Toxicity profile and tolerability of immune checkpoint inhibitors for the treatment of early-stage breast cancer: a systematic review and meta-analysis

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have demonstrated clinical benefit in early-stage breast cancer (eBC), enhancing antitumor immune responses. However, their incorporation into perioperative polychemotherapy has introduced new concerns regarding safety and immune-related toxicities (irAEs). We conducted a systematic review and meta-analysis to comprehensively evaluate the safety profile and tolerability of ICIs in patients with eBC. METHODS: A systematic review was conducted in PubMed, Embase, Cochrane Library, and relevant conference databases (ASCO, ESMO) to identify clinical trials reporting safety outcomes of ICIs in eBC. Data were analyzed using R (v4.2.2), applying random-effects models for both single-arm and comparative (pairwise) analyses. RESULTS: Thirteen studies were included, comprising 3977 patients across all studies, including 3138 treated with ICI-containing regimens and 839 controls. For comparative pairwise analyses, 2715 patients received ICI-based therapy and 2399 received chemotherapy alone. The most frequently reported all-grade AEs in ICI arms were alopecia (AR 86.49%, 95% CI: 59.25-96.57) and leukopenia (AR 52.09%, 95% CI: 15.14-86.89). For grade ≥3 events, decreased neutrophil count (AR 17.88%, 95% CI: 10.65-28.44) and neutropenia (AR 18.19%, 95% CI: 10.81-28.96) were most common. The most common irAE was hypothyroidism (AR 12.70%, 95% CI: 9.27-17.16), while the most frequent severe irAE (grade ≥3) was adrenal insufficiency (AR 1.47%, 95% CI: 0.68-3.12). CONCLUSION: This meta-analysis provides a comprehensive evaluation of ICI safety in eBC. While most AEs were low-grade and manageable, significant risks of endocrine irAEs-particularly adrenal insufficiency and thyroid dysfunction-were identified. These findings underscore the need for proactive monitoring and highlight the importance of future research to better understand the mechanisms of ICI-related toxicity and to develop strategies for its prevention.