Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3)

Abstract

Background: Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit.

Materials and methods: Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data.

Results: A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients.

Conclusion: Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135.

Implications for practice: Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.

Keywords: Cyclin-dependent kinase 4; Cyclin-dependent kinase 6; Neutropenia; Palbociclib.

Figure 1.

Palbociclib/placebo dose modification schema for managing treatment-related toxicities. ^aIf patients still have not returned to grade 2 on day 1 of next cycle. ^bReduce by 2 dose levels. ^cIf uncomplicated grade 3 neutropenia recurs in 2 consecutive cycles, after recovery as per retreatment criteria (ANC≥1,000/mm³ and no fever), treatment may restart at the next lower dose level at investigator’s discretion. ^dIf no further dose reduction is possible (i.e., patient is already receiving 75 mg per day according to schedule 3/1), consider changing the schedule to 75 mg per day, 2 weeks on/2 weeks off, or discontinue palbociclib/placebo and continue with fulvestrant alone. Abbreviation: ANC, absolute neutrophil count.

Figure 2.

Risk difference for AEs (hematologic laboratory and nonhematologic: all cycles, as treated). ^a“Infections” includes any reported preferred terms that are part of the system organ class of infections and infestations. ^b“Rash” includes the following preferred terms: “rash,” “rash maculo-papular,” “rash pruritic,” “rash erythematous,” “rash papular,” “dermatitis,” and “dermatitis acneiform.” Abbreviations: AE, adverse event; CI, confidence interval.

Figure 3.

Kaplan-Meier curves showing cumulative incidences of fatigue (all grades) and grade 3‒4 neutropenia. (A): Fatigue in patients treated with palbociclib plus fulvestrant. (B): Grade 3‒4 neutropenia in patients treated with palbociclib plus fulvestrant. (C): Patients treated with palbociclib plus fulvestrant who had grade ≤2 neutropenia within the first 4 cycles and grade 3–4 neutropenia after cycle 4. “Neutropenia” includes the following preferred terms: “neutropenia,” “neutrophil count decreased.” The Kaplan-Meier estimator was used to estimate the cumulative incidence in the plot.

Figure 4.

Kaplan-Meier curves of progression-free survival in patients treated with palbociclib plus fulvestrant. (A): Patients treated for more than 3 cycles who had maximum grade ≥3 (n = 186) vs. maximum grade ≤2 neutropenia (n = 93), per investigator assessment. (B): Patients who had at least 1 dose reduction because of neutropenia (n = 100) versus no dose reduction (n = 245). (C): Patients who had no dose reduction but had a dose interruption or cycle delay due to neutropenia (n = 199) versus the remaining patients (n = 146). “Neutropenia” was any event having a preferred term equal to “neutropenia” or “neutrophil decreased.” Abbreviations: CI, confidence interval; HR, hazard ratio; max, maximum; NE, not estimable; PFS, progression-free survival.