Abstract P6-11-04: OOTR-N007: A phase II neoadjuvant study of letrozole plus palbociclib in postmenopausal patients with ER positive, HER2 negative breast cancer
Authors: Chow Louis WC , Lam Chi-Kei , Loo Wings TY 
Published: May 2015

Abstract
Background : CDK4-associated kinase activity is required to maintain breast tumorigenesis. Virtually all ER-positive cell lines harbour loss of p16ink4a. Low expression of CDK inhibitors p21 and p27 and high expression level of cyclin E and D1 have all been associated with resistance to anti-estrogen therapy. In preclinical models, Rb deficiency is associated with resistance to antiestrogen therapy. Palbociclib (PD 0332991, Pfizer Inc.) is an oral, potent, highly selective reversible inhibitor of CDK4/6 that prevents cellular DNA synthesis by prohibiting progression from G1 into the S phase. Palbociclib in combination with letrozole has shown promising activity in metastatic setting.
Methods : In an open-label, multi-center, single arm pilot study efficacy and safety of neo-adjuvant palbociclib 100 mg QD for 3 weeks plus letrozole 2.5 mg QD in 4 week cycles for 4 months was studied. Postmenopausal patients of mostly Chinese ancestry, with histologically confirmed ER+, HER2- invasive breast cancer and tumor greater than 2 cm were registered. Patients with T3N1, T4 or any N2, N3 were excluded.
Aim : The primary endpoint is Objective Response Rate (ORR). The secondary end-point include Pathologic Response Rate (PRR), Disease-Free Survival (DFS), safety. Exploratory analysis of gene and protein expression in tumors and serial whole blood is planned.
Results : As of June 2014, 11 patients were recruited. 9 patients completed treatment and 2 are still on study. Of the 9 patients that completed study at time of this abstract, 1 patient had a complete pathological response (pCR) and 7 had a partial response (ORR of 89%). Baseline Ki67 levels were low (median 18%), consistent with luminal type A disease. On average, patients underwent surgery 24 days after completion of the study. Ki67 was measured at baseline, cycle 1 day 15, and at the time of surgery. Median Ki67 at time of surgery was 10%. There were no significant changes in Ki67 that could be related to treatment outcome based on this preliminary data analysis in surgical samples only. In the first 8 patients, whom all started at a dose of 125mg palbociclib, 4 patients developed grade 3/4 neutropenia in the absence of fever. Neutropenia was well manageable with G-CSF and/or dose modification. Protocol amendment allowed starting dose of 100 mg with dose titration to 125mg after the first cycle. 3 patients started at 100mg and grade 4 neutropenia without fever occurred in 1 subject. Another common side effect was low grade mucositis (n=5).
Conclusion : Based on these initial results, the addition of palbociclib to neo-adjuvant letrozole appears to be safe and effective. Historically, ORR in this patient population with letrozole alone is below 55%. The addition of palbociclib increased the preliminary ORR to 89%. One patient had a pCR, uncommon for patients on neo-adjuvant endocrine therapy. Complete safety and efficacy data will be included for at least 11 patients, including initial biomarker results. The study continues enrolment up to 45 patients.
Citation Format: Louis WC Chow, Chi-Kei Lam, Wings TY Loo. OOTR-N007: A phase II neoadjuvant study of letrozole plus palbociclib in postmenopausal patients with ER positive, HER2 negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-04.