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Study: CDK inhibitors may increase survival for ER-positive metastatic breast cancer patients

Summary

The phase III MONALEESA-7 study is a clinical trial looking at the effect of a type of treatment known as a CDK4/6 inhibitor in pre- or perimenopausal women with hormone receptor–positive advanced breast cancer. (7/22/19) 

 

 

CDK inhibitors may increase survival for ER-positive metastatic breast cancer patients

Relevance

This article is most relevant for People with metastatic, hormone-positive, Her2-negative breast cancer

Relevance Rating Details

Relevance: High

Strength of Science: High

Research Timeline: Post Approval

Media Ratings

Did you see the media coverage of this article?

How we rated the media

Who covered this study?

Medscape

First CDK4/6 Inhibitor to Improve Survival in Metastatic Breast Cancer
This article rates 5.0 out of 5 stars

Eureka Alert

Ribociclib plus hormone therapy extends survival for patients with premenopausal advanced hormone receptor-positive breast cancer
This article rates 4.0 out of 5 stars

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Contents

At a glance Questions for your doctor
Findings     In-depth                 
Clinical trials Limitations
Guidelines Resources


STUDY AT A GLANCE

This study is about:

Whether adding a drug known as a CDK4/6 kinase inhibitor (a drug that stops cancer cells from multiplying) added to hormonal therapy improves survival in young women with , hormone positive breast cancer.

Why is this study important?

This is the first large clinical trial to look exclusively at the effect of a CDK4/6 inhibitor on overall survival in pre- or perimenopausal women with , , hormone receptor-positive breast cancer. This report follows up earlier results indicating that a CDK4/6 inhibitor lengthened progression free survival.

Study findings: 

The study looked at 672 premenopausal or perimenopausal patients with , hormone receptor positive breast cancer. All patients received hormonal therapy. Participants were randomly selected to receive the CDK4/6 inhibitor ribociclib (Kisqali) or a .

The primary endpoint of this trial was progression-free survival (PFS). Results were reported in 2018.

  • Median progression-free survival (PFS) was 24 months in the ribociclib group compared with 13 months in the group.

The secondary endpoint, overall survival, was reported at the 2019 American Society of Clinical Oncology Meeting. 

  • Ribociclib plus endocrine therapy resulted in a statistically significant longer overall survival than endocrine therapy alone.
    • Estimated overall survival at 42 months was 70.2% in the ribociclib group and 46.0% in the group.
    • The risk of death was 29% lower in the ribociclib arm.

The most common reported in both groups was a low white blood cell count, also known as neutropenia.

  • 63% of patients who received ribociclib had neutropenia compared to 5% of patients who received a .  
  • 11% of patients who received ribociclib had liver, gallbladder, bile ducts or bile compared to 7% of patients who received a .
  • 2% of patients who received ribociclib had an abnormal heartbeat compared to 1% of patients who received a .

What does this mean for me?

This is the first study to show that ribociclib plus hormone therapy improved overall survival compared with plus hormonal therapy in premenopausal women with , advanced breast cancer. This study confirms that there is benefit for this drug combination in these patients.

 

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Posted 7/22/19

Note: On 09/13/19 the issued a safety alert that Ibrance (palbociclib), Kisqali (ribociclib), and Verzenio (abemaciclib) may cause a rare but severe inflammation of the lungs.

References

Tripathy D, Im SA, Colleoni M, et al. “Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.” Lancet Oncology. 2018;19 (7):904-915. doi: 10.1016/S1470-2045(18)30292-4.

Im SA, Lu YS, Bardia A, et al. “Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer.” New England Journal of Medicine.  June 4, 2019. doi: 10.1056/NEJMoa1903765.
 

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

This article is relevant for:

People with metastatic, hormone-positive, Her2-negative breast cancer

This article is also relevant for:

people with ER/PR + cancer

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IN-DEPTH REVIEW OF RESEARCH
Study background:

In MONALEESA-2, ribociclib plus the aromatase inhibitor letrozole showed improved progression-free survival compared with letrozole alone as treatment for postmenopausal patients with hormone receptor-positive, , advanced breast cancer. However, the impact on premenopausal women was not determined.

Young women with breast cancer tend to have poorer prognoses and more aggressive cancer compared to older women. Premenopausal women are underrepresented in clinical trials. MONALEESA-7 is the first Phase III trial with a CDK4/6 inhibitor exclusively in premenopausal patients. This allows researchers to more directly ask whether CDK4/6 inhibitors may benefit premenopausal women who are often also on endocrine therapy.

Researchers of this study wanted to know:

Building on the MONALEESA-2 results, the MONALEESA-7 trial aimed to assess the usefulness and safety of ribociclib plus endocrine therapy for premenopausal women with advanced, hormone receptor-positive, advanced breast cancer.

Population(s) looked at in the study:

Patients in each group of the study had similar average characteristics. The average age of the 335 participants who received ribociclib was 43 (ages ranged from 25-58).  Most of these participants were white (56%) and did not have prior or endodcrine therapy (62%).  Only 14% had prior chemotherapy for advanced disease.  Similarly, most patients who received were white (60%) and did not have prior or endocrine therapy (48%).  Identical to the ribociclib group, 14% of control patients had prior chemotherapy for advanced disease.   

Study design:

A total of 672 women who had pre- or perimenopausal advanced breast cancer before the age of 59 and who had only up to one prior line of chemotherapy and had not received endocrine therapy for disease were to receive endocrine therapy with either ribociclib or . The primary endpoint was progression free survival with a secondary endpoint of overall survival.

Study findings:

  • Median progression-free survival was almost 24 months in the group that took ribociclib with endocrine therapy compared to 13 months in the group that received endocrine therapy only.
  • Overall survival was analyzed at a pre-specified time; 192 deaths occurred before that time. 
    • Ribociclib plus endocrine therapy resulted in statistically significant longer overall survival than endocrine therapy alone.
      • Estimated overall survival at 42 months was 70.2% in the ribociclib group and 46.0% in the group.

At the interim analysis point (median follow-up was 35 months), 35% of patients receiving ribociclib were still on the trial while only 17% of the patients who received a remained. The predominant reason for ending treatment in both groups was disease progression.

Progression-free survival 2 (PFS2) time from when individuals were to when they progressed to the next line of therapy or died differed between the two groups. Patients in the ribociclib group showed a 31% improvement in PFS2 compared to patients who received .

The time to first subsequent chemotherapy differed by treatment group.  It was longer for the ribociclib group than it was for the group of patients who received . At 42 months, 66% of patient in the ribociclib group had not received chemotherapy compared to 49% of patients in the group. The most common subsequent therapies in both groups after treatment was discontinued were chemotherapy alone and endocrine therapy alone.  

Grade 3 (severe) or 4 (life-threatening) adverse events reported in more than 10% of patients in either group were neutropenia (low white blood cell count), hepatobiliary (chronic liver disease), and long QT interval (erratic heatbeat). Serious adverse events occurred in 18% of patients in the ribociclib group and in 12% of patients in the group, of which 4% and 2%, respectively, were attributed to the study regimen. Adverse events lead to discontinued treatment in 4% of patients in the ribociclib group and 3% of patients in the group.

Limitations:

Few data are available from large studies of for young women with breast cancer. Because ribociclib is four times more selective for the CDK4 enzyme than CDK6 enzyme, more research is needed to determine if the effect observed in this trial was due to ribociclib or if other CDK4/6 inhibitors would be as effective. 

Conclusions:

The results of the MONALEESA-7 trial show that there is substantial clinical benefit with ribociclib and endocrine therapy compared to endocrine therapy alone for young pre- or perimenopausal women with hormone receptor-positive, metastatic breast cancer.

Share your thoughts on this XRAYS article by taking our brief survey.

Posted 7/22/19

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) guidelines for the treatment of advanced or ER-positive breast cancer include the following:

Genetic testing

  • All people diagnosed with breast cancer meet guidelines for genetic counseling and testing. 

NCCN preferred treatment options

The NCCN lists the following as preferred treatments for ER-positive and breast cancer:

  • for people with or mutations:
    • The NCCN lists Lynparza () or () for people with an inherited or mutation. 
  • First line therapy
    • The NCCN lists as the preferred treatment combination of hormonal therapy (aromatase inhibitor or Fulvestrant) + with a CDK4/6 inhibitor:
      •  abemaciclib (Verzenio), palbocicib (Ibrance) or ribociclib (Kisqali). 
  • For second, third or later lines of therapy, the NCCN lists the following targeted therapies or combinations treatments:
    • a combination of hormonal therapy (aromatase inhibitor or Fulvestrant) plus with a CDK4/6 inhibitor for people who have not previously received a CDK4/6 inhibitor
    • Enhertu (trastuzumab deruxtecan) for people whose tumors are HER2-low ( 1+ or 2+), who received chemotherapy in the setting and their cancer no longer responds to hormonal therapy 
    • Piqray (apelisib) for cancers that test positive for a PIK3CA-mutation
    • Oserdu (elacestrant) for , cancers that test positive for an ESR1 mutation
    • Lynparza () or () for BRCA1/BRCA2 for tumors with or mutation
    • a combination of everolimus and hormonal therapy
    • hormonal therapy alone
    • Trodelvy (sacituzumab govitecan-hziy) for , cancers after prior treatment including hormone therapy, a CDK4/6 inhibitor and at least two lines of chemotherapy (including a taxane)

Updated: 03/21/2023

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • Is my cancer and ?
  • Am I candidate for ribociclib plus hormonal therapy?
  • As a premenopausal woman, what is the best therapy for my breast cancer?
  • What are the benefits and risks of hormonal therapy?
  • What are the benefits and risks of CDK4/6 inhibitor therapy?
  • What are the side effects of CDK4/6 inhibitors? 

 

Open Clinical Trials
Open Clinical Trials

The following studies look at treatment for people with ER-positive breast cancer.  

Other clinical trials for people with breast cancer can be found here.

Updated: 12/22/2023

Open Clinical Trials
Open Clinical Trials

The following studies are looking at treatment for people with advanced . 

 

Updated: 02/01/2024

Peer Support
Peer Support

The following organizations offer peer support services for people with, or at high risk for breast cancer:

Updated: 11/29/2022

Related Resources
Related Resources

The following organizations have resources related to breast cancer. 

Updated: 06/28/2023

Who covered this study?

How we rated the media

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Article Rating Details

Medscape: First CDK4/6 inhibitor to improve survival in metastatic breast cancer
Rating: 5 Stars

  • This is a well written article that includes comments from a researcher involved in the study as well as outside experts. 
  • The article may be challenging for a lay audience to understand.
  • The article includes an important discussion by outside experts on the likely benefit of other FDA approved CDK4/6 inhibitors in combination with hormone therapy for premenopausal women with hormone receptor-positive advanced disease.  However, they point out that these studies have not yet been done in this population.

EurkAlert! Ribociclib plus hormone therapy extends survival for patients with premenopausal advanced hormone receptor-positive breast cancer
Rating:  4 Stars

  • The only source consulted for this article was the senior author.  No outside sources were included.
  • The article is clear and easy to read although a lay reader may have difficulty.
  • The article is factually correct and conveys the novelty of the research

Study Rating Details

Relevance Rating: High

  • This study is directly relevant for young breast cancer patients with ER-positive, HER2-negative advanced breast cancer.
  • It is the first time that a CDK4/6 inhibitor — or any targeted therapy — has been shown (in combination with hormone therapy) to significantly improve overall survival among young women with HR+/HER2-negative metastatic disease. 
  • This treatment is only relevant for people with hormone receptor-positive HER-2 negative advanced breast cancer.

Scientific Strength Rating: High

  • This study is a well-designed Phase III clinical trial that directly tests the benefit of ribociclib plus hormone therapy compared hormone therapy alone in treating advanced breast cancer.
  • The statistics, description of controls, sample size and intervention are all well-described and appropriate for this trial.
  • The conclusions that the authors reach are justified by the data shown.
  • Because overall survival and progression outcomes are key factors in medical decision making the results of this study are highly relevant to young patients with advanced disease.

Clinical Timeline: Late stage clinical trial