In a systematic review and network meta-analysis reported in The Lancet Oncology, Giuliano et al found that progression-free survival in postmenopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer was improved with first- or second-line CDK4/6 inhibitors plus hormone therapies vs standard hormone therapies, with no chemotherapy regimens with or without targeted therapy being significantly better than CDK4/6 inhibitors plus hormone therapies.
Study Details
The systematic review included all phase II and III randomized controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as first-line or second-line treatments, or both, in postmenopausal women with HR-positive, HER2-negative metastatic breast cancer published between January 2000 and December 2017; additional recently published relevant randomized controlled trials were also subsequently added. Progression-free survival was the primary outcome measure. All treatments were compared with anastrozole (the most common comparator in trials included in the meta-analysis) and with palbociclib plus letrozole (since it was the first combination of a CDK4/6 inhibitor plus hormone therapy approved for clinical practice and remains a first-line standard of care along with other CDK4/6 inhibitor plus hormone therapy combinations).
A total of 140 studies comprising 50,029 patients were included in the analysis.
Key Findings
Compared with anastrozole alone, progression-free survival was improved with first-line palbociclib plus letrozole (hazard ratio [HR] = 0.42, 95% credible interval [CrI] = 0.25–0.70), ribociclib plus letrozole (HR = 0.43, 95% CrI = 0.24–0.77), and abemaciclib plus anastrozole or letrozole (HR = 0.42, 95% CrI = 0.23–0.76). Progression-free survival was also improved with second-line palbociclib plus fulvestrant (HR = 0.37, 95% CrI = 0.23–0.59), ribociclib plus fulvestrant (HR = 0.48, 95% CrI = 0.31–0.74), abemaciclib plus fulvestrant (HR = 0.44, 95% CrI = 0.28–0.70), everolimus plus exemestane (HR = 0.42, 95% CrI = 0.28–0.67) and, in patients with PIK3CA-mutated disease, alpelisib plus fulvestrant (HR = 0.39, 95% CrI = 0.22–0.66).
“In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival.”— Giuliano et al
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Compared with anastrozole alone, progression-free survival was improved with several regimens of chemotherapy with or without targeted therapies (including anthracycline- and taxane-containing regimens), including fluorouracil plus epirubicin plus cyclophosphamide (HR = 0.47, 95% CrI = 0.26–0.93), paclitaxel plus bevacizumab (HR = 0.39, 95% CrI = 0.18–0.88), capecitabine (HR = 0.41, 95% CrI = 0.24–0.76), and eribulin (HR = 0.45, 95% CrI = 0.23–0.89).
Compared with palbociclib plus letrozole, no chemotherapy or hormone regimens were associated with significantly better progression-free survival. Palbociclib plus letrozole was associated with improved progression-free survival vs fulvestrant plus anastrozole (HR = 0.47, 95% CrI = 0.27–0.83), standard-dose fulvestrant (HR = 0.52, 95% CrI = 0.30–0.91), anastrozole (HR = 0.42, 95% CrI = 0.25–0.70), letrozole (HR = 0.55, 95% CrI = 0.40–0.74), exemestane (HR = 0.43, 95% CrI = 0.25–0.75), and tamoxifen (HR = 0.38, 95% CrI = 0.24–0.61).
Paclitaxel plus bevacizumab was the only relevant regimen associated with higher overall response rates vs palbociclib plus letrozole (odds ratio = 8.95, 95% CrI = 1.03–76.9).
The investigators concluded, “In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival. Our data support treatment guideline recommendations involving the new combinations of hormone therapies plus targeted therapies as first-line or second-line treatments, or in both settings, in women with HR-positive, HER2-negative metastatic breast cancer.”
Mario Giuliano, MD, of the Department of Clinical Medicine and Surgery, Division of Clinical Oncology, University of Naples, is the corresponding author of The Lancet Oncology article.
Disclosure: For full disclosures of the study authors, visit thelancet.com.
