What are the toxicities associated with Palbociclib (Ibrance)?

From the Guidelines

Ibrance (palbociclib) is associated with significant hematologic toxicities, particularly neutropenia, which occurs in approximately 66.4% of patients, as reported in the PALOMA-2 trial 1.

Common Toxicities

The most common toxicities associated with Ibrance include:

• Neutropenia: occurring in 66.4% of patients, with a low incidence of febrile neutropenia (1.4%) 1
• Leukopenia, anemia, and fatigue: also common grade 3 or 4 adverse events (AEs) reported in the PALOMA-2 trial 1
• Other less common toxicities: infections, pulmonary embolism, and elevated liver enzymes, as well as alopecia (hair thinning), although typically mild

Management of Toxicities

Dose reductions or temporary interruptions of Ibrance may be necessary if severe neutropenia develops, highlighting the importance of regular complete blood count monitoring 1.

Quality of Life

Despite the significant toxicities, the addition of palbociclib to letrozole has been shown to maintain patient-reported quality of life (QoL) in the PALOMA-2 trial, with no significant between-arm differences in change from baseline in Functional Assessment of Cancer Therapy (FACT)-Breast Total, FACT-General Total, or EuroQOL 5 dimensions (EQ-5D) scores 1.

Patient Monitoring

Patients should be closely monitored for signs of serious toxicities, including fever, unusual bleeding or bruising, severe fatigue, or shortness of breath, and should report these symptoms immediately to their healthcare provider.

From the FDA Drug Label

At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic exposures were approximately 4 and 9 times the human exposure (AUC) at the recommended dose, respectively. Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation, chronic progressive nephropathy) and adipose tissue (atrophy) were identified in a 27 week repeat-dose toxicology study in rats that were immature at the beginning of the studies and were most prevalent in males at oral palbociclib doses ≥30 mg/kg/day (approximately 11 times the adult human exposure [AUC] at the recommended dose). Toxicities in teeth independent of altered glucose metabolism were observed in rats Administration of 100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] at the recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast degeneration/necrosis, mononuclear cell infiltrate).

Ibrance toxicity can cause several adverse effects, including:

• Myelosuppression and infection, such as fever, chills, dizziness, shortness of breath, weakness, or any increased tendency to bleed and/or to bruise 2
• Interstitial Lung Disease/Pneumonitis, with new or worsening respiratory symptoms 2
• Altered glucose metabolism, with changes in the pancreas, eye, kidney, and adipose tissue 2
• Toxicities in teeth, with abnormalities in growing incisor teeth 2 It is essential to advise patients to immediately report any signs or symptoms of these toxicities and to take precautions to minimize the risk of adverse effects, such as using effective contraception and avoiding strong CYP3A inhibitors and inducers 2.

From the Research

Ibrance Toxicity

• Ibrance, also known as palbociclib, is a cyclin-dependent kinase 4/6 inhibitor used in the treatment of advanced breast cancer.
• The primary toxicity associated with palbociclib is myelosuppression, particularly neutropenia, which can lead to dose modifications 3, 4, 5.
• Studies have shown that grade 3-4 neutropenia is a common adverse event in patients treated with palbociclib, occurring in up to 67% of patients in phase III trials 5.
• Risk factors for palbociclib-induced neutropenia include baseline myelosuppression, recent antibiotic use, and normal weight patients 5.
• African American women with benign ethnic neutropenia may experience worse neutropenia due to palbociclib treatment, with a higher incidence of grade 3 and 4 neutropenia and dose reductions 6.

Dose Modifications and Management

• Dose modifications are often necessary to manage palbociclib-induced neutropenia, with most providers reducing the dose from 125 mg to 100 mg 3.
• Palliative bone radiation within 1 year prior to palbociclib initiation may be associated with greater lymphopenia during the first cycle, but not neutropenia, anemia, or thrombocytopenia 4.
• Real-world studies have shown that palbociclib is effective in a range of breast cancer populations, with similar outcomes in most subgroups examined 7.

Patient Subgroups and Outcomes

• Older age (≥ 65) does not affect palbociclib tolerance, with comparable rates of dose modifications and subsequent dose changes 3.
• Patients with a Duffy null polymorphism may have a higher incidence of grade 3 and 4 neutropenia, require more dose reductions, and have lower overall relative dose intensity and clinical benefit rates 6.
• Real-world data have shown that palbociclib is effective in patients with hormone receptor-positive, HER2-negative advanced/metastatic breast cancer, with high objective response rates, progression-free rates, and survival rates 7.