Abstract PD2-12: Palbociclib in combination with fulvestrant or tamoxifen as treatment for hormone receptor positive (HR+) metastatic breast cancer (MBC) with prior chemotherapy for advanced disease (TBCRC 035) A phase II study with pharmacodynamics markers
Authors: Rugo HS , Mayer EL , Storniolo AM , Isaacs C , Mayer I , Stearns V , Nanda R , Nangia J , Wabl C , Deluca A , Kochupurakkal B , Wolff AC , Shapiro GI 
Published: May 2019

Abstract
Background
Addition of the cyclin dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib to endocrine therapy in the first and later line settings significantly improves progression free survival (PFS) in patients with HR+ MBC. The primary toxicity is neutropenia without an increase in febrile neutropenia. TBCRC035 explored rates of neutropenia in patients who had received prior chemotherapy for MBC with 2 dose levels of palbociclib, and correlated changes in retinoblastoma protein phosphorylation (pRB) and Ki67 expression in proliferating keratinocytes and tumor with response.
Methods
TBCRC035 is a 1:1 randomized multicenter phase II study evaluating palbociclib at either 125 or 100 mg in combination with physician choice fulvestrant or tamoxifen. Eligible patients (pts) with HR+ MBC had received &gt;1 but &lt;3 lines of chemotherapy for MBC, any number of prior hormone therapies, and were naïve to CDK4/6i. The primary endpoint was grade 3/4 neutropenia; secondary endpoints included response, safety/tolerability, inhibition of pRB and change in Ki67 in skin and tumor at day 14-21 of treatment compared to baseline. FFPE sections of skin punch and tumor biopsies obtained before and on treatment were stained using antibodies to Ki67, total RB, and phospho-RB-S780 using BOND polymer red detection. Stained slides were scanned into the Aperio image analysis platform; the percentage of marker positive cells and H-score was determined.
Results
70 pts were enrolled (fully accrued); 35 randomized to 100 vs 125 mg of palbociclib respectively; data for the last 3 pts on the 125 mg arm is pending. Grade 3/4 neutropenia was more common in the 125 mg vs the 100 mg arm (56 vs 34%); dose adjustments for adverse events (AEs) occurred in 47 vs 43%, 4 vs 0 pts discontinued treatment due to AEs. Grade 3 febrile neutropenia was rare (1 patient each arm). Median duration of treatment was 5.2 vs 7.2 months. Response data and correlation with changes in pRB and Ki67 expression in skin and tumor by treatment arm will be reported.
Conclusion
In pts with prior chemotherapy for HR+ MBC, treatment with 100 mg of palbociclib in patients is associated with a lower rate of &gt; grade 3 neutropenia compared to 125 mg. Correlation of response by dose with pRB and Ki67 has the potential to inform palbociclib dosing and reduce toxicity for pts with HR+ MBC.
Citation Format: Rugo HS, Mayer EL, Storniolo AM, Isaacs C, Mayer I, Stearns V, Nanda R, Nangia J, Wabl C, Deluca A, Kochupurakkal B, Wolff AC, Shapiro GI. Palbociclib in combination with fulvestrant or tamoxifen as treatment for hormone receptor positive (HR+) metastatic breast cancer (MBC) with prior chemotherapy for advanced disease (TBCRC 035) A phase II study with pharmacodynamics markers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-12.