Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer (MONALEESA-2)

A Randomized Double-blind, Placebo-controlled Study of LEE011 in Combination With Letrozole for the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative, Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease

The primary purpose of this study was to assess the efficacy of ribociclib, as measured by progression free survival (PFS), in postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who received no prior treatment for advanced disease.

Study Overview

• Status: Completed
• Conditions: Advanced, Metastatic Breast Cancer
• Intervention / Treatment: Drug: Letrozole; Drug: Ribociclib; Drug: Placebo

Detailed Description

This was an international, multi-center, randomized, double-blinded, placebo controlled Phase III trial to determine the efficacy and safety of treatment with ribociclib plus letrozole versus placebo plus letrozole in postmenopausal women with HR+, HER2-negative advanced breast cancer who received no prior therapy for advanced disease.

Eligible patients were randomized in 1:1 ratio to either ribociclib group or placebo group. Study treatment continued until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

Participants who discontinued treatment due to reasons other than disease progression or withdrawal of consent for efficacy follow-up continued to be monitored until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision (post-treatment efficacy follow-up).

All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached.

Following the final OS analysis (performed when approximately 400 deaths were recorded) and with protocol amendment 10 (dated 30-Apr-2021), participants and investigators were unblinded and those participants in the placebo arm had the opportunity to cross-over to the ribociclib arm to receive ribociclib plus letrozole. Cross-over was optional and was conducted at the investigator's discretion and upon participant consent.

• Study Type: Interventional
• Enrollment (Actual): 668
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5002AOQ
    • Novartis Investigative Site
  • La Rioja, Argentina, 5300
    • Novartis Investigative Site
  • Tucuman
    • San Miguel De Tucuman, Tucuman, Argentina, T4000IAK
      • Novartis Investigative Site
• Australia
  • South Australia
    • Kurralta Park, South Australia, Australia, 5037
      • Novartis Investigative Site
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Austria
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
  • Vienna, Austria, A-1100
    • Novartis Investigative Site
  • Wien, Austria, A-1090
    • Novartis Investigative Site
• Belgium
  • Hasselt, Belgium, 3500
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Namur, Belgium, 5000
    • Novartis Investigative Site
  • Wilrijk, Belgium, 2610
    • Novartis Investigative Site
  • Oost Vlaanderen
    • Sint Niklaas, Oost Vlaanderen, Belgium, 9100
      • Novartis Investigative Site
• Brazil
  • SP
    • Ribeirao Preto, SP, Brazil, 14048-900
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 01246 000
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 01317-002
      • Novartis Investigative Site
• Canada
  • Quebec, Canada, G1S 4L8
    • Novartis Investigative Site
  • British Columbia
    • Burnaby, British Columbia, Canada, V5G 2X6
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Novartis Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Novartis Investigative Site
    • Kitchener, Ontario, Canada, N2G 1G3
      • Novartis Investigative Site
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2X 0A9
      • Novartis Investigative Site
• Czechia
  • Brno Bohunice, Czechia, 625 00
    • Novartis Investigative Site
  • Liberec, Czechia, 46063
    • Novartis Investigative Site
  • Olomouc, Czechia, 779 00
    • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 53
      • Novartis Investigative Site
• Denmark
  • Aarhus, Denmark, DK-8000
    • Novartis Investigative Site
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
  • Odense C, Denmark, DK 5000
    • Novartis Investigative Site
  • Vejle, Denmark, 7100
    • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00029
    • Novartis Investigative Site
  • Turku, Finland, FIN-20520
    • Novartis Investigative Site
• France
  • Angers 02, France, 49055
    • Novartis Investigative Site
  • Avignon, France, 84082
    • Novartis Investigative Site
  • Besancon Cedex, France, 25030
    • Novartis Investigative Site
  • Bordeaux, France, 33000
    • Novartis Investigative Site
  • Creteil, France, 94000
    • Novartis Investigative Site
  • Le Mans, France, 72000
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
  • Rouen, France, 76038
    • Novartis Investigative Site
  • Saint Herblain, France, 44805
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
  • Alpes Maritimes
    • Nice, Alpes Maritimes, France, 06189
      • Novartis Investigative Site
• Germany
  • Aschaffenburg, Germany, 63739
    • Novartis Investigative Site
  • Berlin, Germany, 14169
    • Novartis Investigative Site
  • Berlin, Germany, 14195
    • Novartis Investigative Site
  • Bonn, Germany, 53111
    • Novartis Investigative Site
  • Bottrop, Germany, 46236
    • Novartis Investigative Site
  • Duesseldorf, Germany, 40225
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Essen, Germany, 45136
    • Novartis Investigative Site
  • Freiburg, Germany, 79110
    • Novartis Investigative Site
  • Fuerth, Germany, 90766
    • Novartis Investigative Site
  • Goslar, Germany, 38642
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Muenchen, Germany, 80335
    • Novartis Investigative Site
  • Offenbach, Germany, 63069
    • Novartis Investigative Site
  • Ravensburg, Germany, 88214
    • Novartis Investigative Site
  • Recklinghausen, Germany, 45657
    • Novartis Investigative Site
  • Tuebingen, Germany, 72076
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Velbert, Germany, 42551
    • Novartis Investigative Site
  • North Rhine Westphalia
    • Bielefeld, North Rhine Westphalia, Germany, 33604
      • Novartis Investigative Site
• Hungary
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Gyor, Hungary, H-9024
    • Novartis Investigative Site
  • Gyula, Hungary, 5700
    • Novartis Investigative Site
  • Pest Megye
    • Budapest, Pest Megye, Hungary, 1134
      • Novartis Investigative Site
• Ireland
  • Cork, Ireland, 190384
    • Novartis Investigative Site
  • Dublin 4, Ireland, DO4
    • Novartis Investigative Site
• Israel
  • Petach Tikva, Israel, 4941492
    • Novartis Investigative Site
  • Ramat Gan, Israel, 52621
    • Novartis Investigative Site
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • LC
    • Lecco, LC, Italy, 23900
      • Novartis Investigative Site
  • ME
    • Messina, ME, Italy, 98158
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35100
      • Novartis Investigative Site
  • PG
    • Perugia, PG, Italy, 06129
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
  • PN
    • Aviano, PN, Italy, 33081
      • Novartis Investigative Site
  • RC
    • Reggio Calabria, RC, Italy, 89100
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
  • TO
    • Candiolo, TO, Italy, 10060
      • Novartis Investigative Site
  • TR
    • Terni, TR, Italy, 05100
      • Novartis Investigative Site
  • VT
    • Viterbo, VT, Italy, 01100
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 05505
    • Novartis Investigative Site
  • Gyeonggi Do
    • Bundang Gu, Gyeonggi Do, Korea, Republic of, 13620
      • Novartis Investigative Site
  • Korea
    • Gyeonggi do, Korea, Korea, Republic of, 10408
      • Novartis Investigative Site
• Lebanon
  • Ashrafieh, Lebanon, 166830
    • Novartis Investigative Site
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
  • Beirut, Lebanon, 10999
    • Novartis Investigative Site
  • Saida, Lebanon, 652
    • Novartis Investigative Site
• Netherlands
  • Alkmaar, Netherlands, 1815 JD
    • Novartis Investigative Site
  • Deventer, Netherlands, 7416 SE
    • Novartis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Groningen, Netherlands, 9728 NZ
    • Novartis Investigative Site
  • Maastricht, Netherlands, 6229 HX
    • Novartis Investigative Site
  • Tilburg, Netherlands, 5042 AD
    • Novartis Investigative Site
  • Zoetermeer, Netherlands, NL-2722 EP
    • Novartis Investigative Site
  • Zwolle, Netherlands, 8025 AB
    • Novartis Investigative Site
  • BG
    • Sittard-Geleen, BG, Netherlands, 6162 BG
      • Novartis Investigative Site
  • Zuid Holland
    • Leiden, Zuid Holland, Netherlands, 2333 ZA
      • Novartis Investigative Site
• Norway
  • Bergen, Norway, NO-5021
    • Novartis Investigative Site
  • Oslo, Norway, NO-0407
    • Novartis Investigative Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Novartis Investigative Site
  • Nizhniy Novgorod, Russian Federation, 603000
    • Novartis Investigative Site
  • Ryazan, Russian Federation, 390011
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• South Africa
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0081
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Cataluna
    • Barcelona, Cataluna, Spain, 08024
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46009
      • Novartis Investigative Site
  • Galicia
    • Santiago De Compostela, Galicia, Spain, 15706
      • Novartis Investigative Site
  • Santa Cruz De Tenerife
    • La Laguna, Santa Cruz De Tenerife, Spain, 38320
      • Novartis Investigative Site
• Sweden
  • Eskilstuna, Sweden, SE-631 88
    • Novartis Investigative Site
  • Goteborg, Sweden, 413 45
    • Novartis Investigative Site
  • Joenkoeping, Sweden, 551 85
    • Novartis Investigative Site
  • Lund, Sweden, 221 85
    • Novartis Investigative Site
  • Uppsala, Sweden, 751 85
    • Novartis Investigative Site
  • Vaxjo, Sweden, SE-351 85
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 80756
    • Novartis Investigative Site
  • New Taipei City, Taiwan, 23561
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06590
    • Novartis Investigative Site
  • Ankara, Turkey, 06230
    • Novartis Investigative Site
  • Diyarbakir, Turkey, 21000
    • Novartis Investigative Site
  • Istanbul, Turkey, 35100
    • Novartis Investigative Site
  • Izmir, Turkey, 35100
    • Novartis Investigative Site
• United Kingdom
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Novartis Investigative Site
  • Cornwall
    • Truro, Cornwall, United Kingdom, TR1 3LJ
      • Novartis Investigative Site
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Ironwood Cancer and Research Centers
    • Sedona, Arizona, United States, 86336
      • Arizona Oncology Associates PC HAL
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group
    • Jonesboro, Arkansas, United States, 72401
      • NEA Baptist Cancer Center
  • California
    • Berkeley, California, United States, 94704
      • Alta Bates Cancer Center
    • Duarte, California, United States, 91010 3000
      • City of Hope National Medical Center
    • Glendale, California, United States, 91206
      • Glendale Adventist Medical Center
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center SC-5
    • Sacramento, California, United States, 95817
      • Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Univ of Colorado School of Medicine
    • Longmont, Colorado, United States, 80501
      • Rocky Mountain Cancer Centers
  • Florida
    • Boynton Beach, Florida, United States, 33426
      • University Cancer Institute
    • Davie, Florida, United States, 33328
      • Florida Cancer Research Institute
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
    • Hollywood, Florida, United States, 33021
      • Memorial Hospital
    • Miami, Florida, United States, 33136
      • University of Miami
    • Orlando, Florida, United States, 32804
      • Florida Retina Institute
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Medical Oncology
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists-North
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Georgia Cancer Specialists
    • Thomasville, Georgia, United States, 31792
      • Lewis Hall Singletary Onc Ctr at John D. Archbold Mem Hosp.
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Moanalua Medical Center Attn Oncology Dept
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60612
      • University of Illinois Cancer Center at Chicago
    • Evanston, Illinois, United States, 60201
      • Northshore University Health System
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
    • Naperville, Illinois, United States, 60540
      • Edward Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Iu Simon Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel CCC At JH
    • Frederick, Maryland, United States, 21701
      • Frederick Memorial Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Allina Hlth Cancer Inst Minneapolis
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • Jackson Oncology Associates
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • St Lukes Hos Marion Bloch Neur Inst
    • Manchester, Missouri, United States, 63021
      • Mercy Medical Research Institute
  • New Hampshire
    • Nashua, New Hampshire, United States, 03060
      • Foundation Medical Partners
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Cancer Center
    • Edison, New Jersey, United States, 88837
      • Hackensack Meridian Health
    • New Brunswick, New Jersey, United States, 08901
      • Cancer Institute Of New Jersey
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Glens Falls, New York, United States, 12801
      • C R Wood Cancer Center at Glens Falls Hospital
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10016
      • NYU Langone Med Center CV Research
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Univ Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care Inc
    • Columbus, Ohio, United States, 43221
      • The Ohio State University Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Mercy Clinic Oklahoma Communities Mercy Oncology
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Cancer Institute
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Onc And Hem Assoc PC
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Ctr
  • Texas
    • Bedford, Texas, United States, 76022
      • Texas Oncology P A
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75251
      • Texas Oncology
    • Fort Worth, Texas, United States, 76104
      • Ctr For Cancer And Blood Disorders
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology P A
    • Houston, Texas, United States, 77090
      • Millennium Research Clin Develop
    • Houston, Texas, United States, 77030
      • Uni Of TX MD Anderson Cancer Cntr
    • Houston, Texas, United States, 77024
      • Texas Oncology Houston Memorial City
    • McAllen, Texas, United States, 78503
      • Texas Oncology
    • Richardson, Texas, United States, 75082
      • Richardson Hematology Oncology Associates
    • San Antonio, Texas, United States, 78217
      • Texas Oncology P A
    • Tyler, Texas, United States, 75702
      • Texas Oncology Northeast Texas
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
    • Salem, Virginia, United States, 24153
      • Oncology and Hematology Associates of Southwest Virginia Inc
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Regional Cancer Partnership
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties
  • Wisconsin
    • Madison, Wisconsin, United States, 53717
      • Dean Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Women with advanced (locoregionally recurrent or metastatic) breast cancer that was not amenable to curative therapy.

2. The patient was postmenopausal. Postmenopausal status was defined either by:

   • Prior bilateral oophorectomy
   • Age ≥60
   • Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range.
3. There was no prior systemic anti-cancer therapy for advanced disease.
4. The patient had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by the local laboratory.
5. The patient had HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC was 2+, a negative in situ hybridization (FISH, CISH, or SISH) test was required by local laboratory testing.

6. The patient must have had either:

   Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria (Tumor lesions previously irradiated or subjected to other locoregional therapy were considered measurable if disease progression at the treated site after completion of therapy was clearly documented). OR If no measurable disease was present, then at least one predominantly lytic bone lesion must have been present (Patients with no measurable disease and only one predominantly lytic bone lesion previously irradiated were eligible if there was documented evidence of disease progression of the bone lesion after irradiation).

7. The patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Key Exclusion Criteria:

1. The patient had received any CDK4/6 inhibitor.

2. The patient had received any prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy) for advanced breast cancer.

   Note:

   • Patients who had received (neo) adjuvant therapy for breast cancer were eligible. If the prior neo (adjuvant) therapy included letrozole or anastrozole, the disease-free interval had to be greater than 12 months from the completion of treatment until randomization.
   • Patients who had received ≤ 14 days of letrozole or anastrozole for advanced disease prior to randomization were eligible.
   • Any prior (neo) adjuvant anti-cancer therapy had to be stopped at least 5 half-lives or 7 days, whichever was longer, before randomization.
3. The patient was concurrently using other anti-cancer therapy.
4. The patient had a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.

5. The patient had active cardiac disease or a history of cardiac dysfunction, including any of the following:

   • History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry.
   • History of documented congestive heart failure (New York Heart Association functional classification III-IV).
   • Documented cardiomyopathy.
   • The patient had a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
   • History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months.
   • On screening, any of the following cardiac parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 msec, QRS interval >109 msec, or QTcF >450 msec.
   • Systolic blood pressure >160 or <90 mmHg.

6. The patient was currently receiving any of the following medications and could not be discontinued 7 days prior to the start of treatment:

   • Medications known to be strong inducers or inhibitors of CYP3A4.
   • Medications known to have a risk of prolonging the QT interval or inducing Torsades de Pointes.
   • Medications with a narrow therapeutic window and predominantly metabolized through CYP3A4.
   • Herbal preparations/medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ribociclib+ letrozole; Ribociclib 600 mg daily oral (3 weeks on/ 1 week off) in combination with letrozole 2.5 mg daily oral	Drug: Letrozole; Letrozole (2.5 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle); Drug: Ribociclib; Ribociclib (600 mg, in three 200 mg hard gelatin capsules or tablets) was administered orally once daily on Days 1-21 of each 28-day cycle.; Other Names: LEE011
Placebo Comparator: Placebo + letrozole; Placebo daily oral (3 weeks on/ 1 week off) in combination with letrozole 2.5 mg daily oral. Participants were unblinded once the final OS analysis was completed and after the implementation of protocol amendment 10 (30-Apr-21) and were given the option to crossover to treatment with ribociclib + letrozole	Drug: Letrozole; Letrozole (2.5 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle); Drug: Placebo; Placebo (hard gelatin capsules or tablets) was administered orally once daily on Days 1-21 of each 28-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) by Investigator Assessment	PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression.PFS was assessed by investigator assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. A stratified Cox regression model was used to estimate the hazard ratio of PFS, along with 95% confidence interval	Up to 23 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death from any cause. In cases where the patient's death was not recorded, the OS value was censored at the date of the last known patient's survival status.OS was estimated using the Kaplan-Meier method. As per protocol, the final OS analysis was conducted after approximately 400 deaths were documented. The median OS, along with 95% confidence intervals, was reported for each treatment group.The distribution of OS between the two treatment arms was compared using a log-rank test at one-sided cumulative 2.5% level of significance. A stratified Cox regression was used to estimate the OS hazard ratio and the associated 95% CI.	Up to approximately 87 months
Overall Response Rate (ORR) by Investigator Assessment	ORR is the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per investigator assessment. . CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to 23 months
Clinical Benefit Rate (CBR) by Investigator Assessment	Percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1 as per investigator assessment. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease: PD = At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20% the sum must also demonstrate an absolute increase of at least 5 mm.	Up to 23 months
Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score	ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration was defined as the time from the date of randomization to the date of the event, defined as experiencing an increase in ECOG PS by at least one category from the baseline or death. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive deterioration, along with 95% confidence intervals, was reported for each treatment group. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment.	From baseline up to 23 months
Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)	The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive 10% deterioration, along with 95% confidence intervals, was reported for each treatment group. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation.	From baseline up to 23 months
Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30	The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The change from baseline in the GHS/QoL score was assesed. A positive change from baseline indicated improvement. For subjects who discontinued treatment earlier and without disease progression, post-treatment efficacy follow-up visits occurred every 8 weeks after End of treatment (EOT) during the initial 18 months since start of treatment, followed by visits every 12 weeks until disease progression or end of study.	Baseline, every 2 cycles for 18 months, then every 3 cycles until last dose; at EOT (within 15 days from last dose);every 8 or 12 weeks post-treatment until progression (post-treatment efficacy visits), assessed up to 23 months. Cycle=28 days

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Burris HA, Chan A, Bardia A, Thaddeus Beck J, Sohn J, Neven P, Tripathy D, Im SA, Chia S, Esteva FJ, Hart L, Zarate JP, Ridolfi A, Lorenc KR, Yardley DA. Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer. Br J Cancer. 2021 Aug;125(5):679-686. doi: 10.1038/s41416-021-01415-9. Epub 2021 Jun 22.
• Yardley DA. MONALEESA clinical program: a review of ribociclib use in different clinical settings. Future Oncol. 2019 Aug;15(23):2673-2686. doi: 10.2217/fon-2019-0130. Epub 2019 Jul 15.
• Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Hart L, Campone M, Petrakova K, Winer EP, Janni W, Conte P, Cameron DA, Andre F, Arteaga CL, Zarate JP, Chakravartty A, Taran T, Le Gac F, Serra P, O'Shaughnessy J. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med. 2022 Mar 10;386(10):942-950. doi: 10.1056/NEJMoa2114663.
• Hortobagyi GN. Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial. Breast Cancer Res. 2018 Oct 19;20(1):123. doi: 10.1186/s13058-018-1050-7.
• Janni W, Alba E, Bachelot T, Diab S, Gil-Gil M, Beck TJ, Ryvo L, Lopez R, Tsai M, Esteva FJ, Aunon PZ, Kral Z, Ward P, Richards P, Pluard TJ, Sutradhar S, Miller M, Campone M. First-line ribociclib plus letrozole in postmenopausal women with HR+ , HER2- advanced breast cancer: Tumor response and pain reduction in the phase 3 MONALEESA-2 trial. Breast Cancer Res Treat. 2018 Jun;169(3):469-479. doi: 10.1007/s10549-017-4658-x. Epub 2018 Feb 5.
• Prat A, Chaudhury A, Solovieff N, Pare L, Martinez D, Chic N, Martinez-Saez O, Braso-Maristany F, Lteif A, Taran T, Babbar N, Su F. Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies. J Clin Oncol. 2021 May 1;39(13):1458-1467. doi: 10.1200/JCO.20.02977. Epub 2021 Mar 26. Erratum In: J Clin Oncol. 2021 Nov 1;39(31):3525. doi: 10.1200/JCO.21.02277. J Clin Oncol. 2023 Apr 20;41(12):2299-2301. doi: 10.1200/JCO.23.00175.
• Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Petrakova K, Blackwell KL, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Mondal S, Su F, Miller M, Elmeliegy M, Germa C, O'Shaughnessy J. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018 Jul 1;29(7):1541-1547. doi: 10.1093/annonc/mdy155. Erratum In: Ann Oncol. 2019 Nov 1;30(11):1842. doi: 10.1093/annonc/mdz215.
• Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, Andre F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O'Shaughnessy J. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016 Nov 3;375(18):1738-1748. doi: 10.1056/NEJMoa1609709. Epub 2016 Oct 7. Erratum In: N Engl J Med. 2018 Dec 27;379(26):2582. doi: 10.1056/NEJMx180043.

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2013
• Primary Completion (Actual): January 29, 2016
• Study Completion (Actual): March 16, 2023

Study Registration Dates

• First Submitted: October 4, 2013
• First Submitted That Met QC Criteria: October 7, 2013
• First Posted (Estimated): October 8, 2013

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 25, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Phase III; LEE011; Postmenopausal; Letrozole; CDK4/6; HER2-negative; Advanced breast cancer; CDK4; CDK6; CDK; ER-positive; PR-positive; HR-positive
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Letrozole
• Other Study ID Numbers: CLEE011A2301; 2013-003084-61 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No