Abstract P4-22-14: Single agent palbociclib with or without trastuzumab for the treatment of Rb+ advanced breast cancer
Authors: Clark AS , Wang X , Troxel A , Burrell J , Feldman M , Lal P , Zhang P , Rosen M , Gallagher M , Ndicu J , Nivar I , Matro J , Domchek SM , Fox KR , O'Dwyer P , DeMichele A 
Published: March 2017

Abstract
Background: The Cyclin D/CDK4/6/Rb axis is dysregulated in breast cancer (BC). Palbociclib (P) is an oral agent that specifically inhibits CDK 4/6 and is FDA approved for hormone-receptor positive (HR+) disease in combination with letrozole or fulvestrant. We performed a Phase II, multi-disease, basket trial of single agent P in patients (pts) with retinoblastoma positive (Rb+), advanced cancer. We now report the full expansion cohort in BC, including a subcohort of pts with HER2+ disease.
Methods: Pts with Rb+ BC were eligible for enrollment if they had measureable metastatic disease, adequate organ function and ECOG PS ≥ 1, with no limit on number of prior therapies. Pts were stratified on HER2-status, with a planned HER2-positive (HER2+) cohort, with or without trastuzumab (T). Pts with active brain metastases were excluded. Pts received P 125mg for 21 days on, 7 days off of each 28 day cycle. The protocol was amended on May 12, 2014 to allow concomitant T (given every 3 weeks 6mg/kg) for pts with HER2+ disease. Toxicity was assessed every 28 days. Response was assessed every 2 cycles using RECIST 1.0 guidelines.
Results: A total of 62 pts were enrolled: 46 (74.2%) HR+/HER2-, 12% HER2+ (19.3%), and 4 (6.5%) ER/PR/HER2-. 10 of the 12 pts with HER2+ disease received T. As of June 10, 2016 one HER2+ patient (pt) remains on study who is also receiving T. Median age is 58 (range 34-88). Median prior lines of therapy is 6 (range 1-15). Response rates, progression free survival (PFS) and overall survival (OS) are depicted in Table 1 and are stratified by HER2 status and receipt of concomitant T. The most common adverse event was Grade 3 or 4 (G3/4) neutropenia (ntp) which occurred in 30 (48%) pts. There was one episode of febrile ntp in a pt who was progressing and had received 13 prior therapies. Other G3/4 events were leucopenia (n=10, 16.1%) thrombocytopenia (n=9, 14.5%), anemia (n=3, 4.8%).
Summary of Results TotalHR+/HER2-HR any/HER2+ with THR any/HER2+ no THR-/HER2-N62*461024PR4 (6.5%)1 (2.2%)2 (20%)1 (50%)0 (0%)SD ≥6mo9 (14.5%)8 (17.4%)1 (10%)0 (0%)0 (0%)SD &lt;6mo22 (35.5%)16 (34.8%)4 (40%)1 (50%)1 (25%)PD26 (41.9%)20 (43.5%)3 (30%)0 (0%)2 (75%)CBR (PR+SD)13 (22%)9 (19.6%)3 (30%)1 (50%)0 (0%)PFS (mo (95% CI))3.5 (2.1, 5.2)3.2 (2.0, 5.2)6.7 (1.6, 17.8)21.2 (5.2, 37.2)1.7 (0.6, 4.8)OS (mo, (95% CI))13.5 (8.9, 14.7)11.9 (7.8, 14.0)17.9 (3.1, NA)NA7.7 (1.5, 13.5)* 1 pt not evaluable for response. HR: hormone receptor; T: trastuzumab; PR: partial response; SD: stable disease; PD: progressive disease; CBR: clinical benefit rate; mo: months; NA: not available
Conclusions: P is well tolerated in heavily pretreated pts. Grade 3/4 ntp occurred in 48% of pts and required dose reduction without necessity to add growth factor support; febrile ntp was uncommon. Single agent activity is modest (22% in the overall population) in this heavily pretreated cohort. 3 of the 4 partial responses observed were in pts with HER2+ disease 2 of whom received concurrent T. Prolonged stable disease was observed in 9 pts, 8 of whom had HR+ disease. Given the response rate of 30% in those with HER2+ disease receiving T, and PFS of 6.7 months, further investigation into this combination is warranted. Biomarker studies are underway.
Citation Format: Clark AS, Wang X, Troxel A, Burrell J, Feldman M, Lal P, Zhang P, Rosen M, Gallagher M, Ndicu J, Nivar I, Matro J, Domchek SM, Fox KR, O'Dwyer P, DeMichele A. Single agent palbociclib with or without trastuzumab for the treatment of Rb+ advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-14.