LUGANO-MADRID –The results of the MONARCH 3 trial, presented at the ESMO 2017 Congress in Madrid (1), showed that adding the cyclin-dependent kinase (CDK) 4/6 inhibitor abemaciclib to endocrine therapy improved progression-free survival compared to endocrine therapy alone in the total study population. While most women had substantial benefit from the addition of abemaciclib as initial treatment, around one-third of women may not need a CDK 4/6 inhibitor as initial treatment.
MONARCH 3 was a phase III randomised, double blind trial of abemaciclib versus placebo, both on top of endocrine therapy with a non-steroidal aromatase inhibitor (anastrozole or letrozole), as initial therapy in postmenopausal women with hormone receptor positive, HER2 negative advanced breast cancer. The study included 493 patients from 22 countries who had never been treated for metastatic disease. The primary endpoint was progression-free survival.
Results of the interim analysis at 18 months are presented today. The investigators found that compared to single agent endocrine therapy alone, the combination of abemaciclib and endocrine therapy significantly prolonged progression-free survival with a hazard ratio (HR) of 0.543 (p = 0.000021). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm (p = 0.004). Rates of diarrhoea and neutropaenia were 81.3% and 41.3% with abemaciclib, and 29.8% and 1.9% with placebo, respectively.
“This is the third study demonstrating that the combination of endocrine therapy with a CDK4/6 inhibitor is better than endocrine therapy alone,” said lead author Dr Angelo Di Leo, medical oncologist, Sandro Pitigliani Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy. “Abemaciclib reduced the risk of disease progression by 46%.”
The data also show we may be able to better distinguish benefit among groups of patients. In patients with more challenging disease characteristics such as liver metastases, patients had substantial benefit from the addition of abemaciclib. However,in the subgroups with bone metastases only, or with an indolent disease, relapsing years after stopping adjuvant endocrine therapy, patients had an excellent prognosis with endocrine therapy alone.
"It is well known that these patients have a better prognosis than those with liver or lung metastases, or who relapse early during the course of adjuvant endocrine therapy,” said Di Leo. “Now for the first time,we have insights suggesting that patients with certain clinical characteristics may benefit differently from treatment with a CDK 4/6 inhibitor, including the possibility that some patients with a good prognosis may be able to start on endocrine therapy alone. In such patients, CDK 4/6 inhibitorscould potentially be reserved as a next line of treatment for metastatic disease. This idea warrants further study given our data."
"In our study, nearly one-third of patients had bone metastases only or a tumour relapsing several years after stopping adjuvant endocrine therapy," continued Di Leo. "This is a clinically relevant proportion of patients for whom we may consider delaying use of a CDK 4/6 inhibitor. This may be a more optimal treatment strategy for some patients since it can avoid the toxicity of first line CDK 4/6 inhibitors and save costs."
Commenting on the findings, Dr Giuseppe Curigliano, director, Division of New Drug Development, European Institute of Oncology (IEO), University of Milan, Milan, Italy, said: “Abemaciclib is the third CDK4/6 inhibitor to be tested in advanced breast cancer and the MONARCH 3 trial confirms the role of this new class of agents in combination with endocrine therapy in the treatment of metastatic breast cancer.”
“Many patients with metastatic disease still receive chemotherapy, despite guidelines and data from clinical trials,” he added. “This study confirms that we should avoid chemotherapy in hormone receptor positive, HER2 negative metastatic breast cancer if visceral crisis is not present.”
Curigliano concluded: “The major question that still needs to be answered is the optimal sequence of treatment in the era of CDK 4/6 inhibitors. Should we use these agents in the first line setting or is there a space to start with endocrine therapy alone and to add CDK 4/6 inhibitors at progression? An academic driven trial should be designed to address this question.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress
- Abstract 236O_PR ‘MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer’ will be presented by Angelo Di Leo during Presidential Symposium II on Sunday, 10 September 2017, 16:30 to 18:00 (CEST) in Madrid Auditorium.
This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct.
About the European Society for Medical Oncology (ESMO)
ESMO is the leading professional organisation for medical oncology. With 16,000 members representing oncology professionals from over 130 countries worldwide, ESMO is the society of reference for oncology education and information. We are committed to supporting our members to develop and advance in a fast-evolving professional environment.
MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer
A. di Leo1, M. Toi2, M. Campone3, J. Sohn4, S. Paluch-Shimon5, J. Huober6, I.H. Park7, O. Tredan8, S.-C. Chen9, L. Manso10, O. Freedman11, G.G. Jaliffe12, T. Forrester13, M. Frenzel13, S. Barriga14, I.C. Smith15, N. Bourayou16, M.P. Goetz17
1Sandro Pitigliani Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, Prato/ITALY, 2Department Of Breast Surgery, Kyoto University-Graduate school of medicine, Kyoto/JAPAN, 3Medical Oncology, ICO Institut de Cancerologie de l'Ouest René Gauducheau, Saint-Herblain/FRANCE, 4Department Of Internal Medicine, Yonsei Cancer Center, Seoul/KOREA, REPUBLIC OF, 5-, Chaim Sheba Medical Center, Ramat Gan/ISRAEL, 6Breast Center, Department Of Gynecology, University of Ulm, Ulm/GERMANY, 7Breast Cancer, National Cancer Center, Gyeonggi-do/KOREA, REPUBLIC OF, 8Département D'oncologie Médicale Adulte, Centre Léon Bérard, Lyon/FRANCE, 9Gs, Chang Gung Memorial Hospital-Linkou, Taoyuan City/TAIWAN, 10Clinical Oncologist, Hospital Universitario 12 de Octubre, Madrid/SPAIN, 11Oncology, R.S. McLaughlin Durham Regional Cancer Centre, Oshawa/CANADA, 12Medical Oncology, Grupo Médico CAMINO S.C., Mexico City/MEXICO, 13Global Statistical Sciences, Eli Lilly and Company, Indianapolis/UNITED STATES OF AMERICA, 14Oncology Clinical Development, Eli Lilly and Company, Madrid/SPAIN, 15Oncology Clinical Development, Eli Lilly and Company, Indianapolis/UNITED STATES OF AMERICA, 16Oncology Clinical Development, Eli Lilly and Company, Paris/FRANCE, 17Oncology, Mayo Clinic, Rochester/UNITED STATES OF AMERICA
Background: Abemaciclib is an oral selective CDK4 & 6 inhibitor dosed on a continuous schedule and has demonstrated efficacy and tolerability as monotherapy and in combination with fulvestrant in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). MONARCH 3 evaluates abemaciclib plus the non-steroidal aromatase inhibitors (NSAI) anastrozole (A) or letrozole (L) as initial therapy in HR+/HER2- ABC.
Methods: MONARCH 3 is a double-blind, Phase 3 study of abemaciclib + NSAI (A or L) vs placebo (P) + NSAI in postmenopausal women with HR+/HER2- ABC who have had no prior systemic therapy in the metastatic setting. Endocrine naïve pts or pts with disease relapse >12 months after (neo)adjuvant endocrine therapy (ET) were randomized 2:1 and stratified by metastatic site (visceral, bone only, or other) and prior ET (AI vs no ET vs other). Pts received abemaciclib/P (150 mg, twice daily continuous schedule) + 1 mg A or 2.5 mg L, daily. The primary objective was investigator-assessed progression-free survival (PFS). Secondary objectives included objective response rate (ORR) and safety. The study was powered to 80% at 1-sided α=.025 assuming a hazard ratio (HR) of 0.67 in favor of abemaciclib + NSAI, with analyses at 189 and 240 PFS events.
Results: 493 women were randomized to abemaciclib + NSAI (n=328) or P + NSAI (n=165). Pt characteristics were: visceral disease (52.9%), measurable disease (80.5%), prior (neo)adjuvant AI (27.4%), and de novo ABC (39.8%). At the interim analysis, 194 PFS events were observed. The PFS was significantly prolonged with a HR of 0.543 (95% CI, 0.409 to 0.723, P=.000021; median PFS: not reached in abemaciclib arm, 14.7 months in placebo arm). In pts with measurable disease, the ORR was 59% in the abemaciclib arm and 44% in the P arm (P=.004). The most frequent adverse events were (abemaciclib vs P arms) diarrhea (81.3% [grade 3: 9.5%, no grade 4] vs 29.8% [grade 3: 1.2%, no grade 4]), neutropenia (41.3% [grade 3/4: 21.1%] vs 1.9% [grade 3/4: 1.2%]), and fatigue (40.1% [grade 3: 1.8%] vs 31.7% [grade 3: 0%]).
Conclusions: Abemaciclib + NSAI demonstrated a tolerable safety profile and was an effective initial treatment for pts with HR+/HER2- ABC, significantly improving PFS and ORR.
Clinical trial identification: NCT02246621
Keywords: breast cancer, abemaciclib, HR+, CDK4
Funding: Eli Lilly and Company
Disclosure: A. di Leo: Honoraria, consulting, and travel funds: Daichii-Sankyo, Roche, Novartis, Pfizer, AstraZeneca, Genomic Health, Eisai, Lilly, Pierre Fabre, Bayer, Celgene; Consulting and travel funds: Puma Biotechnology; Research funds: Novartis, Pfizer, AstraZeneca.
M. Campone: Honoraria, Consulting/advisory, Speakers’ bureau: Novartis, Pfizer, AstraZeneca; Lilly; Travel funds: Novartis, AstraZeneca
J. Sohn: Research Funding: AstraZeneca, Eli Lilly and Company, Novartis, Genentech, Pfizer, MSD Oncology
S. Paluch-Shimon: Consulting/advisory, Speakers’ Bureau: Pfizer, Novartis, Roche, AstraZeneca
J. Huober: Honoraria, Consulting/advisory, Travel funds: Novartis, Pfizer, Roche; Honoraria, Consulting: Lilly
O. Tredan: Honoraria, Consulting/Advisory, Travel funds: Lilly, Roche, Novartis, AstraZeneca, Pfizer, Celldex
G.G. Jaliffe: Speakers’ Bureau: Roche, Amgen
T. Forrester, M. Frenzel, I.C. Smith, N. Bourayou: Employment and Stock Ownership: Eli Lilly and Company
S. Barriga: Employment: Eli Lilly and Company
M.P. Goetz: Consulting/Advisory: Eli Lilly and Company, Biotheranostics; Research funding: Eli Lilly and Company
All other authors have declared no conflicts of interest.