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by Dr. C.H. Weaver M.D. updated 10/2022

Clinical trial results from the MONARCH clinical trials demonstrate that Verzenio (abemaciclib), a cyclin-dependent kinase (CDK) 4 & 6 inhibitor, when administered in combination with standard hormone therapy, significantly delays the time to cancer progression, and prolongs overall survival in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), high risk early stage and advanced breast cancer.1,5,6,9,10,11

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About Verzenio

Verzenio is an inhibitor of cyclin-dependent kinases (CDK) 4 & 6. A major hallmark of cancer cells is their ability to multiply rapidly; CDK inhibitors interfere with this process by blocking the activity of enzymes known as CDKs, particularly CDK 4 and CDK 6, that help to regulate cell division. For effectively treating breast cancer, CDK inhibitors are usually combined with endocrine therapy, which works by preventing hormones from binding with their respective receptors on the cancer cells.4

Verzenio in High-Risk Early Stage Breast Cancer

Verzenio in combination with standard endocrine therapy administered to patients with high-risk, hormone receptor-positive, HER2-negative early stage breast cancer (ESBC) following completion of primary treatment was associated with an approximately 29% reduction in the risk of developing a recurrence of invasive disease according to early results of a preplanned interim analysis of a phase 3 study.9-12

About the monarchE Study - the monarchE clinical trial enrolled 5,637 patients with HR+, HER2- node-positive, high risk early stage breast cancer to treatment with Verzenio twice daily plus standard adjuvant endocrine therapy or standard adjuvant endocrine therapy alone. Verzino was administered for 2 years following completion of primary therapy that must have included surgery. High-risk disease was characterized by 4 or more positive axillary lymph nodes, or 1 to 3 positive lymph nodes in the setting of a tumor of at least 5 cm, grade 3 or centrally confirmed Ki-67 expression of at least 20% in untreated breast tissue.

The 2-year survival without disease recurrence was 92.2% in patients receiving Verzenio compared to 89.3% for treatment with standard endocrine therapy alone. The risk of recurrence was reduced by 28.3%. The 2-year distant relapse-free survival rate was also improved with Verzenio to 93.8% compared with 90.8%.12

Verzenio is the first CDK4/6 inhibitor to show a significant improvement when combined with endocrine therapy in patients with hormone receptor positive ESBC.

The results of the monarchE study stands in contrast to two other studies of adjuvant CDK4/6 inhibitors plus ET in HR+/HER2- breast cancer. Neither the PALLAS or PENELOPE-B clinical trials found any benefit when adjuvant Ibrance (palbociclib) was added to standard ET. 13-16

There are several factors that could explain the different results between these trials. Verzenio is a more potent inhibitor of CDK4 and CDK6 than ibrance.15 Moreover, verzenio is dosed continuously versus a 21-day on, 7-day off schedule for ibrance. The continuous dosing of might provide an advantage in the form of constant cell cycle inhibition. Longer follow-up is needed to determine if verzenio will have sustained long term benefits.16

The FDA has approved has approved Verzenio in combination with endocrine therapy for the adjuvant treatment of adult patients with hormone receptor–positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of 20% or higher. The addition of Verzenio delayed cancer recurrence and improved the curation of cancer free survival from 79% at 3 years to 86%. The impact on overall survival is not yet clear and longer follow up is required. Sara M. Tolaney, MD, MPH, Harvard Medical School, Dana-Farber Cancer Institute, and investigator on the monarchE study. "This FDA approval for Verzenio in combination with endocrine therapy in the early breast cancer setting has the potential to become a new standard of care for this population. We are encouraged by the marked reduction in the risk of recurrence even beyond the two-year treatment period in these patients, and I'm grateful to be able to offer this as a treatment option to my patients."

Metastatic Breast Cancer

Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012.2 In the U.S. each year, nearly 232,000 individuals will develop invasive breast cancer and about 40,000 women will succumb to their disease.3 Metastatic breast cancer is rarely curable, but is often treatable and controllable for many years.

In the MONARCH 2 clinical trial 669 patients with advanced breast cancer were treated with either Verzenio plus fulvestrant hormone therapy, or fulvestrant alone and directly compared. The combination therapy achieved an objective response rate of 48.1% compared to 21.3% in patients treated with fulvestrant alone. Verzenio™ in combination with fulvestrant significantly extended life by a median of 9.4 months in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (mBC) previously treated with endocrine therapy. Women survived an average of 46.7 months compared to 37.3 months with fulvestrant alone.

The MONARCH 2 clinical trial included both pre/peri- and postmenopausal women. This translated into a delay in the time to cancer progression. This update from the Sept. 2019 ESMO meetings shows that Verzenio continues to demonstrate significant and clinically meaningful improvements in overall survival with the combination,” said study first author Prof George Sledge, Stanford University School of Medicine, USA.

FDA Approves Verzenio™ as Initial Treatment for Advanced Breast Cancer

The U.S. Food and Drug Administration (FDA) has approved Verzenio in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.5

This approval of Verzenio as initial therapy in combination with an AI is based on the pivotal MONARCH 3 clinical trial. MONARCH 3 evaluated Verzenio in combination with an AI as initial endocrine-based therapy in 493 postmenopausal women with HR+, HER2- advanced breast cancer whom had no prior systemic treatment for advanced disease.5

Verzenio treated patients remained cancer free for 28-months on average compared to 14.8 months for treatment with an AI alone. Verzenio plus an AI had an objective response rate of 55.4 percent compared to 40.2 percent for treatment with an AI alone. The average duration of response was 27.4 months with Verzenio plus an AI versus 17.5 months for treatment with an AI alone.5

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Verzenio is now indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer:

  • in combination with an aromatase inhibitor for postmenopausal women as initial endocrine-based therapy
  • in combination with fulvestrant for women with disease progression following endocrine therapy
  • as a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

The results of the the MONARCH 2 and 3 clinical trials confirmed the activity of Verzenio identified in the MONARCH 1 trial in132 patients with HR-positive, HER2-negative MBC. Over half of the patients had over 3 sites of cancer metastases, and had received a median of least 3 prior therapies for advanced breast cancer. All patients were treated with abemaciclib.7

  • Overall anti-cancer responses were achieved in nearly 20% of patients.
  • Approximately 23% of patients had stabilization of their cancer lasting for at least 6 months.
  • Among patients who achieved an anti-cancer response, the median duration of the response was nearly 9 months; over 70% of patients experienced a median duration of response for at least 6 months, and 28.2% of patients experienced a median duration of response for 12 months.
  • The most common side effects of abemaciclib were diarrhea, nausea, fatigue, and loss of appetite.

Cyclin-dependent kinases play a key role in regulating the replication and growth of breast cancer cells and several medicines that target this growth pathway have either been recently approved or are in the development process.

The Science Behind The Discovery

HER2-positive breast cancer often develops resistance to targeted therapies but can be driven back into remission in mice by abemaciclib which blocks the division of cancer cells according to researchers at Dana-Farber Cancer Institute. The results, reported in Cancer Cell, prompted investigators to launch a clinical trial in women with metastatic HER2-positive breast cancer.18

The study demonstrated the potential of CDK4/6 inhibitors to overcome drug resistance in patients with HER2-positive breast tumors, which carry an excess of the human epidermal growth factor receptor 2 (HER2) protein. Although HER2-blocking drugs such as Herceptin often halt the growth of these tumors, many patients’ cancers become resistant, leading to a resurgence of tumor growth. This is particularly true in patients with metastatic tumors.

To probe how resistance occurs, researchers created a strain of genetically modified, “transgenic” mice that carry a genetic switch for turning production of the HER2 protein on and off. With the switch on, the animals developed human-like HER2-positive breast tumors; after it was turned off, the tumors shrank away, only to return months later in about two-thirds of the animals.

Researchers examined tissue samples from original and recurrent tumors to determine how they differed. Using RNA-sequencing techniques, they found that certain genes that control cell division and the cell cycle were overactive in recurrent tumors. Notably, cells from these tumors had abnormally high levels of two proteins associated with the cell cycle: cyclin D1 and CDK4.

“In HER2-positive breast cancer, cyclin D1 partners with CDK4 to drive cell proliferation,” Goel explains. “We hypothesized that cyclin D1 and CDK4 might also enable tumors to become resistant to HER2-targeted treatments and eventually recur.”

He and his colleagues conducted a series of experiments in cells and mice to confirm that that is indeed the case. The results suggested that drugs targeting CDK4 could defeat the resistance mechanism and reinstate tumors’ original susceptibility to HER2 blockers.

“In cells, we found that the drug abemaciclib – which inhibits CDK4 and the related protein CDK6 – was active against HER2-positive breast tumor cells that were resistant to standard treatments,” Goel remarks. “Strikingly, when we added a HER2-targeting drug to abemaciclib, we saw even greater efficacy. This means that abemaciclib restored the cancer cells’ sensitivity to HER2-directed agents.” Studies in mouse models showed the same benefit: the combination of abemaciclib and a HER2-blocking drug was more effective in halting HER2-positive tumor growth than either drug was alone. In their paper, the team also describes the molecular basis by which abemaciclib can reverse drug resistance.

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Finally, the investigators explored whether abemaciclib alone could delay the recurrence of HER2-positive breast cancers in mice. They found that the combination of abemaciclib and HER2-blocking strategies was able to significantly delay the time it took for breast cancers to recur. “This result is particularly exciting as it leads us to speculate the CDK4/6 inhibitors might not only help patients with metastatic breast cancer, but could potentially help in earlier stages of the disease where we aim to prevent recurrence of cancer,” says Goel.

On the strength of these findings, investigators will open a randomized clinical trial across the United States and Europe later this year. It is designed to determine whether abemaciclib is an effective treatment for patients who cancers have developed resistance to standard HER2-targeted drugs. Goel and his Dana-Farber colleague Sara Tolaney, MD, MPH, will lead the trial. “Our preliminary experience in patients has certainly been very encouraging,” remarks Goel.

References:

  1. The data were presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #1000) and simultaneously published online in the Journal of Clinical Oncology.
  2. World Cancer Research Fund International. Breast Cancer..
  3. American Cancer Society. Understanding Advanced Cancer, Metastatic Cancer and Bone Metastases..
  4. Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
  5. Patnaik A, Rosen LS, Tolaney SM, 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 [published ahead of print May 23, 2016]. Cancer Discov. 2016;6:740-753.
  6. Lilly's Verzenio® (abemaciclib) Significantly Extended Life in Women with HR+, HER2- Advanced Breast Cancer in MONARCH 2
  7. Dickler M, et al. MONARCH1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. Proceedings from the 2016 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #510.
  8. Sledge GW, Toi M, Neven P et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced cancer who had progressed while receiving endocrine therapy. JCO 2017; 35: 2875-2884
  9. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib in high risk early breast cancer. Presented at: European Society of Medical Oncology (ESMO) Virtual Congress 2020; September 19-21, 2020. Abstract LBA5_PR.
  10. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE).J Clin Oncol. Published online September 20, 2020. doi:10.1200/JCO.20. 02514
  11. First new drug in years reduces recurrence in high-risk hormone receptor positive early breast cancer [press release]. Published September 20, 2020. Accessed September 20, 2020.
  12. O’Shaughnessy JA, Johnson S, Harbeck N, et al: Primary outcome analysis of invasive disease-free survival for monarchE. 2020 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 9, 2020.
  13. EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2021.
  14. Sibylle Loibl FM, Miguel Martin, Michael Untch, Herve Bonnefoi, Sung-Bae Kim, Harry Bear, Nicole Mc Carthy, Mireia Mele Olive, Karen Gelmon, Jose Garcia Saenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Sabine Seiler, Valentina Nekljudova, Carsten Denkert, Michael Gnant, Andreas Makris, Nicole Burchardi, Gunter von Minckwitz. Abstract GS1-02: Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B. San Antonio Breast Cancer Symposium; 2020; Virtual; 2020.
  15. Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer 2019; 5: 27.
  16. Mayer EL FC, Dueck A, Martin M, Burstein H, Prat A, Rubovsky G, Miller K, Pfeiler G, Winer E, Zdenkowski N, Anderson D, Nowetzki Z, Goetz M, Loibl S, Fohler H, Metzger O, Fumagalli D, Theall K, Hlauschek D, Gnant M, DeMichele A. Treatment exposure and discontinuation in the PALLAS trial: PALbociclib CoLlaborative Adjuvant Study of palbociclib with adjuvant endocrine therapy for HR+/HER2- early breast cancer. San Antonio Breast Cancer Symposium; 2020; Virtual; 2020.
  17. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208716s006s007s008lbl.pdf https://investor.lilly.com/news-releases/news-release-details/fda-approves-verzenior-abemaciclib-first-and-only-cdk46
  18. Dana-Farber Cancer Institute. (2016.) New agent overcomes drug resistance in HER2-positive breast cancer, preclinical study shows. [Press release.] Retrieved from Accessed March 14, 2016.