Researchers with the U.S. Food and Drug Administration (FDA) published a new study in Lancet Oncology that demonstrates that cyclin-dependent kinase 4/6 inhibitors (CDKIs) significantly improve progression free survival across all subgroups of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer.
The team, led by Jennifer Gao, MD, of the FDA’s Center for Drug Evaluation and Research, analyzed pooled data from all phase 3 randomized breast cancer trials of CDKIs plus endocrine therapy submitted to the agency prior to January 1, 2019.
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The meta-analysis included seven studies with 4,200 patients who received a CDKI or placebo plus endocrine therapy with an aromatase inhibitor (letrozole or anastrazole) or fulvestrant. In the aromatase inhibitor studies, 1320 received a CDKI and 932 received placebo; in the fulvestrant studies, 1296 received a CKDI and 652 got a placebo.
The researchers looked at results in both first and second line therapy. They also examined subgroups that included patients with progesterone receptor-negative disease, those with recurrence within 12 months of treatment, and women under age 40. Other groups analyzed had various types of metastases: de novo, lobular histology, bone-only, or visceral.
CDKIs provided a median benefit of 8.8 months across all seven pooled trials compared to endocrine therapy alone, with a nearly 40% reduction in risk of progression or death.
That benefit persisted regardless of how the researchers sliced the data. “Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population,” the researchers found.
In the aromatase inhibitor trials, patients who also received CDKIs in the first line saw a near doubling of median progression free survival, 28.0 months vs 14.9 months for those who received placebo. Patients who received CDKIs in addition to fulvestrant in the first line had a 42% lower risk of progression or death compared to those who received fulvestrant and placebo; the median progression-free survival for the CDKI group was not estimable in this group and was 18.6 months for those who received placebo. In the second line, adding CDKI to fulvestrant increased progression-free survival by 6.9 months, for an overall risk reduction of 44%.
The FDA team’s conclusion suggests that endocrine therapy plus a CDKI should be the first choice for any HR+, HER2- patients with advanced breast cancer: “Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer.”