Review of the monarchE trial suggests no evidence to support use of adjuvant abemaciclib in women with breast cancer - Authors' reply.

The monarchE investigators respectfully disagree with the comments of Tomer Meirson and colleagues in their Essay in The Lancet Oncology regarding the role of adjuvant abemaciclib in patients with early breast cancer. monarchE was a large, global, randomised study conducted in patients with high-risk, hormone receptor-positive, HER2-negative, early breast cancer.1Johnston SRD Toi M O'Shaughnessy J et al.Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial.Lancet Oncol. 2023; 24: 77-90Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar This population was selected on the basis of their substantial unmet medical need, as shown by the high risk of recurrence observed in the control group (>20% at 4 years); outcomes that justified consideration of additional treatment with abemaciclib. Key primary and secondary endpoints were selected on the basis of international consensus guidelines2Hudis CA Barlow WE Costantino JP et al.Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system.J Clin Oncol. 2007; 25: 2127-2132Crossref PubMed Scopus (621) Google Scholar and included invasive disease-free survival, distant relapse-free survival, and overall survival. The standardised endpoints of invasive disease-free survival and distant relapse-free survival were assessed on the basis of comprehensive protocol-defined methods to identify symptoms of recurrence with confirmation by imaging or biopsy, or both, providing objectivity and consistency. The strong correlation between disease recurrence and overall survival justifies the use of these endpoints,2Hudis CA Barlow WE Costantino JP et al.Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system.J Clin Oncol. 2007; 25: 2127-2132Crossref PubMed Scopus (621) Google Scholar, 3Verma S Sehdev S Joy A Madarnas Y Younus J Roy JA An updated review on the efficacy of adjuvant endocrine therapies in hormone receptor-positive early breast cancer.Curr Oncol. 2009; 16: S1-13Crossref PubMed Scopus (4) Google Scholar which are accepted by regulators in situations “where survival may be prolonged, making a survival endpoint impractical”.3Verma S Sehdev S Joy A Madarnas Y Younus J Roy JA An updated review on the efficacy of adjuvant endocrine therapies in hormone receptor-positive early breast cancer.Curr Oncol. 2009; 16: S1-13Crossref PubMed Scopus (4) Google Scholar Given the substantial reduction (34%) in the risk of developing incurable and fatal distant metastases found in the monarchE trial,1Johnston SRD Toi M O'Shaughnessy J et al.Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial.Lancet Oncol. 2023; 24: 77-90Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar overall survival is expected to continue to mature favourably with longer follow-up. Waiting for mature overall survival data, which can take years3Verma S Sehdev S Joy A Madarnas Y Younus J Roy JA An updated review on the efficacy of adjuvant endocrine therapies in hormone receptor-positive early breast cancer.Curr Oncol. 2009; 16: S1-13Crossref PubMed Scopus (4) Google Scholar in hormone receptor-positive early breast cancer, would needlessly delay patient access to treatment innovation. The majority of patients remain in active follow-up to evaluate longer-term efficacy. Permanent dropout rates were low and well balanced between treatment groups, indicating no informative censoring. Thus, the adjustments to the invasive disease-free survival or overall survival curves proposed by Meirson and colleagues to account for informative censoring are unwarranted and inappropriate. We acknowledge the addition of 2 years of abemaciclib adds to the overall side-effect profile of adjuvant therapy. However, as clearly shown by the now fully mature safety data, abemaciclib adverse events were manageable and reversible. Consistent with this, patient-reported outcomes showed maintained overall quality of life during treatment.4Rugo HS O'Shaughnessy J Boyle F et al.Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study.Ann Oncol. 2022; 33: 616-627Summary Full Text Full Text PDF PubMed Google Scholar In summary, the addition of abemaciclib to endocrine therapy led to a robust and sustained reduction in the risk of developing invasive disease with a clinically relevant absolute improvement of 6·4% at 4 years.1Johnston SRD Toi M O'Shaughnessy J et al.Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial.Lancet Oncol. 2023; 24: 77-90Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar The number of patients (n=15) who need to be treated to prevent one additional recurrence in monarchE is lower than for other recently approved adjuvant treatments.5Thaper A Tran J Ali A Current updates in management of HER2-positive and HER2-low breast cancer.Curr Breast Cancer Rep. 2023; (published online April 17.)https://doi.org/10.1007/s12609-023-00486-2Crossref Scopus (0) Google Scholar Consequently, abemaciclib has been approved by global regulators and endorsed by international guidelines with a level 1 rating from the National Comprehensive Cancer Network and a maximum score (A) for curative therapies from the European Society for Medical Oncology on the Magnitude of Clinical Benefit Scale.6National Comprehensive Cancer NetworkClinical Practice Guidelines in Oncology–Breast Cancer. Version 4.https://www.nccn.org/professionals/physician_gls/pdf/breast.pdfDate: 2023Date accessed: April 27, 2023Google Scholar, 7European Society for Medical OncologyESMO-MCBS scorecards: Abemaciclib.https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards/scorecard-371-1Date: March 7, 2023Date accessed: April 27, 2023Google Scholar Declarations of interest are the same as in the original article. Review of the monarchE trial suggests no evidence to support use of adjuvant abemaciclib in women with breast cancerWhen localised cancer is resected surgically, some patients will have recurrence of their disease, and the likelihood of dying from the cancer is then high. Adjuvant therapies are offered before or after surgery in the hope of reducing the probability of recurrence, thereby improving survival. The scientific and clinical community is continuously searching for new adjuvant therapies that can increase survival and cure rates, but when potential advances are proposed, the data must be carefully analysed to establish if the new therapy performs as we hope. Full-Text PDF