Safety and efficacy profile of cyclin‐dependent kinases 4/6 inhibitor palbociclib in cancer therapy: A meta‐analysis of clinical trials

Abstract

Background Palbociclib is a small‐molecule, cyclin‐dependent kinase 4 and 6 inhibitor, which prevents phosphorylation of the retinoblastoma (Rb) protein and inhibits cell‐cycle progression from G1 to S phase. We performed this meta‐analysis to estimate the safety and efficacy of palbociclib in cancer patients from clinical trials. Methods PubMed and EMBASE were searched for eligible studies. Adverse events (AE) of grade ≥3 and all‐grade (1‐5) were extracted to calculate event rates. Odds ratios (ORs) with 95% confidence interval (CI) were calculated to estimate the safety of palbociclib in endocrine treatment‐combined studies. A fixed effects model was used when homogeneity was low (I2 ≤ 50%). A random effects model was adopted when there was a significant heterogeneity (I2 > 50%). For efficacy endpoints, hazard ratio (HR) and 95% CI for progression‐free survival (PFS) or overall survival (OS) were extracted and analyzed. Results Nine clinical trials representing 1534 patients were identified. The most frequently observed all‐grade adverse events (AEs) in patients treated with palbociclib were neutropenia (event rate: 68.1%), leukopenia (51.7%), fatigue (35.9%), anemia (34.7%), and thrombocytopenia (30.9%). The most common grade 3 or more toxicities were neutropenia (51.6%), leukopenia (29.4%), and thrombocytopenia (7.5%). Hematologic adverse events had high occurrence in the palbociclib group. The pooled analysis of survival outcomes suggested that palbociclib produced clinical benefits in breast cancers and Rb‐positive tumors. More specifically, palbociclib was associated with significant improvement of PFS (HR: 0.518, 95% CI: 0.444‐0.604) in the treatment of ER‐positive and HER2‐negative breast cancer. Conclusions Hematologic adverse events were common in palbociclib‐treated cancer patients. Since palbociclib produced a higher PFS rate with a low serious complication rate, it can be a promising novel target therapy drug for treating ER‐positive and HER2‐negative breast cancer.

Targeted Therapy in HR+ HER2− Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options

“…The tolerability of CDK4/6 inhibitors is usually acceptable and manageable with dose modification and side effect treatment. Minor AEs are reported in most patients (60–80%) under CDK4/6 inhibitor therapy, resulting in a dose reduction in every third patient [ 35 , 36 ]. Serious AEs (SAEs; grade 3/4) that lead to discontinuation are reported in up to 12% of patients [ 36 ].…”

“…Minor AEs are reported in most patients (60–80%) under CDK4/6 inhibitor therapy, resulting in a dose reduction in every third patient [ 35 , 36 ]. Serious AEs (SAEs; grade 3/4) that lead to discontinuation are reported in up to 12% of patients [ 36 ]. Hematological toxicities are frequent, especially in palbociclib and ribociclib, leading to neutropenia, anemia, and thrombocytopenia [ 37 ].…”

First clinical experience with CDK4/6 inhibitors in breast cancer therapy

“…Fatigue is a common side effect of palbociclib while neutropenia is a dose-limiting adverse effect of both palbociclib and ribociclib (17). Hematologic adverse events are common in palbociclib therapy, although it is associated with a higher PFS rate and lower serious complication rate (18).…”

Optimizing treatment selection, and sequencing decisions for Management of HR-Positive, HER2-Negative advanced breast cancer – Proceedings from breast cancer expert group meeting

“…Further, an exploratory analysis of the phase III, double-blind, randomized, placebo-controlled BOLERO-2 trial that assessed the safety and efficacy of this combination vs. exemestane monotherapy in first-line setting also revealed a significant PFS benefit with the combination vs. AI monotherapy [ 67 ] (Table 1 ). The combination of everolimus and fulvestrant significantly prolonged PFS vs. fulvestrant monotherapy (10.3 vs. 5.1 months, respectively, p = 0.02) in patients with HR + HER2 − mBC who developed resistance to AI therapy in the adjuvant setting in the PrE0102 trial [ 68 ]. However, considering the limited evidence available in support of everolimus + AI/fulvestrant for the treatment of patients with HR + HER2 − mBC in the first-line setting, caution may be exercised while making clinical decisions on the use of this combination in focus treatment settings.…”

“…Evidence in support of everolimus plus fulvestrant combination in second-line setting comes from the PrE0102 study, which highlighted a significantly better PFS with the combination vs. fulvestrant monotherapy among 131 postmenopausal women with HR + HER2 − mBC resistant to AI (10.3 vs. 5.1 months, respectively; p = 0.01) [ 68 ] (Table 2 ). Everolimus has also been evaluated in combination with exemestane in the second-line setting in several randomized controlled trials and studies in real-world settings.…”