Safety results from a phase 2 study of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer

Background: Palbociclib is a reversible, oral, small molecule inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6). Palbociclib combined with various endocrine agents showed significantly improved progression-free survival in patients with metastatic hormone receptor-positive (HR+) breast cancer (MBC). Preclinical data demonstrates synergy for the combination of tamoxifen and palbociclib and that the combination is effective in a model of acquired tamoxifen resistance. Tamoxifen is an effective treatment for HR+ MBC and presents a different toxicity profile when compared with aromatase inhibitors and fulvestrant. Combining palbociclib with tamoxifen in first line treatment of HR+ MBC offers an alternative to other endocrine combinations. Methods: This is a non-randomized, open-label, single-arm, multicenter, phase II study of palbociclib in combination with tamoxifen in patients with HR+/HER2-negative advanced BC. The primary objective is to determine the objective response rate (complete or partial response) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease). Secondary objectives are: safety and tolerability, progression-free survival, clinical benefit rate, 2-year overall survival. Correlative objectives will explore alterations in circulating tumor DNA and changes in gene expression pattern at the time of progression. Safety assessments were performed at baseline, days 1 and 15 (first 2 cycles) and day 1 with each subsequent cycles. Adverse events (AEs) were graded according to NCI-CTCAE v4. Results: Forty-nine patients from 6 academic centers were enrolled in this trial at the time of this report. Baseline demographics and disease characteristics are reported in the table. Median age was 60 (range 39-82). Twenty-three (47%) patients presented with de-novo metastatic disease. Out of 26 (53%) patients who presented with recurrent metastatic disease, 13 (50%) were receiving adjuvant treatment with aromatase inhibitors at the time of recurrence and 13 (50%) were on surveillance with no active treatment. The most common drug related grade ≥ 3 AE was neutropenia (46%) that was transient and manageable by dose modifications, with no development of febrile neutropenia. The most common drug-related any grade AEs were neutropenia (68%), fatigue (43%), nausea (41%), anemia (32%), minor infections (30%), thrombocytopenia (29%), hot flashes (27%), lymphocytopenia (16%), alopecia (11%), diarrhea (11%).Two patients developed thromboembolic events (grades 2 and 4) and discontinued treatment. One patient died while on treatment. Conclusions: The combination of palbociclib and tamoxifen was well tolerated with expected toxicities. Neutropenia was the most frequently reported AE. This is one of the first trials to assess safety of the combination of palbociclib with tamoxifen in HR+ MBC and has implications for the early stage setting. Citation Format: Oana C Danciu, Kent Hoskins, Cristina Truica, Anne Blaes, Deimante Tamkus, Jatin Rana, Tandra Pavankumar, Lauren Green, Li Liu, Menggang Yu, Deborah Toppmeyer, Ruth O9Regan, Kari Wisinski. Safety results from a phase 2 study of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-30.