Clinical trialPhase 3Breast cancer

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer

N Engl J Med · 2016668 patients

Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. N Engl J Med. 2016. 375:1738-1748

A newer report of this study has been published: Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer (2022)

Study type: Clinical trial
Study name: MONALEESA-2
Phase: Phase 3
Design: Randomised, placebo-controlled trial
Sample size: 668 patients
Source: N Engl J Med · 2016
Trial registration: NCT01958021

In plain words

In this study, postmenopausal women with hormone-sensitive advanced breast cancer who had not yet had drug treatment for advanced disease received letrozole together with either ribociclib or a placebo. Adding ribociclib made the time the disease stayed without progression significantly longer and shrank the tumour in a larger share of patients. On the other hand, low white blood cell counts were much more common in the ribociclib group and need monitoring with blood tests.

Key results

Hazard ratio 0.56 (95% CI 0.43–0.72)

Progression-free survival (PFS)

P=3.29×10^-6 for superiority; median follow-up 15.3 months

63.0% vs 42.2%

PFS rate at 18 months

95% CI 54.6–70.3 in the ribociclib group and 34.8–49.5 in the placebo group

52.7% vs 37.1%

Overall response rate (patients with measurable disease at baseline)

P<0.001

59.3% vs 0.9%

Grade 3 or 4 neutropenia

Ribociclib vs placebo

21.0% vs 0.6%

Grade 3 or 4 leucopenia

Ribociclib vs placebo

7.5% vs 2.1%

Discontinuation due to adverse events

Ribociclib vs placebo

Drugs in this study:Abemaciclib (Verzenio)Fulvestrant (Faslodex)Letrozole (Femara)Palbociclib (Ibrance)Anastrozole (Arimidex)Ribociclib (Kisqali)

Dose and schedule cards

Hormone therapy + CDK4/6 inhibitor (PALOMA-2, MONALEESA-2, MONARCH 3; after progression: PALOMA-3)

Advanced HR-positive/HER2-negative disease; first-line with an aromatase inhibitor, or with fulvestrant after prior hormone therapyOn the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Advanced HR-positive/HER2-negative disease; first-line with an aromatase inhibitor, or with fulvestrant after prior hormone therapy

Drug	Dose	Route	Schedule
One of three drugs
Palbociclib	125 mg once daily	Oral	Days 1–21
Ribociclib	600 mg once daily	Oral	Days 1–21
Abemaciclib	150 mg twice daily	Oral	Continuous
Combined with
Letrozole (or anastrozole 1 mg)	2.5 mg once daily	Oral	Continuous
Or combined with
Fulvestrant	500 mg (two 5-mL injections, one in each buttock)	IM, slowly	Days 1, 15 and 29, then monthly

Cycle length: Palbociclib and ribociclib: every 28 days; abemaciclib continuous
Duration: Until progression or unacceptable toxicity

Ribociclib: reduce to 400 mg and then 200 mg. Abemaciclib: monotherapy 200 mg twice daily.

On the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Ribociclib plus letrozole

Ribociclib 600 mg per day on a 3-weeks-on, 1-week-off schedule, plus letrozole 2.5 mg per day.

2Placebo plus letrozole

Placebo plus letrozole 2.5 mg per day.

Source of the regimen details: Abstract of the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not previously received any systemic therapy for advanced disease.

Endpoints

Primary endpoint: investigator-assessed progression-free survival (PFS). Secondary endpoints: overall survival, overall response rate and safety. The prespecified interim analysis was performed on 29 January 2016 after disease progression or death in 243 patients. The prespecified criterion for superiority was a hazard ratio of 0.56 or less with P below 1.29×10^-5.

Safety and side effects

The most common grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (59.3% in the ribociclib group versus 0.9% in the placebo group) and leucopenia (21.0% versus 0.6%). Rates of discontinuation due to adverse events were 7.5% and 2.1%, respectively. Myelotoxicity was greater in the ribociclib group.

Clinical significance and place in guidelines

This trial showed that adding a CDK4/6 inhibitor (ribociclib) to letrozole in first-line treatment of HR-positive, HER2-negative advanced breast cancer significantly improves progression-free survival, although with more myelosuppression. The abstract does not mention overall survival or the status of drug approvals and clinical guidelines; these should be checked separately.

Limitations

The reported results are based on an interim analysis with a median follow-up of 15.3 months, and the primary endpoint was investigator-assessed. Overall survival data are not reported in the abstract.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.