Elsevier

The Lancet Oncology

Volume 22, Issue 2, February 2021, Pages 212-222
The Lancet Oncology

Articles
Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study

https://doi.org/10.1016/S1470-2045(20)30642-2Get rights and content

Summary

Background

Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.

Methods

PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30).

Findings

Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76–1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths.

Interpretation

At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing.

Funding

Pfizer.

Introduction

Hormone-receptor-positive breast cancer represents the largest subset of this disease, affecting more than 1 million patients annually worldwide.1 A fundamental component of systemic therapy for hormone-receptor-positive early breast cancer is adjuvant endocrine therapy, which provides substantial benefits by reducing disease recurrence and the risk of death from breast cancer.2, 3 However, despite improvements in adjuvant endocrine therapy, including the use of aromatase inhibitors, extended duration of therapy, and luteinising hormone-releasing hormone (LHRH) agonists in premenopausal patients, considerable risk of recurrence persists over several decades.4

Loss of control of the cell cycle is a hallmark of malignancy, including in hormone-receptor-positive breast cancer.5 A well accepted mechanism associated with cell-cycle progression in hormone-receptor-positive breast cancer is overexpression of cyclin D or other alterations, or both, leading to phosphorylation of the retinoblastoma protein and unregulated passage from the G1 to S phase of the cell cycle. Inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) result in hypophosphorylation of the retinoblastoma protein and re-establishment of control of the G1/S transition.6, 7

The combination of a CDK4/6 inhibitor with endocrine therapy has shown antitumour activity by prolonging progression-free survival and overall survival in the first-line and subsequent-line settings of metastatic hormone-receptor-positive, HER2-negative breast cancer, with an acceptable side-effect profile. Currently, three CDK4/6 inhibitors, including palbociclib, are approved for these indications,8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and are considered standard of care in both first-line and pre-treated settings.18, 19 The toxicity profile of palbociclib is well described, and is notable for reversible neutropenia that is typically not associated with serious infections. Aside from the presence of the oestrogen receptor in hormone-receptor-positive breast cancer, there are no currently approved biomarkers for the selection of CDK 4/6 inhibitors.

Based on the broad activity of CDK4/6 inhibitors for treatment of metastatic breast cancer, as well as the need to further reduce the risk of recurrence in the early setting, the phase 3 PALLAS trial was designed to investigate whether the addition of palbociclib to adjuvant endocrine therapy improves outcomes compared with endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative early breast cancer.

Section snippets

Study design and participants

PALLAS is an international, multicentre, open-label, randomised, phase 3 study investigating the addition of 2 years of palbociclib to standard adjuvant endocrine therapy for patients with hormone-receptor-positive, HER2-negative early breast cancer. The trial was open to accrual at 406 cancer centres in 21 countries: Australia, Austria, Belgium, Canada, Germany, Hungary, Ireland, Israel, Italy, Japan, Mexico, Poland, Portugal, South Korea, Spain, Sweden, Switzerland, Taiwan, the Netherlands,

Results

Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to a treatment group and are included in the intention-to-treat population (figure 1). The present analysis included 1013 patients with stage IIA disease enrolled up to Sept 26, 2017. Patient characteristics are shown in table 1. The median age was 52 years (IQR 45–61) and 4729 (82·1%) of 5760 patients had stage IIB or III tumours. 4754 (82·5%) of 5760 patients had received adjuvant or neoadjuvant chemotherapy before

Discussion

In this second interim analysis of the PALLAS trial, the addition of palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with endocrine therapy alone in patients with stage II–III hormone-receptor-positive, HER2-negative breast cancer. This analysis was done after 67% of expected invasive disease-free survival events had occurred, and a futility boundary had been crossed. In the treatment group, 42% of patients stopped palbociclib prematurely,

Data sharing

Pseudonymised individual participant data will be made available after completion of the study (ie, at the end of the follow-up phase) at the latest; the specific data made available will depend on the data needed to answer the question in the application. Other documents that will be available include the master informed consent form, the study protocol and amendments, and the PALLAS Policy for Access to Study Data or Surplus Samples for Research Projects not related to the protocol (policy).

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