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.

Conflict of interest statement

Erica L. MayerConsulting or Advisory Role: Lilly, Novartis, AstraZeneca, Gilead SciencesResearch Funding: Pfizer (Inst) Christian FeslResearch Funding: Pfizer (Inst) Dominik HlauschekResearch Funding: Pfizer (Inst) Laura Garcia-EstevezConsulting or Advisory Role: Daiichi Sankyo/Astra Zeneca, Palex, Seattle GeneticsResearch Funding: Roche/Genentech (Inst) Nicholas ZdenkowskiHonoraria: Roche, Pfizer, EisaiConsulting or Advisory Role: Lilly, AstraZeneca, EisaiResearch Funding: Roche (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Roche, Amgen, Novartis Kathy D. MillerThis author is the Senior Deputy Editor of Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Merck, Genentech/Roche, Athenex, AstraZeneca, Bristol Myers Squibb/CelgeneResearch Funding: Taiho Pharmaceutical (Inst), Novartis (Inst), Seattle Genetics (Inst), Pfizer (Inst), Astex Pharmaceuticals (Inst), British Biotech (Inst), CytomX Therapeutics (Inst), Alphamab (Inst) Marija BalicConsulting or Advisory Role: Amgen, AstraZeneca, Daiichi Sankyo/Astra Zeneca, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, SamsungSpeakers' Bureau: Amgen, AstraZeneca, Daiichi Sankyo/Astra Zeneca, Lilly, Novartis, Pierre Fabre, Pfizer, Roche, Seattle GeneticsResearch Funding: Lilly (Inst), Novartis (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: MSD Ingrid A. MayerConsulting or Advisory Role: Novartis, AstraZeneca, Lilly, Genentech, GlaxoSmithKline, Immunomedics, Macrogenics, Pfizer, AbbVie, Seattle Genetics, Puma Biotechnology, Cyclacel, Blueprint Medicines, SanofiResearch Funding: Novartis (Inst), Pfizer (Inst), Genentech (Inst) David CameronConsulting or Advisory Role: Lilly (Inst), Novartis (Inst), Novartis (Inst), Research Triangle Institute RTI Health Solutions (Inst), Daiichi Sankyo (Inst), Prima BioMed (Inst), Merck Sharp & Dohme (Inst), Zymeworks (Inst), Eisai (Inst), Puma Biotechnology (Inst), Pfizer (Inst), Oncolytics (Inst), Roche (Inst), Roche (Inst), Samsung Bioepis (Inst), Seattle Genetics (Inst), Synthon (Inst), Clarity Pharmaceuticals (Inst), Bexon/Zymeworks (Inst), Sanofi (Inst)Research Funding: Roche (Inst), Novartis (Inst), AstraZeneca (Inst) Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, Zymeworks, AthenexResearch Funding: Genentech (Inst)Other Relationship: InfiniteMD José Juan Ponce LorenzoHonoraria: Seattle Genetics, Novartis, Pfizer, AstraZeneca/Daiichi Sankyo, Lilly, RocheConsulting or Advisory Role: Seattle Genetics, Novartis, AstraZeneca/Daiichi Sankyo, Roche Tufia C. HaddadResearch Funding: Takeda (Inst) Hiroji IwataHonoraria: Chugai Pharma, AstraZeneca, Eisai, Pfizer, Daiichi Sankyo, Lilly Japan, Kyowa Hakko Kirin, Taiho PharmaceuticalConsulting or Advisory Role: Chugai Pharma, Daiichi Sankyo, Pfizer, AstraZeneca, Lilly Japan, Kyowa Hakko Kirin, NovartisResearch Funding: MSD (Inst), AstraZeneca (Inst), Kyowa Hakko Kirin (Inst), Daiichi Sankyo (Inst), Chugai Pharma (Inst), Nihonkayaku (Inst), Lilly Japan (Inst), Novartis (Inst), Bayer (Inst), Pfizer (Inst), Boehringer Ingelheim (Inst), Sanofi (Inst) Matthew GoetzConsulting or Advisory Role: Lilly, bioTheranostics, Genomic Health, Novartis, Eisai, Sermonix Pharmaceuticals, Context Therapeutics, Pfizer, BiovicaResearch Funding: Lilly (Inst), Pfizer (Inst), Sermonix Pharmaceuticals (Inst)Patents, Royalties, Other Intellectual Property: Methods and Materials for Assessing Chemotherapy Responsiveness and Treating Cancer, Methods and Materials for Using Butyrylcholinesterases to Treat Cancer, Development of Human Tumor Xenografts from Women with Breast Cancer Treated with Neoadjuvant Chemotherapy (Inst)Travel, Accommodations, Expenses: Lilly Fatima CardosoConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Teva, Astellas Pharma, Merus, Celgene, Eisai, Daiichi Sankyo, Genentech, Merck Sharp & Dohme, Sanofi, Pierre Fabre, Macrogenics, Amgen, GE Healthcare, GlaxoSmithKline, Mylan, Mundipharma, Seattle Genetics, Samsung Bioepis, Medscape, Prime OncologyTravel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Tiffany A. TrainaConsulting or Advisory Role: Genentech/Roche, Pfizer, AstraZeneca, Merck, Puma Biotechnology, Athenex, Daiichi Sankyo, Ionis Pharmaceuticals, Seattle Genetics, Eisai, Exact Sciences, Foundation Medicine, Ayala Pharmaceuticals, Gilead Sciences, Blueprint Medicines, Ellipses Pharma, Fuji Pharma, ITeos Therapeutics, AgendiaResearch Funding: Eisai (Inst), Pfizer (Inst), Novartis (Inst), Innocrin Pharma (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Immunomedics (Inst), Genentech/Roche (Inst), Daiichi Sankyo (Inst), Carrick Pharm (Inst), Ayala Pharmaceuticals (Inst) Urs BreitensteinConsulting or Advisory Role: AstraZeneca (Inst), Elie Lilly (Inst), Novartis (Inst), Pierre Fabre (Inst), Roche (Inst) Kerstin AckerlResearch Funding: Pfizer (Inst) Otto Metzger FilhoHonoraria: Grupo Oncoclinicas, RocheResearch Funding: Susan G. Komen for the Cure (Inst), Pfizer (Inst), Roche/Genentech (Inst), Eisai (Inst), Cascadian Therapeutics (Inst), AbbVie (Inst)Travel, Accommodations, Expenses: Grupo Oncoclinicas Karin ZehetnerResearch Funding: Pfizer (Inst) Kadine SolomonEmployment: Alliance Foundation TrialsStock and Other Ownership Interests: Pfizer, Merck, Moderna Therapeutics Sarra El-AbedEmployment: Astellas Pharma (I), argenx (I)Research Funding: Novartis (Inst), Roche/Genentech (Inst), Pfizer (Inst) Kathy Puyana TheallEmployment: Pfizer (I)Stock and Other Ownership Interests: Pfizer (I)Honoraria: PfizerTravel, Accommodations, Expenses: Pfizer Dongrui Ray LuEmployment: PfizerStock and Other Ownership Interests: Pfizer Amylou DueckPatents, Royalties, Other Intellectual Property: Royalties from licensing fees for a patient symptom questionnaire (MPN-SAF) Michael GnantEmployment: Sandoz (I)Honoraria: Amgen, Novartis, AstraZeneca, LillyConsulting or Advisory Role: Daiichi-Sankyo, Veracyte, Tolmar, LifeBrain, Lilly Angela DeMicheleResearch Funding: Pfizer (Inst), Genentech (Inst), Calithera Biosciences (Inst), Novartis (Inst)No other potential conflicts of interest were reported.

Figures

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

FIG 4.

HR for palbociclib exposure intensity (≥ or

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.