In an analysis reported in the Journal of Clinical Oncology, Erica L. Mayer, MD, MPH, and colleagues found that early discontinuation and lower exposure intensity of oral palbociclib did not appear to account for the lack of invasive disease–free survival benefit observed with the addition of palbociclib to adjuvant endocrine therapy in patients with hormone receptor (HR)-positive, HER2-negative breast cancer enrolled in the phase III PALLAS trial.
Study Details
The analysis involved 5,743 patients randomly assigned between September 2015 and November 2018 to receive 2 years of palbociclib with ongoing adjuvant endocrine therapy (n = 2,840) or endocrine therapy alone (n = 2,903). At the second interim analysis at 23.7 months of follow-up, the Independent Data Monitoring Committee determined that a futility boundary was crossed for the primary endpoint of invasive disease–free survival.
The current analysis assessed palbociclib exposure and discontinuation and potential effects on invasive disease–free survival.
Erica L. Mayer, MD, MPH
Key Points
Overall, 1,199 patients (42.2%) stopped palbociclib before 2 years. Most (n = 772, 27.2%) stopped due to adverse events, with the most common reasons being neutropenia (n = 461, 59.7%) and fatigue (n = 71, 9.2%).
In competing risk analysis, estimated cumulative rates of discontinuation were 17.9% at 6 months, 30.0% at 12 months, 38.0% at 18 months, and 44.9% at 24 months. Endocrine therapy was discontinued in 6.9% of patients in the palbociclib plus endocrine therapy group vs 6.3% in the endocrine therapy group.
The proportion of patients stopping palbociclib for non–protocol-defined reasons was greatest in the first 3 months of treatment and decreased over subsequent months, with protocol-defined toxicity being the predominant cause of discontinuation. The rate of early discontinuation for non–protocol-defined toxicity was greatest in the first year of study and declined over the subsequent years.
In landmark analyses, no significant differences in invasive disease–free survival were observed according to palbociclib treatment duration or exposure intensity. For example, adjusted analysis showed hazard ratios of 0.84 (95% confidence interval [CI] = 0.50–1.40) for patients taking palbociclib for ≥ 6 months vs < 6 months and 0.76 (95% CI = 0.44–1.31) for those taking palbociclib for ≥ 18 months vs < 18 months. Hazard ratios on adjusted analysis were 0.80 (95% CI = 0.47–1.37) for those with ≥ 70% vs < 70% exposure intensity at 6 months and 0.77 (95% CI = 0.43–1.37) for ≥ 70% vs < 70% at 18 months.
In a baseline characteristic–weighted per-protocol analysis limited to adherent patients (those without non–protocol-defined discontinuation), no significant difference in invasive disease–free survival was observed for palbociclib plus endocrine therapy vs endocrine therapy alone (HR = 0.89, 95% CI = 0.72–1.11).
The investigators concluded, “Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant invasive disease–free survival difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.”
Dr. Mayer, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Pfizer, Inc. For full disclosures of the study authors, visit ascopubs.org.
