Adverse events and tolerability of immune checkpoint inhibitors (ICI) for the treatment of early stage of breast cancer (BC): A systematic review and meta analysis.

Abstract

e14621 Background: Programmed cell death-ligand 1 (PD-L1) is an immune checkpoint protein that can downregulate the antitumor immune response by impairing T-cell function. Immune Checkpoint Inhibitors (ICIs), have shown clinically meaningful improvement in outcomes of patients with early-stage breast cancer (BC). However, it has also been accompanied by clinically relevant toxicities. Thus, we conducted a systematic review and meta-analysis to evaluate the safety and tolerability of ICI in this patient population. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases, and ASCO and ESMO websites for clinical trials (CTs) assessing the safety of ICIs in early stage of BC patients. All analyses were performed in R software (v.4.2.2) using random effects models, and pairwise and single-arm assessments were made. Heterogeneity was assessed using I 2 test. Results: Nine randomized clinical trials (RCTs) were included, comprising 2.715 patients receiving ICI and 2.399 on treatment of standard of care. The median patient age ranged from 49.5 to 54 years, and no trials reported prior treatment lines. The most common all-grade adverse events (AEs) in the ICI group were alopecia (76%, 95% CI: 59–87%) and anemia (55%, 95% CI: 28–79%). Among grade ≥3 AEs, the highest proportions were decreased neutrophil count (18%, 95% CI: 11–28%) and neutropenia (16%, 95% CI: 9–28%). Hypothyroidism was the most common immune-related (ir)AEs (12%, 95% CI: 9-15%) and severe skin reactions the most common grade ≥ 3 irAEs (1.35%, 95% CI: 0.3-6.1%). Compared to control arms, the overall risk of all-grade and grade ≥3 AEs were not significantly different. However, ICIs were associated with a higher risk of adrenal insufficiency (RR 8.96, 95% CI: 2.62–30.65, I² = 36%; p < 0.01) and thyroid dysfunction, including hyperthyroidism (RR 8.37, 95% CI: 3.84–18.23, I² = 33%; p < 0.01) and hypothyroidism (RR 7.11, 95% CI: 3.73–13.56, I² = 67%; p < 0.01). For grade ≥3 AEs, adrenal insufficiency demonstrated the highest risk in the ICI group compared to control (RR 13.12; p < 0.01). As expected, the ICI group showed an increased risk of immune-related AEs overall (RR 2.16; p < 0.01). Serious AEs were observed in 7.91% (95% CI: 1.90–27.62), treatment discontinuation occurred in 3%, ICI patients and death was reported in 1% of patients. Conclusions: This systematic review and meta-analysis provides extensive data on the safety of ICI toxicity in early-stage BC patients across clinical trials. Concerning risk of permanent irAEs were observed. We highlight the need for better understanding of mechanisms of immunotoxicities to support the development ofstrategies to mitigate ICI-related toxicity.