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JAMA Oncol. 2019 Sep 29. doi: 10.1001/jamaoncol.2019.4782. [Epub ahead of print]

The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial.

Author information

Stanford University School of Medicine, Stanford, California.
Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Universitaire Ziekenhuizen Leuven, Leuven, Belgium.
Yonsei Cancer Center, Seoul, Korea.
Saitama Cancer Center, Saitama, Japan.
Centre Paul Strauss, INSERM 110, Strasbourg, France.
Arkhangelsk Regional Clinical Oncology Dispensary, Arkhangelsk, Russia.
Adelaide Cancer Centre, Adelaide, Australia.
National Hospital Organization, Osaka National Hospital, Osaka, Japan.
University of Vermont Cancer Center, Burlington.
Kaiser Permanente, Bellflower, California.
Universitäts-Frauenklinik Tubingen, Eberhard Karls University, Tubingen, Germany.
DiSCOG, University of Padova and Medical Oncology 2, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
Eli Lilly and Company, Indianapolis, Indiana.
Eli Lilly and Company, Madrid, Spain.
The Royal Marsden NHS Foundation Trust, London, United Kingdom.
Hospital Arnau Vilanova, Valencia, Spain.



Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated.


To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET.

Design, Setting, and Participants:

MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019.


Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary).

Main Outcomes and Measures:

The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02.


Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib.

Conclusions and Relevance:

Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy.

Trial Registration: Identifier: NCT02107703.

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