Erica L. Mayer, MD, MPH of the Dana-Farber Cancer Institute discusses Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.
Summary
Context
In hormone-receptor-positive, HER2-negative, metastatic breast cancer, the addition of palbociclib to endocrine therapy increases progression-free survival. The aim of the PALLAS trial was to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy enhances invasive disease-free survival in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer over endocrine therapy alone.
Methodology
PALLAS is an ongoing multicentre, open-label, randomized, phase 3 trial that has recruited patients with histologically confirmed hormone-receptor-positive, HER2-negative breast cancer within 12 months of initial diagnosis at 406 cancer centers in 21 countries worldwide. Eligible patients were aged 18 years or older with a 0 or 1. rating score from the Eastern Cooperative Oncology Association. Patients were randomly allocated (1:1) to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of the 28-day cycle) in permuted blocks of random size (4 or 6), stratified by anatomical level, previous chemotherapy, age, and geographical area, using central telephone-based and web-based interactive response technology. In the intention-to-treat population, the primary outcome of the research was invasive disease-free survival. Protection was examined in all patients who began palbociclib or endocrine therapy who were randomly assigned. This study presents the findings of the second interim, pre-planned review initiated on January 9, 2020, when 67% of the total number of invasive disease-free survival events predicted were observed. ClinicalTrials.gov (NCT02513394) and EudraCTT are registered for the trial (2014-005181-30).
Conclusions
5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877) between Sept 1, 2015, and Nov 30, 2018. At the time of the scheduled second interim study, 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 at a median follow-up of 23·7 months (IQR 16·9–29·2). For palbociclib plus endocrine therapy, 3-year invasive disease-free survival was 88·2 percent (95 percent CI 85·2–90·6) and 88·5 percent (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 [95 percent CI 0·76–1·15]; log-rank p=0·51). The independent data review committee recommended that palbociclib be stopped in patients still receiving palbociclib and endocrine therapy, as the test statistics comparing invasive disease-free survival between groups exceeded the prescribed futility boundary. Neutropenia (1742 [61·3 percent] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3 percent] of 2903 on endocrine therapy alone), leucopenia (857 [30·2 percent] vs 3 [0·1 percent]), and exhaustion (60 [2·1 percent] vs 10 [0·3 percent]) were the most common grade 3–4 adverse effects. In 351 (12·4 percent) of 2840 patients on palbociclib plus endocrine therapy, severe adverse effects occurred, versus 220 (7·6 percent) of 2903 patients on endocrine therapy alone. No treatment-related deaths have occurred.
Interpreting
The addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not enhance invasive disease-free survival compared with adjuvant endocrine therapy alone in the proposed second interim study. On the basis of these results, this regimen in the adjuvant setting cannot be recommended. Long-term PALLAS population follow-up and correlational research are underway.