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

Educational Objective
To learn the effect on overall survival of the addition of abemaciclib to fulvestrant in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy.
1 Credit CME
Key Points

Question  Does treatment with abemaciclib plus fulvestrant prolong the overall survival (OS) of patients with hormone receptor (HR)–positive, ERBB2 (formerly HER2)-negative advanced breast cancer who progressed during prior endocrine therapy?

Findings  In the randomized, placebo-controlled MONARCH 2 trial of 669 patients with HR-positive, ERBB2-negative advanced breast cancer, abemaciclib plus fulvestrant significantly improved median OS to 46.7 months compared with 37.3 months for patients receiving placebo plus fulvestrant.

Meaning  The addition of abemaciclib to fulvestrant provided a clinically meaningful median OS benefit of 9.4 months for patients with HR-positive, ERBB2-negative advanced breast cancer that had progressed on endocrine therapy.

Abstract

Importance  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.

Objective  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.

Interventions  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.

Results  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  ClinicalTrials.gov identifier: NCT02107703

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Article Information

Accepted for Publication: September 5, 2019.

Published Online: September 29, 2019. doi:10.1001/jamaoncol.2019.4782

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2019 Sledge GW Jr et al. JAMA Oncology.

Corresponding Author: George W. Sledge Jr, MD, Stanford University School of Medicine, 269 Campus Dr, CCSR 1115, Stanford, CA 94305 (gsledge@stanford.edu).

Author Contributions: Dr Sledge had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of Interest Disclosures: Dr Sledge reported grants and nonfinancial support from Stanford University during the conduct of the study; personal fees from Radius Pharmaceuticals and Verseau Therapeutics, grants from Pfizer, personal fees from Symphogen, personal fees and nonfinancial support from Tessa, and personal fees from Syndax outside the submitted work. Dr Toi reported grants, personal fees, and other support from Daiichi Sankyo, grants, personal fees, and other support from Kyowa Kirin, personal fees and other support from Konica Minolta, grants and personal fees from Chugai, grants and personal fees from Pfizer, grants and personal fees from Taiho, grants and personal fees from Eisai, grants and personal fees from Astra Zeneca, grants and personal fees from Shimadzu, grants and personal fees from Astellas, other support from Nippon Kayaku, grants from Terumo, grants from AFI Technologies, grants from Japan Breast Cancer Research Group, grants from Kyoto Breast Cancer Research Network, personal fees from Takeda, personal fees and other from Bristol-Myers Squibb, personal fees and other support from Eli Lilly and Company, personal fees and other support from Genomic Health, and personal fees from Novartis outside the submitted work; and has been involved in the Japan Breast Cancer Research Group association trials and translational research as a board member and the Kyoto Breast Cancer Research Network as a board member. Dr Sohn reported grants from Merck Sharp & Dohme, Roche, Novartis, AstraZeneca, Lilly, Pfizer, Bayer, GSK, CONTESSA, and Daiichi Sankyo outside the submitted work. Dr Inoue reported grants and personal fees from Eli Lilly during the conduct of the study; grants and personal fees from Pfizer and Chugai, grants from Novartis, grants and personal fees from Eisai, grants from Parexel/Puma Biotechnology, grants from Daiichi-Sankyo, Merck Sharp & Dohme, and Bayer outside the submitted work. Dr Masuda reported grants from Eli Lilly during the conduct of the study; grants and personal fees from Chugai, grants and personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from Eli Lilly, grants and personal fees from Eisai, personal fees from Takeda, grants from Kyowa Kirin, grants from Merck Sharp & Dohme, grants from Novartis, and grants from Daiichi-Sankyo outside the submitted work. Dr Kaufman reported grants and personal fees from Lilly during the conduct of the study; grants and personal fees from Roche-Genentech, Macrogenics, and Polyphor, grants and other support from Amgen, and grants and personal fees from Eisai outside the submitted work. Dr Conte reported personal fees from Eli Lilly and grants and personal fees from Novartis outside the submitted work. Dr Lu reported personal fees, nonfinancial support, and other from Eli Lilly and Company during the conduct of the study. Dr Barriga is an employee of and owns stock in Eli Lilly stock. Dr Hurt reported other from Eli Lilly and Company during the conduct of the study. Dr Frenzel reported other from Eli Lilly and Company during the conduct of the study. Dr Johnston reported grants and personal fees from Pfizer, Puma Biotechnology, Eli Lilly, AstraZeneca, Novartis, Roche/Genentech, and personal fees from Eisai outside the submitted work. Dr Llombart-Cussac reported personal fees and nonfinancial support from Eli Lilly, grants, personal fees, and nonfinancial support from Roche and Pfizer, personal fees from Novartis, grants and personal fees from AstraZeneca and Genomic Health, grants from Merck Sharp & Dohme, personal fees and nonfinancial support from Celgene, grants from EISAI, Pierre Fabre, personal fees from Agendia and Amgen during the conduct of the study; and is a cofounder and stockholder of Medica Scientia Innovation Research. No other disclosures were reported.

Funding/Support: This study was funded by Eli Lilly and Company.

Role of the Funders/Sponsor: Eli Lilly and Company was responsible for design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Meeting Presentation: This paper was presented at the ESMO (European Society for Medical Oncology) Congress 2019; September 29, 2019; Barcelona, Spain.

Additional Contributions: We thank the MONARCH study steering committee, the patients and their caregivers for participating in this trial, and the investigators and their support staff who generously participated in this work. Writing and editorial assistance were funded by Eli Lilly. Sarah C. Nabinger, Eli Lilly and Company (Indianapolis, IN), provided writing assistance, Annie-Carole Trampont, Eli Lilly and Company (Indianapolis, IN), provided figure generation support, and Teri Tucker and Antonia Baldo, Syneos Health, provided editorial assistance. Fulvestrant was provided by AstraZeneca for this trial.

Disclaimer: Dr Sledge is an associate editor of JAMA Oncology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

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