Ribociclib/Letrozole Combination an Important Advance in HR+ Metastatic Breast Cancer

Findings of a recent multicenter randomized trial<sup>&nbsp;</sup>showed postmenopausal women with hormone receptor (HR)-positive metastatic breast cancer (MBC) had significant slowing of disease progression with the addition of the investigational cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib to endocrine therapy.

Gabriel N. Hortobagyi, MD

Findings of a recent multicenter randomized trial1showed postmenopausal women with hormone receptor (HR)-positive metastatic breast cancer (MBC) had significant slowing of disease progression with the addition of the investigational cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib to endocrine therapy.

The ribociclib arm had a 44% reduction in the hazard for progression or death compared with patients who received placebo in addition to hormonal therapy (HR, 0.556; 95% CI, 0.43-0.72;P= .00000329), and the difference satisfied prespecified statistical requirements for superiority.

&ldquo;The treatment benefit was consistent across patient subgroups and for other secondary endpoints,&rdquo; Gabriel N. Hortobagyi, MD, professor of Medicine at the University of Texas MD Anderson Cancer Center, said during a press conference announcing the results at the 2016 ESMO Congress in Copenhagen.

&ldquo;Ribociclib was well tolerated. The combination of ribociclib and letrozole represents an important advance for patients with metastatic, hormone receptor-positive breast cancer.&rdquo;

Results from the trial were published online simultaneously in theNew England Journal of Medicine.2

Inhibition of CDK 4/6 offers an attractive therapeutic strategy for hormone-receptor breast cancer. CDK 4 and 6, along with their protein regulator, cyclin D1, regulate cell-cycle progression. CDK4/6 overexpression and amplification of cyclin D1 gene occur frequently in HR-positive breast cancer, and increased CDK 4/6 activity, in particular, is associated with resistance to endocrine therapy, Hortobagyi explained.

The efficacy of anti—CDK 4/6 therapy in advanced HR-positive breast cancer was demonstrated at the 2016 ASCO annual meeting in June. The addition of the CDK 4/6 inhibitor palbociclib to the endocrine agent fulvestrant significantly improved PFS in advanced breast cancer that had relapsed following first-line endocrine therapy.3

Hortobagyi reported findings from the MONALEESA-2 trial, a first-ever phase III study of a CDK 4/6 inhibitor and an endocrine agent as first-line therapy for advanced HR-positive breast cancer. The trial involved 668 postmenopausal women with untreated HR-positive, HER2-negative MBC.

All patients received the aromatase inhibitor letrozole at a dose of 2.5 mg/day, and investigators randomly assigned study participants evenly to ribociclib 600 mg/day (3 weeks on/1 week off) or placebo. The trial had a primary endpoint of PFS by investigator assessment. Secondary endpoints included overall survival, response rate, and safety.

The trial ended prematurely after an initial interim data analysis demonstrated a significant benefit in favor of the ribociclib arm. The analysis occurred after 243 qualifying events, including progression or death. Hortobagyi reported that 93 (27.8% of randomized patients) events occurred in the ribociclib arm compared with 150 (44.7%) in the placebo arm.

After a median follow-up of 15.3 months, the ribociclib group&rsquo;s median PFS had yet to be reached, whereas the placebo group had an estimated median PFS of 14.7 months. Blinded PFS assessment by an independent review committee resulted in a hazard ratio of 0.59 in favor of the ribociclib arm (P= .002).

The 18-month PFS was 63.0% with ribociclib versus 42.2% for the placebo group. Among patients with measurable disease, the overall response rate was 52.7% with letrozole plus ribociclib and 37.1% with letrozole and placebo.

Ribociclib did add to treatment-associated toxicity, as 59.3% of patients who received the CDK 4/6 inhibitor developed grade 3/4 neutropenia, as compared with 0.9% of patients who received placebo. Grade 3/4 leukopenia occurred in 21.0% of the ribociclib arm and 0.6% of the placebo group. Hematologic adverse events were uncomplicated and resolved without incident in most cases, Hortobagyi said.

The most common nonhematologic adverse events (all grades) were nausea (51.5% with ribociclib, 28.5% with placebo), diarrhea (35.0% vs. 42.4%), fatigue (36.5% vs. 30.0%), and diarrhea (35.0% vs. 22.1%). The events were grade 1/2 severity in most cases. Rates of discontinuation were 7.5% with ribociclib and 2.1% with placebo.

Hortobagyi said the MONALEESA-2 trial and the PALOMA-3 trial involving palbociclib will have a paradigm-changing impact on management of HR-positive MBC. However, in the absence of reliable biomarkers to guide treatment decisions, the drugs&rsquo; role in disease management will continue to evolve.


  1. Hortobagyi GN, Stemmer SM, Burris HA, et al. First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA1.
  2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer [published online ahead of print October 8, 2016]. NEJM.
  3. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib with letrozole compared with letrozole alone in postmenopausal women with ER+/HER2— advanced breast cancer. J Clin Oncol. 2016;34(suppl; abstr 507).
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