Abstract PO5-14-11: Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant

Abstract

Abstract Background: Vepdegestrant is a potent, selective, orally bioavailable PROteolysis TArgeting Chimeric (PROTAC) estrogen receptor (ER) degrader. A phase 3 study will evaluate the combination of vepdegestrant and palbo in participants with ER+, human epidermal growth factor receptor negative (HER2[-]) advanced/metastatic breast cancer (NCT05909397). The recommended starting dose of palbo is 125 mg once daily for 3 weeks followed by 1 week off treatment for each 28-day cycle in combination with aromatase inhibitors or fulvestrant.1 Neutropenia is the most frequently reported adverse event for patients receiving palbo in clinical trials.1 When co-administered with vepdegestrant in a phase 1b cohort of the first-in-human phase 1/2 study (NCT04072952), higher rates of medically manageable neutropenia and increased palbo concentrations were observed compared with historical studies of palbo administered with letrozole or fulvestrant.1 Reduced starting doses of palbo (100 mg, 75 mg) are planned to mitigate increased rates of Grade 4 neutropenia while maintaining similar palbo exposure when combined with vepdegestrant. The analysis objective was to leverage a PK/PD model to simulate palbo exposure and neutropenia taking into consideration the dose modification and management for hematologic toxicities provided in the palbo prescribing information.1 Methods: A Monte-Carlo simulation platform2 was utilized to monitor absolute neutrophil count (ANC) in 1000 patients with weekly monitoring over 4 cycles (112 days) of palbo administration. Simulated ANC was determined using a semi-mechanistic model of chemotherapy-induced myelosuppression as previously described.3 Palbo dose modification methods included both dose hold and reduction based on an individual’s ANC and thresholds for Grade 3 (< 1000 mm3) or Grade 4 (< 500 mm3) neutropenia. Simulated neutropenia and exposures from palbo starting doses of 100 mg and 75 mg in the presence of a 25%, 49%, and 67% increase in typical exposure were compared to a palbo starting dose of 125 mg in the absence of increased exposure (historical reference). Average concentration is calculated as the cumulative area under the curve divided by the simulation duration. Results: After a 4-cycle simulation, the 100 mg starting dose of palbo simulated across varying levels of increased exposure resulted in similar Grade 4 neutropenia incidence and average concentration compared to the reference simulation (< 12% difference). The 75 mg starting dose of palbo simulated across varying levels of increased exposure resulted in lower Grade 4 neutropenia incidence as well as lower average concentration compared to the reference simulation (Table 1). Conclusion: The PK/PD model simulation allows for relative comparison of Grade 4 neutropenia incidence and average palbo concentration between the planned reduced starting doses of palbo in the context of increased exposure relative to standard palbo dosing, i.e., without vepdegestrant. This simulation indicates a reduced dose of palbo (100 mg) in combination with vepdegestrant produces similar incidence of Grade 4 neutropenia and comparable average palbo concentration compared to historical reference providing additional support for the study lead-in of NCT05909397. Citations: 1. IBRANCE® (Palbociclib) [Package Insert]. New York, US: Pfizer, Inc. 2. Jermain et al. ACOP13 2023. 3. Friberg et al. J Clin Oncol 2002. Table 1. 4-cycle simulation results comparing reduced starting doses of palbociclib in the presence of increased typical exposure to a reference standard palbociclib dosing in the absence of increased exposure Citation Format: Brian Jermain, Derek Yang, Weiwei Tan, Julia Perkins-Smith, Justin Hoffman, Jason Williams. Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-11.