Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-associated deaths in women worldwide (Giaquinto et al., 2022). Approximately 70% of breast cancer patients are positive for hormone receptors (estrogen receptor and/or progesterone receptor) and lack human epidermal growth factor receptor 2 (HER2) overexpression (Dai et al., 2015). Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are an important class of medications for targeted therapy for hormone receptor (HR)-positive/HER2-negative breast cancer (Morrison et al., 2023). Three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been widely used as first-line treatments for patients with HR-positive/HER2-negative breast cancer (Guo et al., 2023; Elfgen and Bjelic-Radisic, 2021). Although they exhibit favorable outcomes, adverse reactions, such as neutropenia, gastrointestinal toxicity, diarrhea and pulmonary embolism, pose a great challenge to their clinical application (Thill and Schmidt, 2018). Additionally, it is noteworthy that some differences in adverse reactions to these three CDK4/6 inhibitors have been reported. In particular, neutropenia is the most common adverse reaction to palbociclib and ribociclib, and gastrointestinal toxicity is strongly associated with abemaciclib (Sammons et al., 2017).

Infectious diseases are responsible for numerous deaths and financial burdens worldwide (Omosigho et al., 2023; Fan et al., 2018). Neutropenia caused by anti-tumor therapy is a high-risk factor for infection (Joudeh et al., 2023; Villeneuve and Aftandilian, 2022). These CDK4/6 inhibitors cause reversible bone marrow suppression by inducing cell cycle arrest at the G1-S phase, which is different from the irreversible bone marrow suppression caused by cytotoxic chemotherapy (Bas et al., 2022; Hu et al., 2016). Therefore, bone marrow function can recover after the withdrawal of CDK4/6 inhibitors. According to the manufacturer’s instructions, infection is a common adverse reaction associated with CDK4/6 inhibitors. Recent studies have reported CDK4/6 inhibitor-related infections in post-marketing setting (Algwaiz et al., 2021; Rajendran et al., 2021; Sarkisian et al., 2020; Okayasu et al., 2023; Felip et al., 2020). Given the potential clinical benefits, a comprehensive study of infection-related adverse events (AEs) of these three CDK4/6 inhibitors in post-marketing setting is needed to better evaluate the occurrence of infection.

The USA Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, the largest pharmacovigilance database, is a public spontaneous reporting system (Rodriguez et al., 2001). Several case reports on AEs associated with FDA-approved medications available in the FAERS database (Sakaeda et al., 2013). It has been widely used to identify novel signals of medications and alert physicians and patients to pay attention to potential medication-related AEs (Javed and Kumar, 2024; Sharma et al., 2023; Jain et al., 2023; Sharma and Kumar, 2022). Therefore, this study is of great significance for evaluating the occurrence of infection-related AEs for CDK4/6 inhibitors based on real-world data from the FAERS database from 2015Q1 to 2022Q3. A disproportionality analysis was conducted to assess the potential association between infection-related AEs and CDK4/6 inhibitors. This study aimed to provide a comprehensive understanding of the occurrence of CDK4/6 inhibitor-associated infections.

Although AEs associated with CDK4/6 inhibitors have been widely reported, comprehensive studies on infection-related AEs associated with CDK4/6 inhibitors are lacking (Thill and Schmidt, 2018). To the best of our knowledge, this study is the first pharmacovigilance analysis about infection-related AEs associated with CDK4/6 inhibitors using real-world case reports from the FAERS database in a post-marketing setting. In the present study, the occurrence of infection-related AEs associated with these three CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, was discussed. Our study showed that the proportion of infection-related AEs for these three CDK4/6 inhibitors ranged from 1.24% to 8.58% during 2015Q1-2022Q3, with a higher prevalence in patients aged >40 year old.

Palbociclib was first approved in the United States in 2015 and was used in combination with letrozole to treat postmenopausal women with estrogen receptor (ER)-positive/HER-2 negative advanced breast cancer (Dhillon, 2015). The occurrence of infections in patients treated with palbociclib has been reported in several clinical trials. An open-label, randomized phase II study (PALOMA-1/TRIO-18) conducted in 2014 showed a higher incidence of infection-related AEs, including nasopharyngitis, stomatitis, influenza, and upper respiratory tract infection, in the palbociclib plus letrozole group than in the letrozole group (Finn et al., 2015). In 2016, a phase III, randomized PALOMA-2 study in postmenopausal women with ER-positive/HER2-negatvie advanced breast cancer further revealed that infection (any preferred term under the System Organ Class Infections and Infestations) was the most common serious AE among both Asian and non-Asian patients in the palbociclib plus letrozole group (Im et al., 2019). Consistent with the results of the PALOMA-1 and PALOMA-2 studies, the PALOMA-3 study in 2016 evaluating palbociclib in combination with fulvestrant for the treatment of women with HR-positive/HER2-negative advanced metastatic breast cancer showed that the palbociclib arm had a significantly higher incidence of infection-related AEs compared to the placebo arm (p < 0.02). Moreover, infection was the most frequently reported serious AE in the palbociclib group. Most infection-related AEs may be due to upper respiratory tract infections caused by viruses (Verma et al., 2016). Furthermore, xu et al. conducted a phase III PALOMA-4 trial in Asian postmenopausal women with ER-positive/HER2-negative advanced breast cancer in 2022 and found that the most common serious AEs in the palbociclib arm were infections (Xu et al., 2022). In the present study, the proportion of infection-related AEs associated with palbociclib was 2.72%. Case reports of serious outcomes for palbociclib accounted for approximately 30% of the cases. Most of the reports were from the United States. Based on the ROR method, fourteen infection-related PTs were strongly associated with palbociclib treatment.

The FDA granted accelerated approval for ribociclib in 2017 based mainly on the results of the MONALEESA-2 trial. The MONALEESA-2 study was a randomized, double-blind, placebo-controlled, phase III trial conducted in twenty-nine countries and showed that the incidence of infections in the ribociclib and placebo groups was 50.3% and 42.4%, respectively. Urinary tract infections and upper respiratory tract infections are the most common AEs but are generally grade 1 or 2 (Hortobagyi et al., 2016). In accordance with the results of the MONALEESA-2 study, Tripathy et al. conducted the MONALEESA-7 trial and found that the incidence of infection in the ribociclib and placebo groups was 47% and 37%, respectively. The most common AEs were urinary tract infections and upper respiratory tract infections, which were generally grade 1 or 2 (Tripathy et al., 2018). In addition, the MONALEESA-3 trial revealed that pneumonia (1.9% vs. 0%) was the most common all-grade all-causality serious AEs reported in no less than 1% of patients (ribociclib plus fulvestrant vs. placebo plus fulvestrant) (Slamon et al., 2018). Our study showed that infection-related AEs for ribociclib accounted for 8.58% in all AEs associated with ribociclib, which was the highest proportion of infection-related AEs among the three CDK4/6 inhibitors. Infection-related reports with serious outcomes for ribociclib accounted for 67.65% of cases. Most reports were from the United States and Germany. Sixteen infection-related PTs showed a strong relationship with ribociclib, according to the ROR method. Among these, the most frequently reported PTs was pneumonia; However, mastitis showed the strongest association with ribociclib treatment.

Abemaciclib, the third CDK4/6 inhibitor in the market, received FDA approval for the treatment of HR-positive/HER2-negative advanced or metastatic breast cancer in 2017 (Kim, 2017). The phase 3 MONARCH 2 study evaluating women with HR-positive/HER2-negative advanced breast cancer showed a higher incidence of infection in the abemaciclib arm (42.6%) than it did in the placebo arm (24.7%). The severity of these infections was generally grade 1 or 2, with grade 3 AEs accounting for only 6.6% of the abemaciclib arm and 3.6% of the placebo arm (Sledge et al., 2017). The phase 3 MONARCH 3 study showed that infections accounted for 39.1% of the patients in the abemaciclib arm and 28.6% in the placebo arm, of which grade 1 and 2 infections occurred in 33.3% of the abemaciclib arm and 25.5% of the placebo arm (Goetz et al., 2017). Furthermore, a subpopulation analysis in Japan from the MONARCH 3 study indicated that the incidence of pneumonitis of any grade was 10.5% in the abemaciclib arm and 6.7% in the placebo arm, while for grade ≥3, it was 2.6% in the abemaciclib arm and 0% in the placebo arm (Takahashi et al., 2022). In this study, infection-related AEs for abemaciclib accounted for 1.24% of all AEs associated with abemaciclib, and it presented the lowest number of infection-related AEs among the three CDK4/6 inhibitors. This is attributed to the distinct roles of CDKs. CDK4 is a prominent oncogene in breast cancer, and CDK6 is closely related to the differentiation of human hematopoietic stem cells. Abemaciclib shows higher selectivity for CDK4 and thus results in less myelosuppression compared to palbociclib or ribociclib (Braal et al., 2021). Infection-related reports with serious outcomes for abemaciclib accounted for 48.08% of the cases. Most of the reports were from the United States. According to the ROR method, two infection-related PTs showed a strong relationship with ribociclib.

This study had some limitations. This was a retrospective pharmacovigilance analysis based on data from the FAERS database. The FAERS database has some inherent biases, such as incomplete clinical characteristics of patients and infection types (Hauben et al., 2007). In addition, the incidence of AEs could not be evaluated because of the absence of a total population treated with these three CDK4/6 inhibitors. Furthermore, the disproportionality analysis only indicated a statistically significant association between these three CDK4/6 inhibitors and AEs but could not reveal whether there was a causal relationship. Therefore, these findings should be interpreted with caution. However, reports from the FAERS database provide a valuable assessment of post-marketing safety in real-world data to some extent.

Disproportionality analysis revealed that fourteen, sixteen and two infection-related PTs were detected for palbociclib, ribociclib, and abemaciclib, respectively. Ribociclib was not only more likely to cause infection, but also to cause serious outcomes compared to palbociclib and abemaciclib. However, the disproportionality analysis only indicated a statistically significant association, and further causality assessment is required.