Overall Survival in Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer Treated with a CDK 4/6 Inhibitor Plus Fulvestrant: A U.S. Food and Drug Administration Pooled Analysis

Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as 1st or 2nd line treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival (PFS) of patients in certain clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI and fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of CDKI in combination with fulvestrant submitted to the US Food and Drug Administration (FDA) in support of marketing applications. All analyzed patients received at least one dose of CDKI or placebo in combination with fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Patients were analyzed collectively, by number of prior lines of systemic endocrine therapy in any disease setting (1st-line or endocrine naive vs. 2nd -line and later), and in various clinicopathologic subgroups of interest. Findings: In all pooled patients (n=1948), the estimated OS HR was 0∙77 (95% CI 0∙68-0∙88), with a median follow-up of 43∙7 months (interquartile range, (IQR): 37∙8, 47∙7) and deaths in 48% of patients. The difference in estimated median OS was 7∙1 months, favoring CDKIs. In patients who were endocrine therapy naive and received CDKIs as 1st -line systemic endocrine therapy (2 trials, n=396), the estimated OS HR was 0∙74 (95% CI 0∙52-1∙07), with a median follow-up of 39∙4 months (IQR: 37∙0, 42∙2) and deaths in 31% of patients. The median OS difference could not be calculated, since median OS was not reached on CDKI arm. In patients who received CDKIs as 2nd-line or later systemic endocrine therapy (3 trials, n=1552), the estimated OS HR was 0∙77 (95% CI 0∙67-0∙89), with a median follow-up of 45∙1 months (IQR: 39∙2, 48∙5) and deaths in 52% of patients. The median OS difference was 7∙0 months, favoring CDKIs. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding CDKI to fulvestrant. Patients with de novo metastatic disease (n=470, OS HR 0∙91 [95% CI 0∙68-1∙21]) and Asian patients (n=394, OS HR 0∙95 [95% CI 0∙81-1∙60]) appeared to benefit relatively less from the addition of CDKI to fulvestrant. Although the estimated OS HR appeared to favor fulvestrant alone in patients age < 40 [HR 1∙5 (95% CI 0∙75-3∙02)], this result must be interpreted with caution, given the small sample size (n=89) and correspondingly wide confidence interval. Evaluation of other age subgroups showed results in favor of the addition of CDKI to fulvestrant. All results presented are considered exploratory and hypothesis-generating. Interpretation: Addition of CDKIs to fulvestrant appears to confer a consistent overall survival benefit across all pooled patients and within most clinicopathological subgroups of interest. Funding: None. Declaration of Interest: All authors declare no competing interests. Ethical Approval: All patients in the included trials were required to provide informed written consent, and all trials had institutional review board or ethical approval.