Elsevier

The Lancet Oncology

Volume 21, Issue 6, June 2020, Pages 763-775
The Lancet Oncology

Articles
Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial

https://doi.org/10.1016/S1470-2045(20)30112-1Get rights and content

Summary

Background

Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer.

Methods

This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1–21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up.

Findings

Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7–25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9–12·6) and group C (5·7 months, 5·4–7·0; HR 0·67 [95% CI 0·45–1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2–7·2) and group C (HR 0·94 [0·64–1·38]; p=0·77). The most common grade 3–4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C.

Interpretation

The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer.

Funding

Eli Lilly and Company.

Introduction

Breast cancer is the most commonly diagnosed cancer in females globally,1 with hormone receptor-positive, HER2 (also known as ERBB2)-positive breast cancer representing an estimated 10% of all breast cancer subtypes in the USA.2 The addition of HER2-targeted therapies to standard chemotherapy has improved outcomes for patients with HER2-positive breast cancer.3, 4 Effective anti-HER2 agents include the monoclonal antibody trastuzumab and the small molecule inhibitor lapatinib. More recent advances include the dimerisation inhibitor pertuzumab and the antibody drug conjugate trastuzumab emtansine.5 Unfortunately, multiple mechanisms of resistance are known to emerge against HER2-targeted therapies, notably those mediated by effectors downstream of the HER2 receptor.6 International guidelines recommend that patients whose tumours progress on an anti-HER2 therapy in combination with a cytotoxic or endocrine agent should be offered additional anti-HER2 agents to achieve ongoing suppression of HER2 pathway signalling.7 Patients with heavily pretreated HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. In this setting, HER2-targeted therapy combined with cytotoxic chemotherapy agents offer modest clinical benefit with associated toxicities.8, 9

Abemaciclib, a potent oral cyclin-dependent kinase 4 (CDK4) and 6 (CDK6) inhibitor, has shown activity in hormone receptor-positive, HER2-negative advanced breast cancer as a monotherapy10 and in combination with endocrine therapy.11, 12 However, activity of abemaciclib is not restricted to hormone receptor-positive, HER2-negative disease. In a phase 1 study of abemaciclib, four patients among a subset of 11 with hormone receptor-positive, HER2-positive advanced breast cancer (three of whom were receiving concomitant endocrine therapy) achieved a partial response (36%, 95% CI 10·9–69·2).13 The median progression-free survival for this subpopulation was 7·2 months (95% CI 2·8–12·0). These results provide a clinical rationale to further investigate the role of abemaciclib in HER2-positive disease.

Preclinical studies have provided a biological rationale supporting the study of abemaciclib in HER2-positive advanced breast cancer. Using genetically engineered mouse models, cell lines, and patient-derived xenografts of HER2-therapy resistant breast cancer, Goel and colleagues14 showed that the CDK4 and CDK6 pathway can mediate resistance to HER2-targeted therapies and that this can be overcome by abemaciclib. O'Brien and colleagues15 subsequently confirmed this observation and showed that the addition of endocrine therapy further enhanced the efficacy of abemaciclib plus trastuzumab in models of hormone receptor-positive, HER2-positive breast cancer.

Here, we report the results of the monarcHER trial comparing the efficacy of abemaciclib plus trastuzumab with or without fulvestrant versus standard-of-care, single-agent chemotherapy of physician's choice plus trastuzumab in women with hormone receptor-positive, HER2-positive advanced breast cancer.

Section snippets

Study design and participants

This phase 2, randomised, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries (Argentina, Australia, Belgium, Brazil, Canada, France, Germany, Greece, Italy, Mexico, Spain, South Korea, the UK, and the USA; appendix pp 16–24). Women aged 18 years or older of any menopausal status (premenopausal or perimenopausal patients received a gonadotropin-releasing hormone agonist initiated at least 28 days before day 1, cycle 1), with a confirmed

Results

Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 (intention-to-treat population) were randomly assigned, with 79 patients assigned to each study group (figure 1). Baseline demographics and disease characteristics are given in table 1. Across all groups, 207 (87%) had measurable disease. 119 (50%) patients had received two to three previous systemic therapies for advanced breast cancer, and 118 (50%) patients had received more than three. Overall, patients in the

Discussion

To our knowledge, this trial is the first randomised study of a CDK4 and CDK6 inhibitor to report positive results in combination with endocrine therapy and HER2-targeted therapy compared with standard-of-care chemotherapy with trastuzumab in patients pretreated with at least two HER2-targeted treatments. monarcHER showed an improved progression-free survival in group A (abemaciblib, trastuzumab, and fulvestrant) compared with group C (standard-of-care chemotherapy and trastuzumab) in women

Data sharing

Eli Lilly provides access, after anonymisation, to all individual participant data collected during the trial, except for pharmacokinetic and genetic data. Data can be requested 6 months after the indication studied has been approved in the USA and EU or after primary publication acceptance, whichever is later. No expiration date for data requests is set once the data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this

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    S Goel was affiliated with Dana-Farber Cancer Institute, Boston, MA, USA during trial initiation through to data lock for progression-free survival analysis

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