Abstract OT3-02-06: Femara plus ribociclib or placebo as neo-adjuvant endocrine therapy for women with ER+, HER2-negative early breast cancer - The Feline trial

Abstract

Background: In early ER+ breast cancer, neo-adjuvant (NA) endocrine therapy (ET) may identify a subset of patients with endocrine sensitive disease with excellent outcomes without chemotherapy. In patients receiving a NA aromatase inhibitor, on- therapy, short term (day 14) Ki-67 of <10% and post NA pre-operative endocrine prognostic index (PEPI) 0 at surgery are associated with low relapse rates without chemotherapy. Ribociclib, a novel CDK4/6 inhibitor is active in ER+ metastatic breast cancer. We hypothesize that ribociclib+letrozole as NA ET for stage II-III breast cancer will increase the number of women with a PEPI 0 at surgery. Trial Design: Randomized, placebo-controlled, multi-center, phase II, investigator initiated trial of NA letrozole +/- ribociclib in postmenopausal women with ER+, HER2-, breast cancer. Subjects will be randomized 1:1:1 to letrozole 2.5 mg daily + placebo, letrozole 2.5mg daily + ribociclib 600mg daily on D1-21 of a 28 day cycle (intermittent dosing), or letrozole 2.5mg daily + ribociclib 400mg daily (continuous dosing). Treatment will be continued for 6 months followed by surgery. Research core biopsies and blood will be collected at baseline, at day 14, and at surgery. A Ki67 >10% at day 14 will result in discontinuation of the subject from the protocol as this may be an early indicator of resistance to endocrine therapy. An MRI will be done after 2 months of therapy to assess response/progression. Primary endpoint is a PEPI score of 0 at surgery. Key Eligibility Criteria: Postmenopausal (natural or surgical) women with stage II/III ER+, HER2- breast cancer. Must have a palpable breast mass of at least 2 cm. Multicentric/contralateral invasive disease not allowed. Ipsilateral/contralateral DCIS is allowed. Inflammatory breast cancer is excluded. Specific Aims: Primary objective: To determine if ribociclib+letrozole as a 24 week NA ET increases rate of PEPI score of 0 at surgery compared to letrozole. Secondary objectives: To determine if ribociclib+letrozole as a 24 week NA ET increases the proportion of tumors with complete cell cycle arrest compared to letrozole; to determine if ribociclib in combination with letrozole for 24 weeks results in improved 5 year RFS compared to letrozole; to examine differences in response rates between the two ribociclib containing arms vs letrozole. Statistical Methods: The two ribocilib containing arms (n=80) will be combined for analysis against placebo + letrozole (n=40). Assuming that addition of ribociclib will increase the rate of PEPI 0 by 20%, and setting Type I error rate at 10% and Type II error rates at 20% in the final analysis, a sample size of 80 women in the treatment arms (40 in each arm) and 40 women in the control arm are needed to show significance. Patient accrual and target accrual: Participating sites include The Univ of Kansas Med Ctr, City of Hope National Med Ctr, Massachusetts General Hospital, University of Miami Sylvester Comprehensive Cancer Ctr, University of Arkansas for Medical Sciences, and University of Wisconsin. The trial has accrued 16 patients with a target accrual of 120 patients. Accrual should be complete in 2/2017. Contact information: Qamar Khan, MD (qkhan@kumc.edu). Citation Format: Khan QJ, Prochaska LH, Mohammad J, Yuan Y, O'Dea A, Bardia A, Wisinski K, Hard M, Baccaray S, Makhoul I, Wagner J, Laura S, Ma C, Sharma P. Femara plus ribociclib or placebo as neo-adjuvant endocrine therapy for women with ER+, HER2-negative early breast cancer - The Feline trial [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 OT3-02-06.

Cancer cells communicate with macrophages to prevent T cell activation during development of cell cycle therapy resistance

“…We studied the tumor-wide communication among cells in tumors of post-menopausal women with node positive or >2 cm ER and or PR+, HER2 negative breast cancer enrolled on the FELINE clinical trial 10,21,22 (clinicaltrials.gov # NCT02712723). This trial evaluated the efficacy of combining CDK inhibition with endocrine therapy in the neoadjuvant setting.…”

Serial single-cell genomics reveals convergent subclonal evolution of resistance as patients with early-stage breast cancer progress on endocrine plus CDK4/6 therapy

“…We studied the evolution of endocrine and CDK inhibitor resistant cancer cell genotypes and phenotypes in post-menopausal women with node positive or >2 cm ER and or PR+, HER2 negative breast cancer enrolled in the FELINE trial ( clinicaltrials.gov # NCT02712723 ) ( 19 ). This trial evaluated of the addition of CDK inhibition to endocrine therapy in the neo-adjuvant setting Patients (n=120) were randomized equally into three arms: A) endocrine therapy alone (letrozole plus placebo), B) intermittent high dose combination therapy (letrozole plus ribociclib (600 mg/d, three on/one week off)) or C) continuous lower dose combination therapy (letrozole plus ribociclib (400 mg/d)) ( Figure 1a ).…”

MONALEESA Clinical Program: A Review of Ribociclib use in Different Clinical Settings

“…These trials are randomizing HR+, HER2-breast cancer patients to treatment with ribociclib in combination with ET or to standard of care treatment. In the neoadjuvant setting, the Phase II FELINE trial is comparing ribociclib plus letrozole versus placebo plus letrozole in postmenopausal women with HR+, HER2early breast cancer (NCTT02712723) [41,42]; the Phase II NEOLBC trial is comparing ribociclib plus letrozole versus standard chemotherapy as a neoadjuvant therapy in postmenopausal women with HR+, HER2-luminal breast cancer (NCT03283384) [43]; and the CORALLEEN trial is comparing ribociclib plus letrozole versus standard chemotherapy as a neoadjuvant therapy in postmenopausal women with luminal B, HER2-breast cancer (NCT03248427) [44,45]. In addition, the Phase III NATALEE trial will evaluate the efficacy and safety of ribociclib plus ET compared with ET alone as an adjuvant treatment in pre/perimenopausal and postmenopausal women with early breast cancer (NCT03701334) [46].…”