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CDK4/6 Inhibitors Combined With Fulvestrant for Hormone Receptor–Positive, HER2-Negative Advanced Breast Cancer: FDA Analysis of Overall Survival


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In an exploratory U.S. Food and Drug Administration (FDA) pooled analysis reported in The Lancet Oncology, Jennifer J. Gao, MD, and colleagues found that the addition of CDK4/6 inhibitor treatment to fulvestrant resulted in a consistent overall survival benefit vs placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer.   

Study Details

The pooled analysis included individual patient data from three phase III randomized trials submitted to FDA in support of marketing applications for abemaciclib, palbociclib, and ribociclib. Agents included in the analysis were approved before August 2020. Across the trials, 1,948 patients who received at least one dose of study treatment were randomly assigned between October 2013 and June 2016 to receive either CDK inhibitors (1,296) or placebo (n = 652) plus fulvestrant.


The addition of CDK inhibitors to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDK inhibitors plus fulvestrant for the treatment of patients with HR-positive, HER2-negative advanced breast cancer.
— Jennifer J. Gao, MD, and colleagues

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Key Findings

Among all patients, the estimated hazard ratio (HR) for overall survival for the CDK inhibitors group vs placebo was 0.77 (95% confidence interval [CI] = 0.68–0.88) after a median follow-up of 43.7 months (HR range = 0.73–0.79 in individual trials). The improvement in estimated median overall survival was 7.1 months.

Among patients who received CDK inhibitors or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n = 396), the estimated hazard ratio for overall survival was 0.74 (95% CI = 0.52–1.07) after a median follow-up of 39.4 months. The difference in estimated median overall survival could not be calculated, since median overall survival was not estimable (95% CI = 50.9 months–not estimable) in the CDK inhibitors group and 45.7 months (95% CI = 41.7 months–not estimable) in the placebo group.

In patients who received CDK inhibitors or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1,552), the estimated hazard ratio for overall survival was 0.77 (95% CI = 0.67–0.89) after a median follow-up of 45.1 months. The improvement in estimated median overall survival was 7.0 months.

In subgroup analyses, hazard ratios for overall survival were: 0.91 (95% CI = 0.68–1.21) in patients with and 0.73 (95% CI = 0.63–0.85) in those without de novo metastatic disease; 0.66 (95% CI = 0.42–1.04) in those with lobular and 0.75 (95% CI = 0.61–0.93) in those with ductal histology; and 0.77 (95% CI = 0.66–0.89) among White patients, 0.95 (95% CI = 0.69–1.32)  among Asian patients, and 0.56 (95% CI = 0.35–0.91) among those with other race/ethnicity. Hazard ratios were 1.50 (95% CI = 0.75–3.02) among 89 patients aged ≤ 40 years and 0.98 (95% CI = 0.72–1.34) among 388 aged ≤ 50 years, compared with hazard ratios of 0.67 to 0.79 in other age groups. Hazard ratios were 0.77 and 0.78 for patients with progesterone receptor–negative vs –positive status, 0.73 and 0.79 for patients with vs without bone-only metastases, and 0.76 and 0.78 among those with vs without liver or lung metastases. 

The investigators concluded, “The addition of CDK inhibitors to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDK inhibitors plus fulvestrant for the treatment of patients with [hormone receptor–]positive, HER2-negative advanced breast cancer.”

Dr. Gao, of the Oncology Center of Excellence, U.S. Food and Drug Administration, is the corresponding author for The Lancet Oncology article.

Disclosure: The investigators reported that there was no funding for the study. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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