events by cancer type. C, Mean incidences of serious adverse events by cancer type. D, Mean incidences of adverse events that resulted in drug discontinuation by cancer type. For both panels, values to the left of the line are lower than the mean, to the right, higher. CrI, Bayesian credible intervals.

Fig. 4

mean incidences of adverse events by drug type. A, Mean incidences of all grade adverse events by drug and dose. B, Mean incidences of grade 3 or higher adverse events by drug and dose. C, Mean incidences of serious adverse events by drug and dose. D, Mean incidences of adverse events that resulted in drug discontinuation by drug and dose. E, Comparisons of mean incidences of adverse events between different drugs and dose. CrI, Bayesian credible intervals.