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

Abstract

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 Author(s) 2018. Published by Oxford University Press.

Figures

Figure 1.

Kaplan-Meier curves showing cumulative event rates over time among palbociclib-treated patients for the (A) hematologic adverse events (AEs) of neutropenia, leukopenia, anemia, and thrombocytopenia and for (B) selected nonhematologic AEs. *Cluster terms were used and are defined in the Supplementary Methods (available online).

Figure 2.

Forest plot depicting the estimated hazard ratios and 95% confidence intervals (CIs) in descending order for hematologic and selected nonhematologic adverse events (AEs; all causalities, all cycles) in the as-treated population. A log-rank test was used to derive P values (two-sided) without adjustment for multiplicity. *Cluster terms were used and are defined in the Supplementary Methods (available online). †Includes data up to 28 days after last dose of study drug, and the time to an event in days was calculated as the date of AE onset minus the date of the first dose of palbociclib/placebo + 1. Endocrine therapy included placebo in PALOMA-2 and -3, but not in the PALOMA-1 study.

Figure 3.

Adverse event (AE) incidence rate of selected nonhematologic AEs in the safety population after adjusting by person-years of exposure to study drugs. *Cluster terms were used and are defined in the Supplementary Methods (available online). †Incidence rate for selected AEs (preferred term/cluster of preferred terms) = (sum of total number of events)/(sum of total person-years).

Figure 4.

Dose reductions (A), dose interruptions (B), and granulocyte colony-stimulating factor (G-CSF) therapy (C) by cycle. Patients could have had a dose reduction and/or dose interruption in more than one cycle. Patients with one or more dose reductions or one or more dose interruptions in a cycle are only reported once in the respective cycle. Patients with one or more G-CSF medications (including filgrastim, pegfilgrastim, lenograstim, and/or G-CSF) concomitant in the respective cycle are reported. Percentages were computed as n/N*100. n = number of patients with at least one dose reduction or dose interruption per dosing records in the respective cycle; N = number of patients taking palbociclib during the cycle.