Higher BMI = Less Neutropenia With CDK4/6 Inhibitor for Early Breast Cancer

A higher body mass index (BMI) translated into less neutropenia and fewer discontinuations among women with early hormone receptor (HR)-positive breast cancer treated with a CDK4/6 inhibitor, a secondary analysis of the randomized trial PALLAS showed.

Among patients who received palbociclib (Ibrance) in addition to endocrine therapy, increasing BMI was associated with a small but statistically significant decrease in neutropenia and a 25% reduction in the likelihood of treatment discontinuation. Patients with higher BMI who received palbociclib also had fewer dose reductions and higher relative dose intensity. Heavier patients had more frequent and severe nonhematologic toxicity with the combination, though this is seen with endocrine therapy alone as well, suggesting the effects were not attributable to the CDK4/6 inhibitor.

Adding the CDK4/6 inhibitor to endocrine therapy had no effect on the primary endpoint of invasive disease-free survival (iDFS) for any weight category, reported Georg Pfeiler, MD, of the Medical University of Vienna, and co-authors in the Journal of Clinical Oncology.

“These findings suggest that higher BMI reduces the pharmacodynamic impact of palbociclib,” the authors concluded. “A preplanned second analysis with a longer follow-up will assess the efficacy of palbociclib, also considering BMI.”

“This observation may have clinical implications for dose optimization in both metastatic and early-stage breast cancer,” they added.

Trailing only tobacco use, obesity is the second most common preventable cause of cancer, contributing to 5.4% of all cancers in women and to as much as 35% of some cancers. In the 5,700-patient PALLAS trial of palbociclib, almost two-thirds of patients were overweight or obese at baseline. Postmenopausal overweight and obesity increase the risk of developing breast cancer and are associated with worse outcomes.

The distributional volume of systemic therapy may be increased in overweight and obese patients, leading to reduced plasma concentrations. As a result, weight-based dosing is typically used with cytotoxic chemotherapy to compensate for distributional volume, the authors noted. Palbociclib is an oral medication administered in a fixed dose, irrespective of patient weight, height, or BMI. Although the drug is generally well tolerated, hematologic toxicity, and neutropenia in particular, affect more than 75% of patients, with varying severity.

Neutropenia is the primary reason for dose reduction and discontinuation of palbociclib, the authors continued. A reduced pharmacodynamic impact in overweight and obese patients could affect outcome and decrease side effects, especially neutropenia.

Pfeiler and colleagues hypothesized that overweight and obese patients’ higher distributional volume might reduce the pharmacodynamic impact of palbociclib in the PALLAS trial, leading to fewer side effects, but possibly to inferior long-term outcomes as well. They reported findings from a preplanned analysis of the relationship between BMI and side effects. They focused on neutropenia as a surrogate for bioavailability and efficacy.

The trial included patients with stage II-III HR-positive/HER2-negative breast cancer, randomized to 5 years of endocrine therapy alone or with 2 years of palbociclib. Patients were classified as underweight (BMI <18.5; 1.2%), normal weight (BMI 18.5-24.9; 36.5%), overweight (BMI 25-29.9; 31.9%) or obese (BMI ≥30; 30.4%). The study population had a median BMI of 26.7. Underweight patients were excluded from the analysis because of small numbers.

Overweight and obese patients had significantly (P<0.001) less frequent and severe neutropenia when compared with normal-weight patients, respectively:

• Overall: 85.7% and 74.7% vs 88.5%
• Grade III: 62% and 43.9% vs 64.1%
• Grade IV: 3.6% and 2% vs 7%

In unadjusted and adjusted analyses, each 1-unit increase in BMI was associated with a 7% reduction in the odds ratio for neutropenia (95% CIs of 0.91-0.94 and 0.92-0.95). Overweight and obese patients also had significantly less thrombocytopenia (21.4% and 19.0% vs 24.0% in normal-weight patients, P=0.0318). Other side effects occurred more often in overweight/obese patients in both treatment groups, including arthralgia, nausea, diarrhea, and cough.

The differences in neutropenia translated into higher rates of dose reduction at 6 months for the normal-weight group (52.3%) compared with the overweight and obesity groups (43.4%/28.9%). Additionally, each 10-unit increase in BMI was associated with a 25% decrease in the rate of discontinuation. Discontinuation for adverse events was driven entirely by neutropenia (21.1% vs 14.0%/5.9%, respectively). Overall discontinuation rates were 48.3% for the normal-weight group, 37.8% for the overweight group, and 34.7% for the obesity group.

The higher rates of dose reduction and discontinuation in the normal-weight group translated into a lower average relative dose intensity for palbociclib (53.7% vs 60.6%/66.1% for overweight/obese patients).

A preliminary analysis of the relationship between BMI and iDFS (median follow-up of 31 months) showed no significant differences in the primary endpoint for overweight/obese patients versus normal-weight patients.

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