Adverse Events of PD-1 or PD-L1 Inhibitors in Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis

Abstract

(1) Background: This study aimed to develop a comprehensive understanding of the treatment-related adverse events when using PD-1 or PD-L1 inhibitors in triple-negative breast cancer (TNBC). (2) Methods: We conducted a meta-analysis of Phase II/III randomized clinical trials. Studies were searched for using PubMed, Embase, and Cochrane Library from 1 March 1980 till 30 June 2022. Data on adverse events were mainly extracted from ClinicalTrials.gov and published articles. A generalized linear mixed model with the logit transformation was employed to obtain the overall incidence of adverse events across all studies. For serious adverse events with low incidences, the Peto method was used to calculate the odds ratio (OR) and 95% confidence interval (95%CI) in the PD-1 or PD-L1 inhibitors groups compared to the control groups. (3) Results: Nine studies were included in the meta-analysis, including a total of 2941 TNBC patients treated with PD-1 or PD-L1 inhibitors (including atezolizumab, pembrolizumab and durvalumab) and 2339 patients in the control groups. Chemotherapy alone was the control group in all studies. The average incidences of all serious immune-related adverse events of interest (hypothyroidism, hyperthyroidism, pneumonitis, pruritus, rash) were less than 1%, except for adrenal insufficiency (1.70%, 95%CI: 0.50–5.61%) in the PD-1 or PD-L1 groups. PD-1 or PD-L1 inhibitors significantly increased the risk of serious pneumonitis (OR = 2.52, 95%CI: 1.02–6.26), hypothyroidism (OR = 5.92, 95%CI: 1.22–28.86), alanine aminotransferase (ALT) elevation (OR = 1.66, 95%CI: 1.12–2.45), and adrenal insufficiency (OR = 18.81, 95%CI: 3.42–103.40). For non-serious adverse events, the patients treated with PD-1 or PD-L1 inhibitors had higher risk of aspartate aminotransferase (AST) elevation (OR =1.26, 95%CI: 1.02–1.57), hypothyroidism (OR = 3.63, 95%CI: 2.92–4.51), pruritus (OR = 1.84, 95%CI: 1.30–2.59), rash (OR = 1.29, 95%CI: 1.08–1.55), and fever (OR = 1.77, 95%CI: 1.13–2.77), compared with chemotherapy alone. (4) Conclusions: The incidence of serious immune-related adverse events in PD-1 or PD-L1 inhibitors groups is low but significantly higher than in chemotherapy groups. When using PD-1 or PD-L1 inhibitors for the treatment of TNBC, serious pneumonitis, hypothyroidism, ALT elevation, and adrenal insufficiency should be considered. Non-serious adverse events, such as AST elevation, rash, and fever, should also be taken into consideration.

A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors

“…In another meta‐analysis, the risk of pneumonitis was significantly increased with anti‐PD‐1/PD‐L1 therapies in TNBC (odds ratio: 2.52; 95% CI: 1.02–6.26) 33 . The reasons for the higher rates of pneumonitis in this study are unknown, but it is generally agreed that this immune‐related AE is tumor‐specific, 31,32 occurring due to the immunosuppressive effects of the anti‐PD‐(L)1 drug combination 33 ; nevertheless, underlying reasons for this warrant further research. Notwithstanding the rates of pneumonitis, mivavotinib in combination with nivolumab appeared to have a generally manageable safety and tolerability profile.…”

“…Two meta‐analyses of previous studies have reported rates of ~1% for grade ≥3 pneumonitis with anti‐PD‐1 monotherapy across cancer types, with only slightly increased rates for combination therapy 31,32 . In another meta‐analysis, the risk of pneumonitis was significantly increased with anti‐PD‐1/PD‐L1 therapies in TNBC (odds ratio: 2.52; 95% CI: 1.02–6.26) 33 . The reasons for the higher rates of pneumonitis in this study are unknown, but it is generally agreed that this immune‐related AE is tumor‐specific, 31,32 occurring due to the immunosuppressive effects of the anti‐PD‐(L)1 drug combination 33 ; nevertheless, underlying reasons for this warrant further research.…”

Breaking Barriers: The Promise and Challenges of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer

“…The United States Food and Drug Administration (FDA) granted approval in the year 2019 for the utilization of the PD-L1 inhibitor (Atezolizumab) in conjunction with chemotherapy (Abraxane) as a treatment for patients with metastatic TNBC [45]. Later, numerous cancer studies have been involved in using ICIs as alternative cancer therapy, particularly in triple-negative breast cancer.…”

Nebenwirkungsmanagement unter Immuntherapie

“…IrAEs können prinzipiell jedes Organsystem betreffen und sich in unterschiedlichster Form zeigen. Das Spektrum der Nebenwirkungen ist homogen, die Häufigkeit der Toxizitäten variiert jedoch abhängig von Substanz und Dosis des gewählten ICIs sowie der Art des Malignoms und reicht von 45–96 % [ 4 – 7 ]. Im Generellen sind Rate und Schweregrad an irAEs unter CTLA4-Inhibitoren größer als unter PD-1/PD-L1-Inhibitoren, wobei PD-L1-Inhibitoren etwas besser verträglich zu sein scheinen als PD-1-Inhibitoren [ 2 , 5 ].…”