1470 - monarcHER: A randomized Phase 2 study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer (ABC)

Background

Abemaciclib, an oral selective inhibitor of CDK4 & 6, showed efficacy & tolerability in patients (pts) with HR+, HER2- ABC. In preclinical models, inhibition of CDK4 & 6 by abemaciclib enhanced the activity of HER2-directed agents and re-sensitized resistant tumors to HER2 blockade, suggesting a crosstalk between HER2 signaling and the cyclin D1/CDK4 signaling pathways in HR+ tumors only.

Methods

monarcHER (NCT02675231), a phase II study, compared 3 treatment arms in pts with HR+, HER2+ ABC; arm A (abemaciclib 150mg PO Q12H Days 1-21 of a 21-day cycle + trastuzumab [T] IV infusion Day 1 of 21-day cycle + fulvestrant 500 mg IM Cycle 1 D1 and D15 and Cycle 2 D8, then Q4W), arm B (abemaciclib + T), vs arm C (T + investigator’s choice chemotherapy, 21-day cycle). Eligible pts were postmenopausal women, ≥2 HER2-directed therapies for ABC, prior T-DM1 and taxane, ECOG PS ≤ 1. 237 pts were randomized 1:1:1 and stratified by number of prior systemic regimens for ABC (2 to 3 vs > 3) and measurable vs nonmeasurable disease. The gated primary objective was to compare investigator assessed PFS of Arm A to C and, if positive, then B to C. Secondary objectives include: OS, objective response rate (ORR), safety, patient reported outcomes, and pharmacokinetics. Primary analysis was planned after approximately 165 PFS events, providing 80% power to detect superiority of Arm A over C, assuming a HR of .667 at 1-sided α = .1.

Results

Analysis was performed at 169 events. Median PFS was longer in Arm A vs C (HR [95% CI], 0.673 [0.451 – 1.003]; p = 0.0253; 8.3 vs 5.7 mo). No difference in Arm B vs C (HR [95% CI], 0.943 [0.643 – 1.383]; p = 0.385; 5.7 vs 5.7 mo). ORR was 35.4%, 16.5% and 22.8% in arms A, B, and C respectively. Most common grade 3/4 adverse events (AEs) in Arms A, B, and C were neutropenia (26.9%, 22.1%, and 26.4%), leukopenia (10.3%, 2.6%, and 9.7%), thrombocytopenia (10.3%, 6.5%, and 2.8%), and diarrhea (9.0%, 6.5%, and 2.8%). AE-on treatment related deaths: 2 in arm A, 1 in B, and 1 in C.

Conclusions

The study met its primary endpoint of improved PFS in the ITT population in Arm A over Arm C. Safety data was similar to the known safety profile of abemaciclib.

Clinical trial identification

NCT02675231.

Editorial acknowledgement

Writing assistance was provided by Rachel Richardson.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

S.M. Tolaney: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement : Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement : Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement : Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Honorarium; travel expense reimbursement: Immunomedics ; Research grant / Funding (institution), Institutional Research Funds : Exelixis; Research grant / Funding (institution), Institutional Research Funds : Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institutional Research Funds; honorarium; travel expense reimbursement: Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institutional Research Funds; honorarium; travel expense reimbursement: Nanostring; Advisory / Consultancy, Honorarium; travel expense reimbursement : Puma; Research grant / Funding (institution), Institutional Research Funds: Cyclacel; Honoraria (self), Advisory / Consultancy, Honorarium: Sanofi; Honoraria (self), Advisory / Consultancy, Honorarium: Tesaro; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses, Honorarium; travel expense reimbursement: Celldex . A.M. Wardley: Advisory / Consultancy, Speaker Bureau / Expert testimony, Sponsorship for meetings: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZenaca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: NAPP; Honoraria (self), Advisory / Consultancy: ACCORD; Honoraria (self), Advisory / Consultancy: Athenex; Advisory / Consultancy: Gerson Lehman Group Guidepoint Global ; Advisory / Consultancy: Coleman Expert Network; Travel / Accommodation / Expenses, Sponsorship for meetings: Daiichi Sankyo; Officer / Board of Directors: Andrew Wardley LTD. J. Hilton: Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Officer / Board of Directors: BMS. T. Troso-Sandoval: Research grant / Funding (institution): Eli Lilly and Company. S. Im: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Hanmi. S. Kim: Research grant / Funding (institution): Norvartis; Research grant / Funding (institution): Sanofi-Genzyme; Research grant / Funding (institution): Dingkook Inc. S.R.D. Johnston: Advisory / Consultancy, Research grant / Funding (institution): Astrazeneca; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Puma Biotechnology; Speaker Bureau / Expert testimony: Eisai. S. Goel: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Lab funding and Clinical trial research support : Eli Lilly and Company; Advisory / Consultancy, Research grant / Funding (institution), Clinical trial research support: Novartis; Advisory / Consultancy: G1 therapeutics. K. Catron: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. Z. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. C. Gainford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. F. André: Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: GlaxoSmithKline; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Pfizer. All other authors have declared no conflicts of interest.