MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and …...May 20, 2017 · MONARCH 1 study (NCT02102490) was launched. MONARCH 1 is a multicenter, single-arm, open-label study to
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MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer Authors: Maura N. Dickler1*, Sara M. Tolaney2, Hope S. Rugo3, Javier Cortés4,5, Véronique Diéras6, Debra Patt7,8, Hans Wildiers9, Clifford A. Hudis1, Joyce O’Shaughnessy8, Esther Zamora4, Denise A. Yardley10, Martin Frenzel11, Andrew Koustenis11, José Baselga1
Affiliations: 1Memorial Sloan Kettering Cancer Center, New York, NY; 2Dana-Farber Cancer Institute, Boston, MA; 3University of California San Francisco Comprehensive Cancer Center, San Francisco, CA; 4Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 5Ramón y Cajal University Hospital, Madrid, Spain; 6Institut Curie, Paris, France; 7Texas Oncology, Austin, TX, 8Baylor University Medical Center, Texas Oncology, US Oncology, Dallas TX; 9Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; 10Sarah Cannon Research Institute,Tennessee Oncology PLLC, Nashville, TN; 11Eli Lilly and Company, Indianapolis, IN
Running Title: Phase 2 Study of Abemaciclib in HR+/HER2- MBC Keywords: abemaciclib, metastatic breast cancer, refractory, CDK4, CDK6 Financial support: This study was funded by Eli Lilly and Company. MND has funding from the National Cancer Institute (P30 CA008748).
*Corresponding Author: Maura N. Dickler, MD Maura N. Dickler, MD Memorial Sloan Kettering Cancer Center 300 East 66th St, Rm 859 New York, NY 10065 Phone: 646-888-4560 Email: [email protected]
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
neuropathy.13 Although a direct comparison with chemotherapy in this setting has not been
done, the ORR of 19.7% (95% CI: 13.3, 27.5; 15% not excluded) observed with single agent
abemaciclib in MONARCH 1 is consistent with the approximate ORR range historically
observed in approved chemotherapy treatments for patients who have previously received a
taxane, with a safety profile consistent with previous phase 1 observations.22
In conclusion, the MONARCH 1 study has demonstrated that abemaciclib as a single
agent dosed on a continuous schedule has antitumor activity and manageable toxicities in
patients with HR+ HER2- MBC who had previously progressed on or after endocrine therapy
and received 1-2 lines of chemotherapy in the metastatic setting. The future role of abemaciclib
in the therapy of HR+ MBC will be delineated by a number of clinical trials, and two ongoing
phase 3 trials are investigating abemaciclib in combination with endocrine therapy in the first-
and second-line settings (NCT02246621 and NCT02107703).
Acknowledgements: We thank the patients and their caregivers for participating in this trial. We also thank the investigators and their support staff who generously participated in this work. Karen T. Smith and Susan P. Whitman, employees of Eli Lilly and Company, provided medical writing support.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
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16. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 2011;11:558-572. 17. Johnston SR. Enhancing Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: Cotargeting Signaling Pathways. J Natl Cancer Inst 2015;107: djv212. 18. Altucci L, Addeo R, Cicatiello L, Dauvois S, Parker MG, Truss M, et al. 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. Oncogene 1996;12:2315-2324. 19. Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 1997;272:10882-10894. 20. Miller TW, Balko JM, Fox EM, Ghazoui Z, Dunbier A, Anderson H, et al. ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 2011;1:338-351. 21. Lallena MJ, Boehnke, K., Torres, R., Hermoso, A., Amat, J., Calsina, B., De Dios, A., Buchanan, S., Du, J., Beckmann, R.P., Gong, X., Mcnulty, A. : In-vitro characterization of Abemaciclib pharmacology in ER+ breast cancer cell lines. Proceedings of the 106th Annual Meeting of the American Association for Cancer Research 2015;75(15 Suppl): 3101. 22. Patnaik A RL, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, et al. Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov 2016;6:740-753. 23. Eisenhauer EA, Therasse P, Bogaerts J, Scwartz LH, Sarget D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
24. Hammond MEM, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer. J Clin Oncol 2010;28:2784-2795. 25. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015;33:3199-3212. 26. NCI: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, 27. Onopiuk A, Tokarzewicz A, Gorodkiewicz E. Cystatin C: a kidney function biomarker. Adv Clin Chem 2015;68:57-69. 28. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367:20-29. 29. Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 2012;18:568-576.
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30. IBRANCE® [package insert]. Pfizer INY, NY; February 2016, Accessed June 2, 2016 31. Infante JR SG, Witteveen P, Gerecitano JF, Ribrag V, Chugh R, Issa I, Chakraborty A, Matano A, Zhao X, Parasuraman S, Cassier P. A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. J Clin Oncol 2014;suppl 32:5s abstr 2528. 32. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015;21:995-1001. 33. Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature 2001;411:1017-1021. 34. Yu Q, Sicinska E, Geng Y, AhnstrÖm M, Zagozdzon A, Kong y, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006;9:23-32. 35. Laurenti E, Frelin C, Xie S, Ferrari R, Dunant CF, Zandi S, et al. CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell Stem Cell 2015;16:302-313. 36. Scheicher R, Hoelbl-Kovacic A, Bellutti F, Tigan AS, Prchal-Murphy M, Heller G, et al. CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood 2015;125:90-101. 37. O'Brien NA CD, Luo T, Kalous O, Euw EV, Hurvitz SA, Beckmann RP, Mockbee C, and Slamon DJ. Preclinical activity of abemaciclib as a single agent or in combination with anti-mitotic or targeted therapies for breast cancer. Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; New Orleans, LA, USA. 2016;76(14suppl):2828. 38. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs 2014;32:825-837. 39. Tolaney SM CJ, Dickler MN, Zamora E; Caldwell CW; Nguyen TS; Nanda S; Koustenis A, Rugo HS. Exploratory biomarkers in MONARCH 1, a phase II study of abemaciclib monotherapy in hormone-receptor positive (HR+) HER2- metastatic breast cancer (MBC), European Society for Medical Oncology Congress, Copenhagen, Denmark, 2016; 27:1-36. 40. Johnston SR. The role of chemotherapy and targeted agents in patients with metastatic breast cancer. Eur J Cancer 2011; 47 Suppl 3:S38-47. 41. Swallow E, Zhang J, Thomason D, Tan RD, Kageleiry A, Signorovitch J. Real-world patterns of endocrine therapy for metastatic hormone-receptor-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) breast cancer patients in the United States: 2002-2012. Curr Med Res Opin 2014;30:1537-1545.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Age in years, median (range) 58 (36-89) ≥65 years, n (%) 42 (31.8)
ECOG PS, n (%) 0 73 (55.3) 1 59 (44.7)
Disease locations, n (%) Visceral 119 (90.2)
Liver 93 (70.5) Lung 31 (23.5)
Bone 82 (62.1) Bone-only 3 (2.3)
Number of metastatic sites, n (%) 1 19 (14.4) 2 46 (34.8) ≥3 67 (50.8)
Prior endocrine therapy for metastatic disease Number of regimens
1 48 (36.4) 2 25 (18.9) 3 24 (18.2) ≥ 4 18 (13.6)
Fulvestrant 67 (50.8) Prior chemotherapy for metastatic disease
Number of regimens 1 67 (50.8) 2 64 (48.5) 3 1 (0.8)a
Taxanesb 91 (68.9) Capecitabine 73 (55.3)
Other therapies for metastatic disease Everolimus 37 (28.0) Investigational drug 16 (12.1)
aPatient first received capecitabine, and then received docetaxel; the patient had a break from docetaxel treatment and then restarted docetaxel without progression in between. The treatment with docetaxel was reported by the site as 2 regimens. bThe remainder (31.1%) received prior taxane in the adjuvant setting.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Hyponatremia 17.7 0 3.1 0 20.8 aCTCAE Version 4.0 bN = 130 for lab abnormalities listed, except platelet count decreased (N=128) cOne patient who received cytotoxic chemotherapy within the 30 day follow up window experienced febrile neutropenia
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Figure 1. a. The best percent change in tumor size from baseline is plotted for each patient who had an available assessment b. Time on treatment with abemaciclib is plotted for each patient treated in the MONARCH 1 study (N=132). The colors in a and b represent response status per RECIST v1.1 and each bar in a and b represents one patient.
Figure 2. Analysis of Adverse Event of Diarrhea. Time on treatment (in days) is presented for each patient (N=132). Each bar represents one patient and the length of the bar represents the duration on treatment. The start and end of treatment emergent adverse events of diarrhea while on treatment are color-coded by grade.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754
Correction: MONARCH 1, A Phase II Study ofAbemaciclib, a CDK4 and CDK6 Inhibitor, asa Single Agent, in Patients with RefractoryHRþ/HER2� Metastatic Breast Cancer
In the original version of this article (1), the stated disclosure of José Baselga isincorrect. The error has been corrected in the latest online HTML and PDF versions ofthe article. The authors regret this error.
Reference1. DicklerMN, Tolaney SM, RugoHS, Cort�es J, Di�eras V, Patt D, et al. MONARCH1, a phase II study of
abemaciclib, aCDK4 andCDK6 inhibitor, as a single agent, in patientswith refractoryHRþ/HER2�metastatic breast cancer. Clin Cancer Res 2017;23:5218–24.
Published first November 1, 2018.doi: 10.1158/1078-0432.CCR-18-3193�2018 American Association for Cancer Research.
Published OnlineFirst May 22, 2017.Clin Cancer Res Maura N. Dickler, Sara Tolaney, Hope S. Rugo, et al. HR+/HER2- metastatic breast cancerinhibitor, as a single agent, in patients with refractory MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 22, 2017; DOI: 10.1158/1078-0432.CCR-17-0754