Evaluation of an Alternative Schedule of Palbociclib in Patients with HR-Positive, HER2-Negative Metastatic Breast Cancer

It has been recognized that the approved schedule for palbociclib (Ibrance), which is 3 weeks on and 1 week off, results in a significant number of patients (66%) developing grade ≥3 neutropenia and requires dose reduction and sometimes discontinuation of treatment. Jairam Krishnamurthy, MD, FACP, Assistant Professor, Oncology & Hematology, University of Nebraska Medical Center, Omaha, and colleagues hypothesized that an alternative schedule (Alt Dose Pal), with 5 days on then 2 off every week, would possibly reduce the rate of neutropenia, thereby allowing continued weekly dosing. Furthermore, they proposed that this alternative dosing schedule may address potential compromises in efficacy, due to treatment discontinuation.

A single-arm phase 2 trial was conducted in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who received up to 1 previous endocrine therapy treatment for metastatic breast cancer. Patients received palbociclib 125 mg daily, 5 days on then 2 days off weekly, plus letrozole or fulvestrant based on the treating physician’s choice, on a 28-day cycle. If the patient was premenopausal, goserelin was administered every 28 days.

The primary objective was to determine the rate of ≥grade 3 neutropenia during cycle 1. Secondary objectives were to assess the rate of all cycle grade ≥3 neutropenia, palbociclib dose reductions and discontinuations, side effects, progression-free survival (PFS), objective response rate (complete and partial responses), and clinical benefit rate (no disease progression in 24 weeks).

In total, 54 patients were enrolled from July 2017 to February 2020. Unrelated to the study, 3 patients discontinued treatment in cycle 1, leaving 51 patients remaining in the trial; the letrozole group included 38 patients and 13 patients were included in the fulvestrant group. The median age of the participants was 62 years, with 16% of the patients being premenopausal, and a little more than half (51%) of the patients having visceral metastases.

Treatment is ongoing for 45% of patients with a median follow-up of 12 months. In cycle 1, grade 3 neutropenia was experienced by 21.3% of patients. There were no reported life-threatening grade 4 events. In all cycles, 40.7% of patients reported grade 3 (N = 21) or grade 4 (N = 1) neutropenia, and 59.3% of patients were without grade ≥3 neutropenia. Together, these results exceeded the expectation for better tolerability.

In 20.3% of patients, the dose of palbociclib was reduced, and discontinued in 4.8% of patients due to side effects. The objective response rate was 50%, with 2 complete responses and 13 partial responses. The clinical benefit rate was 81.63%, which was maintained for at least 24 weeks.

Overall, the median PFS was 24.3 months. In patients sensitive to endocrine therapy, the median PFS was 33.5 months and 12 months for the resistant population.

The investigators concluded that the Alt Dose Pal trial met its primary end point with reduced incidence of grade ≥3 neutropenia. The efficacy data are comparable to previous reports.