Palbociclib (Ibrance), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has gained FDA accelerated approval for use in combination with letrozole as a first-line treatment for postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). This approval marks a significant advancement in the treatment landscape for this patient population, offering a new targeted therapy option. The FDA approval was based on the results of the PALOMA-1/TRIO-18 trial (NCT00721409).
The PALOMA-1 trial, an open-label phase II study, evaluated the efficacy and safety of palbociclib in combination with letrozole versus letrozole alone in postmenopausal women with ER+/HER2- MBC who had not received prior treatment for advanced disease. The study's findings demonstrated a significant improvement in progression-free survival (PFS) for patients treated with the combination therapy. Specifically, the median PFS was 20.2 months (95% CI: 13.8–27.5 months) in the palbociclib plus letrozole arm, compared with 10.2 months (95% CI: 5.7–12.6 months) in the letrozole-alone arm (HR = 0.488; 95% CI: 0.319–0.748).
Dosing and Administration
Palbociclib is administered orally at a dose of 125 mg once daily for 21 consecutive days, followed by 7 days off, constituting a 28-day cycle. It is taken in conjunction with letrozole 2.5 mg daily throughout the cycle. Dose modifications may be necessary based on individual patient tolerability and the occurrence of adverse events. Monitoring of complete blood cell counts is recommended before initiating palbociclib, every 2 weeks for the first two cycles, and prior to each cycle thereafter.
Adverse Effects and Drug Interactions
The most common grade 3/4 adverse reactions observed in the PALOMA-1 study with the combination of palbociclib and letrozole compared with letrozole alone were neutropenia (54% vs. 1%), leukopenia (19% vs. 0%), and fatigue (4% vs. 1%). Due to palbociclib's metabolism via CYP3A4, concomitant use of strong CYP3A4 inhibitors should be avoided, and caution should be exercised with moderate or strong inducers of CYP3A4.
Clinical Implications
While palbociclib plus letrozole represents a valuable first-line treatment option for ER+/HER2- MBC, clinicians should carefully consider the potential for toxicities and quality-of-life implications when making treatment decisions. Alternative endocrine-based therapies, such as fulvestrant (with or without an aromatase inhibitor), everolimus with an aromatase inhibitor, or tamoxifen, may also be considered. Cost considerations are also important, as palbociclib is significantly more expensive than some alternative therapies.
