Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer

Véronique Diéras; Hope S. Rugo; Patrick Schnell; Karen Gelmon; Massimo Cristofanilli; Sherene Loi; Marco Colleoni; Dongrui R. Lu; Ave Mori; Eric Gauthier; Cynthia Huang Bartlett; Dennis J. Slamon; Nicholas C. Turner; Richard S. Finn


J Natl Cancer Inst. 2019;111(4):419-430. 

In This Article

Abstract and Introduction


Background: Palbociclib administered with endocrine therapy was tolerable when the overall incidence of toxicities was assessed separately for three PALOMA studies. This study analyzed pooled, longer-term PALOMA safety data longitudinally.

Methods: Data were pooled from three randomized phase II and III studies (ClinicalTrials.gov: NCT00721409, NCT01740427, NCT01942135) of hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer patients. Front-line patients were randomly assigned to receive letrozole with/without palbociclib (PALOMA-1) or letrozole plus palbociclib/placebo (PALOMA-2). In PALOMA-3, patients with prior endocrine resistance received fulvestrant plus palbociclib/placebo. The cumulative event rates of adverse events (AEs), reporting up to 50 months of treatment, were assessed over time.

Results: Patients who received endocrine therapy (n = 1343) were included in this pooled analysis (872 were also treated with palbociclib, and 471 were not). The most common AEs with palbociclib plus endocrine therapy were neutropenia and infections (any grade, 80.6% and 54.7%, respectively), which were higher than in the endocrine monotherapy arm (any grade, 5.3% and 36.9%). The most common hematologic AEs (≥15.0% in the palbociclib arm) were more likely to be reported in the initial months of the study, after which time the cumulative event rate did not substantially increase. With palbociclib plus endocrine therapy, any grade AEs leading to permanent discontinuation over three years occurred in only 8.3% of patients.

Conclusions: Based on these long-term safety analyses, there is no evidence of specific cumulative or delayed toxicities with palbociclib plus endocrine therapy, supporting the ongoing investigation of palbociclib plus endocrine therapy in early breast cancer (NCT02513394).


The novel and selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, used in combination with endocrine therapy, has demonstrated efficacy and tolerable safety in the management of metastatic or locally advanced breast cancer.[1–4] Palbociclib targets dysregulated cell cycle machinery within the cyclin D-CDK4/6-retinoblastoma pathway to inhibit the uncontrolled cellular proliferation critical to pathophysiologic processes.[5–7] In prospective, randomized phase II and III trials, palbociclib combined with endocrine therapy resulted in statistically significant (P < .001) improvement in progression-free survival (PFS) compared with endocrine therapy alone, in both firstline metastatic and previously treated hormone receptor−positive/human epidermal growth factor receptor 2−negative (HR+/HER2-) patients with advanced breast cancer.[1–4]

The therapeutic window of any new treatment regimen needs to be evaluated for efficacy vs the clinically tolerable safety profile, particularly in the advanced disease setting, where maintaining quality of life and minimizing toxicity are a priority. Decisions on treatment with CDK4/6 inhibitors, including palbociclib in combination regimens, need to be based on an assessment of their immediate and long-term toxicity. The safety profile of palbociclib plus endocrine therapy has been reported for each of the three PALOMA studies at both interim and final analysis of the primary end point (investigator-assessed PFS).[1–3] Further analysis of the safety profile to characterize the incidence of adverse events (AEs) over time will enhance the ability of clinicians to manage toxicities, optimize treatment decisions, and appropriately counsel their patients.[8] In this analysis, we evaluate the safety of palbociclib combined with endocrine therapy for up to 50 months—which extends beyond the cutoff dates of the safety data reported previously for PALOMA-1, -2, and -3—to characterize toxicities and identify any unusual trends and/or potential cumulative AEs based on a longitudinal analysis of a large, pooled clinical trial data set comprising all three randomized studies.