It has been 5 years since the first cyclin-dependent kinase (CKD) 4/6 inhibitor was approved for the management of advanced breast cancer. Currently, three CDK 4/6 inhibitors are on the market: abemaciclib, Palbociclib, and ribociclib. The beneficial effects of these agents in improving overall survival (OS) in metastatic breast cancer (BC), however, remains unclear.
A recent systematic review and meta-analysis (SR/MA) published in JAMA Network Open sought to determine whether CDK 4/6 inhibitors in conjunction with endocrine therapy (ET) versus ET monotherapy improved OS in patients with hormone receptor positive (HR+), ERBB2 (formerly HERS2)-negative metastatic BC. A secondary objective of this SR/MA was to assess progression-free survival (PFS), objective response rate (ORR), and grade 3 or grade 4 (grade 3/4) adverse events (AEs) in patients receiving these agents.
Investigators searched PubMed, Embase, and international meeting reports (European Society of Medical Oncology, American Society of Clinical Oncology, the San Antonio Breast Cancer Symposium) for phase II or III randomized clinical trials involving the use of CDK4/6 inhibitors in patients with HR+, ERBB2-negative metastatic BC. Patients had to be randomly assigned to receive either CDK 4/6 inhibitors and ET or ET monotherapy and studies had to have an endpoint of either OS or PFS in order to be included in the SR/MA.
Nine clinical trials, one 1 phase I and eight phase II, totaling 5,043 participants were included in the SR/MA. Two-thirds of trials included OS as an endpoint, whereas all included PFS and ORR as outcomes.
Data on OS were available for 2,030 patients and revealed a 33% (HR 1.33; 95% CI, 1.19-1.48) increase in OS for patients who received combination therapy versus ET monotherapy. Similarly, for PFS, there was an 84% (HR 1.84; 95% CI, 1.70-1.98) increase in PFS among the 3,448 patients who had received a CKD 4/6 inhibitor and ET therapy compared with the 2,267 patients who had been given ET alone. ORR was assessed in 3,113 patients on the combination therapy and 1,930 in the ET-only group and revealed an odds ratio of 2.02 (95% CI, 1.61-2.53) in favor of the duo regimen.
Subgroup analyses were performed based on whether the combination regimen was used as first- or second-line therapy; in pre- versus postmenopausal women; in those with visceral compared with bone-only metastasis; and in those younger or older than age 65 years. Benefit was seen in all groups.
However, the gains in OS, PFS and ORR came at a cost as grade 3/4 AEs were markedly increased among patients who received the combination regimen. There was a 57% (HR, 57,05; 95% CI, 38.26-85.05), 36% (HR 36.36; 95% CI, 19.35-68.34), and approximately 5-fold (HR. 4.97; 95% CI, 2.84-8.69) increase in neutropenia, leukopenia, and diarrhea, respectively, in those who received CKD 4/6 inhibitors in conjunction with ET compared with those in the ET-only group.
Pharmacists can utilize the information from this paper to help recommend treatment options and to identify metastatic BC patients who may need more intensive monitoring for AEs.
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