BMI May Positively Impact the Pharmacodynamics of Palbociclib in Patients With eBC

Erica Mayer, MD, MPH

Patients with early breast cancer (eBC) treated with palbociclib (Ibrance) and endocrine therapy (ET) who were overweight or obese experienced lower incidences of grade 3/4 neutropenia, resulting in fewer treatment discontinuations vs average-weight patients, according to a preplanned analysis of the PALLAS trial (NCT02513394).¹

“This preplanned analysis of the phase 3 PALLAS study of adjuvant palbociclib did not show a relationship between BMI and survival outcomes with or without palbociclib. So, we would not describe BMI as a predictive marker for benefit from adjuvant palbociclib,” Erica L. Mayer, MD MPH, director, Clinical Research and institute physician in the Breast Oncology Center at Dana-Farber Cancer Institute, and associate professor of Medicine, Harvard Medical School told Targeted Oncology™.

In the primary analysis of PALLAS, a prospective, 2-arm, multicenter, randomized, open-label, phase 3 study, palbociclib added to ET failed to improve outcomes, including the primary end point of 4-year disease-free survival (DFS).² The 4-year DFS rate shown was 84.2% with the addition of palbociclib, compared with 84.5% with ET alone. Investigators of PALLAS led by Michael Gnant, MD, of Medical University of Vienna, cited the occurrence of neutropenia and treatment discontinuations resulting from neutropenia. Investigators wrote in the Journal of Clinical Oncology, “the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.³”

Research shows that roughly 75% of patients treated with palbociclib experience either neutropenia or leukopenia4,5, however, it is neutropenia that results in the highest number of discontinuations. Considering that overweight and obese patients had higher distributional volume, PALLAS investigators hypothesized that there would be a lower pharmacodynamic impact of palbociclib in this group.¹

The analysis included 5,698 patients with eBC of whom 68 (1.2%) were underweight, 2,082 (36.5%) were normal weight, 1,818 (31.9%) were overweight, and 1,730 (30.4%) were obese. A correlation was shown between higher body mass index (BMI) and a decrease in neutropenia compared with normal weight individuals (unadjusted odds ratio, 0.93; 95% CI, 0.91-0.94). Patients with a higher BMI also had a decrease in treatment discontinuation rate compared with patients who had an average rate (adjusted HR, 0.75; 95% CI, 0.67-0.83).

No significant improvement in DFS was shown in the higher BMI population. The HRs for the difference were (HR, 0.84; 95% CI, 0.63 to 1.12) for normal-weight patients, vs (HR, 1.10; 95% CI, 0.82 to 1.49) in the overweight group, and (HR, 0.95; 95% CI, 0.69 to 1.30).

“Our analysis did show that patients with a higher BMI appeared to have less toxicity from the CDK4/6 inhibitor and demonstrated less early discontinuation of drug for toxicity. Why less toxicity was connected to higher BMI is not definitively known, but this observation highlights that a patient’s ability to adhere to oral cancer therapy may be directly influenced by the experience of toxicity, and supports the importance of discussing toxicity with patients,” Mayer stated.

Overall, the weight groups experienced the same number of any-grade adverse events (AEs). However, while any-grade neutropenia was seen in 88.5% of normal-weight patients, only 85.7% of overweight patients experienced any-grade neutropenia, and only 74.7% of obese patients. Grade 3 neutropenia was observed in 64.1% of patients with average weight, 62.0% of those who were overweight, vs 43.9% of those who were obese. Finally, 7.0% of the normal-weight population vs 5.1% of the overweight group, and 3.8% of the obese patients experienced grade 4 neutropenia (P =.9619). Similar findings were shown with the incidence of leukopenia.

“This study focused on the PALLAS trial of palbociclib. Whether BMI is a predictive biomarker for other CDK4/6 inhibitors is not known, however could be addressed through the monarchE [NCT03155997] or NATALEE [NCT03701334] studies of abemaciclib [Verzenio] and ribociclib [Kisqali], respectively,” added Mayer.

_REFERENCES:

_{1. Pfeiler G, Hlauschek D, Mayer EL, et al. Impact of BMI in patients with early hormone receptor–positive breast cancer receiving endocrine therapy with or without palbociclib in the PALLAS trial. J Clin Oncol. Published August 9, 2023. doi: 10.1200/JCO.23.00126}

_{2. Gnant M, Dueck AC, Frantal S, et al. Adjuvant palbociclib for early breast cancer: The PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293. doi: 10.1200/JCO.21.02554}

_{3. Mayer EL, Fesi C, Hlauscek D, et al. Treatment exposure and discontinuation in the palbociclib collaborative adjuvant study of palbociclib with adjuvant endocrine therapy for hormone receptor–positive/human epidermal growth factor receptor 2–negative early breast cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03). J Clin Oncol. 2022;40(5):449-458. doi: 10.1200/JCO.21.01918}

_{4. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. doi: 10.1056/NEJMoa1607303}

_{5. Mayer EL, Dueck AC, Martin M, et al: Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): Interim analysis of a multicentre, open-label, randomised, phase 3study. Lancet Oncol. 2021;22(2):212-222. doi: 10.1016/S1470-2045(20)30642-2}