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Purpose

Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach.

Methods

In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2– MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%.

Results

Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median 5.29 months, 95% CI 3.02-8.12 months) versus switched ET plus placebo (median 2.76 months, 95% CI 2.66-3.25 months) HR 0.57 (95% CI 0.39-0.85), P=0.006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo.

Conclusion

In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2– MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

Read an interview about the study here and expert commentary about it here.