Results From MONALEESA-2: Are All CDK4/6 Inhibitors Equal?

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Given these compelling results and the manageable toxicity profiles seen, the combination of an aromatase inhibitor plus a CDK4/6 inhibitor should be the standard first-line treatment for the majority of patients with advanced hormone receptor–positive breast cancer.
— Sara M. Tolaney, MD, MPH

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Hormone receptor–positive breast cancer is the most common subtype of breast cancer, and while endocrine therapy has long been a mainstay of therapy for these patients, treatment resistance ultimately develops. Therefore, better therapeutic approaches are needed. There are some data to suggest that resistance to endocrine therapy may occur due to cyclin D overexpression and retinoblastoma phosphorylation, making cyclin-dependent kinase (CDK) 4/6 inhibition an attractive strategy to improve outcomes for patients with hormone receptor–positive disease.


As reported in this issue of The ASCO Post, Hortobagyi at el recently published the results of the MONALEESA-2 trial in The New England Journal of Medicine.1 This was a randomized, placebo-controlled, phase III trial of 668 patients that evaluated the efficacy and safety of the CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in women with hormone receptor–positive/HER2-negative recurrent or metastatic breast cancer.

After a preplanned interim analysis demonstrated superiority of ribociclib plus letrozole, the independent data and safety monitoring committee recommended stopping the trial early, as it had met the primary endpoint. The median progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio [HR] = 0.56, 95% confidence interval [CI] = 0.43–0.72, P = 3.29 × 10–6 for superiority). Moreover, in patients with measurable disease at baseline, the overall response rate was 52.7% in those receiving ribociclib and 37.1% in those receiving placebo (P < .001). The most common grade 3 or 4 adverse event was neutropenia (59.3% in the ribociclib group vs 0.9% in the placebo group).


The results of MONALEESA-2 confirmed the striking benefit of adding CDK4/6 inhibition to first-line endocrine therapy in patients with hormone receptor–positive/HER2-negative breast cancer that had been previously demonstrated with the addition of palbociclib (Ibrance) to letrozole in the PALOMA-2 trial. The magnitude of benefit with regard to progression-free survival favoring the ribociclib arm in MONALEESA-2 was very similar to that shown with palbociclib in ­PALOMA-2. While both trials included a similar population overall, PALOMA-2 had more patients with a short disease-free interval from diagnosis (≤ 12 months, 22.3% vs 1.2% in MONALEESA-2) and fewer patients with visceral disease (48.2% vs 59.0% in MONALEESA-2).

Both phase III trials confirmed the data of the phase II PALOMA-1 trial that led to accelerated U.S. Food and Drug Administration (FDA) approval of palbociclib in combination with letrozole in the first-line setting for women with advanced hormone receptor–positive/HER2-negative breast cancer. In addition, palbociclib was granted FDA approval to be used in combination with fulvestrant (Faslodex) for the treatment of pre- and postmenopausal patients with advanced hormone receptor–positive/HER2-negative breast cancer following disease progression on a previous line of endocrine therapy, based on the results of the PALOMA-3 study.2

Of note, accrual for the phase III MONALEESA-3 trial ( identifier NCT02422615)—in which patients are randomized to receive fulvestrant with or without ribociclib in the first- or second-line metastatic setting—is completed, and results are anticipated in 2017.


There is also a third CDK4/6 inhibitor in development: abemaciclib (LY2835219). The phase III clinical trials evaluating abemaciclib in the first-line (MONARCH 3; NCT02246621) and second-line (MONARCH 2; NCT02107703) settings have completed accrual, and data are anticipated in the near future.

This agent has shown promising clinical activity in earlier trials.3 Abemaciclib, as opposed to ribociclib and palbociclib, has demonstrated significant activity when given as monotherapy. The MONARCH 1 study demonstrated an impressive objective response rate of 19% (95% CI = 16%–25%) as monotherapy in heavily pretreated patients with metastatic hormone receptor–positive breast cancer.4 Although the reason for the higher monotherapy response rate compared to other CDK4/6 inhibitors is not clear, it may be related to its greater potency for CDK4 inhibition or due to its continuous dosing schedule, possibly driving senescence and ultimate tumor regression.5

Although the toxicity profiles of ribociclib and palbociclib are similar, with the most common toxicities being neutropenia and fatigue,1,6 abemaciclib has a different toxicity profile, with the most common toxicities being diarrhea and fatigue.4 The lower rate of neutropenia seen with abemaciclib may be due to its greater selectivity for CDK4 than for CDK6, as CDK6 inhibition is thought to contribute to the neutropenia seen with these agents.

Looking Ahead

While palbociclib is the only currently FDA-approved CDK4/6 inhibitor, ribociclib was granted FDA Priority Review for first-line treatment based on the MONALEESA-2 findings. Assuming the data with abemaciclib are also positive, it may be possible that we could have three CDK4/6 inhibitors available to us. Without randomized trials comparing the three agents, selecting which agent to use will be a challenge for clinicians.

While we do not yet have data for overall survival from any of the phase III trials of CDK4/6 inhibitors, the doubling in progression-free survival seen with the addition of CDK4/6 inhibition to endocrine therapy represents a breakthrough in the treatment of patients with metastatic hormone receptor–positive breast cancer. Given these compelling results and the manageable toxicity profiles seen, the combination of an aromatase inhibitor plus a CDK4/6 inhibitor should be the standard first-line treatment for the majority of patients with advanced hormone receptor–positive breast cancer. ■

Disclosure: Dr. Tolaney has received research funding from Genentech, Exelixis, Lilly, Novartis, AstraZeneca, Merck, and Pfizer.


1. Hortobagyi GN, Stemmer SM, Burris HA, et al: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738-1748, 2016.

2. Cristofanilli M, Turner NC, Bondarenko I, et al: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425-439, 2016.

3. Patnaik A, Rosen LS, Tolaney SM, et al: Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 6:740-753, 2016.

4. Dickler MN, Tolaney SM, Rugo HS, et al: MONARCH1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. 2016 ASCO Annual Meeting. Abstract 5100.

5. Barroso-Sousa R, Shapiro GI, Tolaney SM: Clinical development of the CDK4/6 inhibitors ribociclib and abemaciclib in breast cancer. Breast Care (Basel, Switzerland) 11:167-173, 2016.

6. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925-1936, 2016.

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First-Line Ribociclib Prolongs Progression-Free Survival in Hormone Receptor–Positive, HER2-Negative Breast Cancer

The duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.
— Gabriel N. Hortobagyi, MD, and colleagues