Combination of Ribociclib and Letrozole Improved Progression-Free Survival in Hormone Receptor–Positive Advanced Breast Cancer

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In my view, this is a practice-changing study. When ribociclib is approved, this drug will be one of the major choices for advanced breast cancer.
— Gabriel ­Hortobagyi, MD

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The combination of the selective CDK4/6 inhibitor ribociclib plus letrozole significantly improved progression-free survival in hormone receptor–positive advanced breast cancer. When ribociclib was added to letrozole, progression-free survival improved by 44% compared with letrozole alone, according to the first interim analysis of the phase III MONALEESA-2 trial.1 Ribociclib was granted Breakthrough Status by the U.S. Food and Drug Administration in September 2016. Results of the trial were presented at the 2016 ESMO (European Society for Medical Oncology) Congress1 and published in The New England Journal of Medicine2 to coincide with the presentation.

“The combination of ribociclib plus letrozole achieved a statistically significant and clinically meaningful increase in progression-free survival, with a consistent treatment benefit observed across all subgroups and for other secondary endpoints. Ribociclib was well tolerated. This combination represents an important advance for patients with metastatic, hormone receptor–positive breast cancer,” stated lead author ­Gabriel ­Hortobagyi, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This was the definitive study to demonstrate the superiority of the combination of ribociclib and letrozole over letrozole alone,” he added.

Hormonal therapy is the treatment of choice for both primary and metastatic hormone receptor–positive breast cancer, but tumors eventually develop resistance to hormonal therapy. “Cyclin-dependent kinase inhibitors [such as ribociclib] are a promising development to overcome resistance to hormonal therapy. This line of research is 15 to 20 years old, but only recently have selective CDK4/6 inhibitors [such as ribociclib] become available,” Dr. Hortobagyi explained.

Study Details and Results

The study enrolled 668 postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer who had not been previously treated with systemic therapy for advanced disease. Women were excluded from the trial if they had received prior systemic therapy for advanced disease, inflammatory breast cancer, or a history of cardiac disease. Women were randomized to receive ribociclib (600 mg/d, 3 weeks on and 1 week off) plus letrozole (2.5 mg/d given continuously) or letrozole plus placebo.

At a preplanned interim analysis, 243 patients had a pogression-free survival event (progression or death; 70% of expected events). At a median follow-up of 15.3 months, the primary endpoint of progression-free survival was significantly improved in the combination therapy group. After 18 months, the progression-free survival rate was 63% for the combination vs 42.2% for letrozole alone, representing a 44% improvement favoring the combination, which was highly statistically significant (P = .00000329). Median progression-free survival had not yet been reached for the combination arm at the time of data cutoff but was 14.7 months for letrozole alone.

“The [progression-free survival] curves for the two arms separate early. We need longer follow-up, but we expect [progression-free survival for the combination] to far exceed that in the control arm,” Dr. Hortobagyi said at an official ESMO press conference.

A significantly higher objective response rate was observed with ribociclib plus letrozole vs letrozole alone: 53% vs 37% (P = .00028). The clinical benefit rate (ie, responses and stable disease that exceeds 24 weeks) was also significantly higher in the combination arm: 80% vs 72%, respectively (P = .02). Progression-free survival was significantly better for the combination across all subgroups, regardless of age, race, performance status, site of metastasis, and prior treatment.


Serious adverse events were reported in fewer than 5% of patients in both arms. Adverse events more frequently reported in the combination arm were mainly uncomplicated asymptomatic hematologic effects, especially myelosuppression, neutropenia, anemia, and thrombocytopenia. Any grade of neutropenia was reported in 75% of the combination arm vs 5.2% of the letrozole arm, but the rate of febrile neutropenia was only 1.5% vs 0, respectively.

Other adverse events seen more frequently in the combination arm—such as nausea, vomiting, diarrhea, alopecia, rash, and transaminase elevations—were mainly grades 1 and 2.

“Very few patients discontinued treatment with ribociclib plus letrozole. Toxicities were managed by dose interruptions and dose reduction, and the great majority of patients were able to continue therapy,” revealed Dr. ­Hortobagyi.

Fertile Area of Study

CDK4/6 inhibition is a fertile area of study in breast cancer, he said. Two other phase III trials of CDK4/6 inhibition have completed accrual: MONALEESA-3, which is evaluating ribociclib plus fulvestrant (Faslodex) vs placebo plus fulvestrant as first- or second-line therapy for advanced breast cancer, and MONALEESA-7, which is studying ribociclib plus tamoxifen plus goserelin (Zoladex) or goserelin plus an aromatase inhibitor in premenopausal and perimenopausal advanced breast cancer.

“There are three leading CDK4/6 inhibitors in clinical trials, and they seem to be similar in terms of therapeutic efficacy and toxicity profile. Abemaciclib is not as far along in development as ribociclib or palbociclib and may have some distinctive features,” he noted. “Additional studies will be needed to separate these drugs out.”

New Standard of Care Emerging in Advanced Breast Cancer?

  • Adding the selective CDK4/6 inhibitor ribociclib to standard hormonal therapy with letrozole significantly improved progression-free survival by 44% compared with letrozole alone in women with hormone receptor–positive advanced breast cancer.
  • The benefit of the combination was seen across the board for all subgroups.
  • The combination was well tolerated with acceptable toxicity.
  • The combination is poised to become a standard of care, once ribociclib is approved.

The MONALEESA-2 results, along with the results of PALOMA-2 in a similar patient population showing a 42% improvement in progression-free survival with palbociclib plus letrozole vs letrozole alone, are moving the field forward.

“The million dollar question is whether this study, along with ­PALOMA-2, will change practice. Both trials are precedent-setting, showing the greatest magnitude of benefit seen in advanced breast cancer,” stated Dr. Hortobagyi. “We don’t have biomarkers to select patients most likely to benefit, but we are working hard in this area. It is possible to treat asymptomatic hormone receptor–positive breast cancer with endocrine therapy alone, but that is not evidence-based. For the maximum benefit, use the combination of a selective CDK4/6 inhibitor plus letrozole,” Dr. Hortobagyi told press conference attendees.

“In my view, this is a practice-changing study. When ribociclib is approved, this drug will be one of the major choices for advanced breast cancer,” he stated. ■

Disclosure: Dr. Hortobagyi has received grants and personal fees from Novartis, the funder of the MONALEESA-2 trial, during the conduct of the study as well as personal fees from Eli Lilly and Pfizer outside the submitted work.


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. 2016 ESMO Congress. Abstract LBA1_PR. Presented October 8, 2016.

2. Hortobagyi GN, Stemmer SM, Burris HA, et al: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. October 7, 2016 (early release online).

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