Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)

Abstract

Purpose: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS.

Methods: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS.

Results: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11).

Conclusion: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS 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.

Trial registration: ClinicalTrials.gov NCT02513394.

FIG 1.

Association of baseline variables with palbociclib discontinuation and dose reduction to 100 mg. Individual forest plots can be found in the Data Supplement. AI, aromatase inhibitor: ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; G, grade; HR, hazard ratio; PgR, progesterone receptor; Tis, carcinoma in situ; Tx, primary tumor cannot be assessed.

FIG 2.

Reasons for early palbociclib discontinuation, categorized by central study management teams as protocol-defined or non–protocol-defined, for palbociclib + ET patients by 3-month time points as presented to the IDMC in May 2020. The percentages in the 3-month periods refer to the number of patients who were still receiving palbociclib treatment up to the respective period. ^aThe increased rate of early discontinuation for nonprotocol reasons unrelated to toxicity in months 22-24 reflects administrative reasons early in the course of the study. ET, endocrine therapy; IMDC, Independent Data Monitoring Committee.

FIG 3.

HR for palbociclib intake duration (≥ or < the given landmark) up to 6, 12, 18, and 24 months (HR < 1 suggests that longer palbociclib duration is associated with improved iDFS). HR, hazard ratio; iDFS, invasive disease-free survival.

FIG 4.

HR for palbociclib exposure intensity (≥ or < 70%) up to 6, 12, 18, and 24 months (HR < 1 suggests that ≥ 70% exposure intensity is associated with improved iDFS). HR, hazard ratio; iDFS, invasive disease-free survival.

FIG 5.

Per-protocol analysis of iDFS in palbociclib + ET versus ET alone in adherent patients (ie, without non–protocol-defined discontinuation). Naive analysis is a simple, unadjusted comparison between arms; IPTW analysis is a comparison between arms after balancing groups on baseline characteristics (see Statistical Analysis). ET, endocrine therapy; iDFS, invasive disease-free survival; IPTW, inverse probability treatment weighted; Palbo, palbociclib. The results of the PALLAS trial of the CDK4/6 inhibitor palbociclib as adjuvant therapy for HR+, HER2– breast cancer cannot be explained by inadequate exposure to palbociclib; neither longer duration of palbociclib therapy nor greater drug exposure intensity predicted improved clinical outcomes. The development of novel agents in the adjuvant oncology setting can be challenging, and highlights the need for effective interventions to help improve persistence with oral cancer therapies.