CDK4/6 inhibitors with ET are widely used in the management of advanced hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) BC. Palbociclib, ribociclib, and abemaciclib with ET are approved for advanced BC, while abemaciclib/ET is also approved for high-risk early BC in node-positive patients.
Discrepancies exist as to whether there are clinically significant differences among the various CDK4/6 inhibitors. A recent network meta-analysis (NMA), which only focused on overall survival (OS) and included 17 studies and 4,415 patients with advanced BC, found that there was no statistically significant difference in this parameter between the various agents despite the presence of differing statistical significance levels in the included trials.
Another more comprehensive analysis called an umbrella review, which is a review of systematic reviews or meta-analyses and is one of the highest levels of evidence, was conducted to explore the impact of CDK4/6 inhibitors with ET on invasive disease–free survival (IDFS) and distant relapse–free survival (DRFS) in early BC and on progression-free survival (PFS), OS, objective response rate (ORR), clinical benefit response (CBR), second progression-free survival (PFS2), and time to subsequent chemotherapy (TTC) in advanced BC.
The investigators searched Cochrane, PubMed, Embase, and Web of Science databases from inception to August 1, 2022, for meta-analyses and systematic reviews that examined the use of CDK4/6 inhibitors in BC. To be included in the umbrella review, the study populations in the trials had to be diagnosed with BC; a CDK4/6 inhibitor with ET had to be compared with ET alone or to placebo; relevant endpoints, such as relative risk, advantage ratio, relative ratio, risk ratio, and clinical efficacy outcomes, had to be included in the studies; and the systematic reviews and meta-analyses had to only include randomized, controlled trials.
Using a vigorous methodology, the investigators assessed the methodological quality of studies using AMSTAR-2, the quality of reporting using PRISMA 2020, and the quality of the evidence using the GRADE system.
A total of 24 papers (representing meta-analyses and systematic reviews) were included in the umbrella review. Of these papers, only two involved patients with early BC. For the endpoint of IDFS, which was analyzed in 12,647 patients, the authors concluded that CDK4/6 inhibitors with ET had more IDFS benefit compared with ET alone that was independent of tumor size, TNM (tumor, node, metastasis) stage, histologic grade, prior neoadjuvant chemotherapy, age, race, and menopausal status; however, these findings were based on low-quality evidence. The greatest benefit in IDFS may be in patients with N2/N3 nodal-stage BC. For DRFS, CDK4/6 inhibitors were not found to be beneficial based on low-quality evidence.
The benefits of CDK4/6 inhibitors and ET were determined based on 22 studies in patients with advanced BC. A total of 20 studies examined PFS. Those that were of middle- or high-quality evidence, which accounted for 50% of the meta-analyses/systematic reviews, found that CDK4/6 inhibitors in combination with fulvestrant, aromatase inhibitors, or other ET agents were better than ET alone for both postmenopausal women with HR+/HER2- BC and those with metastatic BC. Improved PFS was observed in the combination group regardless of histopathological classification, endocrine resistance, estrogen- or progesterone-receptor status, site and number of metastases, menopausal status, race, age, prior chemotherapy, ET regimen, advanced disease treatment line, CDK4/6 inhibitor type, and disease- and treatment-free interval. OS, which was reported in 13 papers, was superior in the CDK4/6 inhibitor/ET group compared with ET alone. Further, those who received ribociclib and abemaciclib with ET demonstrated considerably better OS than ET monotherapy, but these findings did not apply to the palbociclib/ET group. This conclusion is in contrast to that of the NMA previously mentioned, whose authors had ties to the pharmaceutical industry.
Statistically significant differences in favor of the CKD4/6 inhibitor/ET group over ET monotherapy were seen for ORR based on 13 studies. Although combination therapy also favored CBR based on seven papers, this finding was less robust. Lastly, PFS2 and TTC were only assessed in one paper, and although improvement was seen with combination therapy, it did not reach statistical significance and the quality of evidence was low.
The authors concluded that in patients with HR+/HER2- BC, there is a large body of middle-to-high-quality evidence supporting the use of combination CDK4/6 inhibitor/ET therapy in improving PFS, OS, ORR, and CBR compared with ET monotherapy. However, palbociclib/ET therapy did not demonstrate long-term benefits in OS. Evidence supporting the use of CDK4/6 inhibitor/ET combination therapy is limited and of low quality for early BC, although abemaciclib/ET improved IDFS compared with palbociclib. Nonetheless, abemaciclib did not improve DRFS in early BC.
As patient advocates, pharmacists should be aware of the beneficial effects of CDK4/6 inhibitor/ET combination therapy for patients with HR+/HER2- BC, especially for those with advanced disease, and they should assist in choosing an agent based on the comparative evidence.
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