Changing the Natural History of ER-Positive, HER2-Negative Breast Cancer With the Introduction of CDK4/6 Inhibition

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It has been 14 years since a collaboration between the University of California, Los Angeles (UCLA) and Pfizer identified a unique role for cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in estrogen receptor (ER)-positive human cell line models and demonstrated that these agents act synergistically with agents targeting the ER pathway.1 This work led to the proof-of-concept PALOMA-1 study, which for the first time demonstrated a significant improvement in progression-free survival in postmenopausal women with advanced ER-positive/HER2-negative breast cancer treated with the combination of a CDK4/6 inhibitor—palbociclib—and letrozole vs letrozole alone.2 

These data supported the accelerated approval by the U.S. Food and Drug Administration in February 2015. They have since been validated in eight phase III randomized, placebo-controlled studies in advanced ER-positive/HER2-negative breast cancer with three different CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—in various lines of therapy and in different patient populations.3

Richard S. Finn, MD

Richard S. Finn, MD

From Progression-Free to Overall Survival

Given the relatively long natural history of advanced ER-positive/ HER2-negative breast cancer, all these studies used progression-free survival as their primary endpoint. Although the progression-free survival of the control arms differed slightly from study to study, based on differences in the inclusion/exclusion criteria and study populations, all of them showed remarkably similar magnitudes of benefit, with hazard ratios in the 0.5 range for the combination of endocrine therapy with a CDK4/6 inhibitor vs endocrine therapy alone. All three CDK4/6 inhibitors cause the “on-target” effect of neutropenia, to some degree, but each differs somewhat in its adverse-event profile. As it stands now, all three have global approval in the treatment of advanced ER-positive/HER2-negative breast cancer. Abemaciclib also has approval in the adjuvant treatment of higher-risk, ER-positive/HER2-negative breast cancer.

When these phase III studies were designed, around 2012, the idea of demonstrating a survival advantage in the front-line setting of advanced ER-positive/HER2-negative breast cancer was met with some skepticism. This was not because the endpoint was not considered important; one would argue that improving overall survival while maintaining quality of life is the most important goal in managing an incurable illness. Rather, the long natural history, which at the time these studies were launched, was in the realm of 3 years, and the multiple active agents used sequentially in the disease would require a very large population of patients. Studies have shown that as survival poststudy disease progression becomes longer, the more difficult it is to show an overall survival benefit.4 The overall survival analysis of the MONALEESA-2 trial, reported by Hortobagyi et al and summarized in this issue of The ASCO Post, challenges this concept.5

MONALEESA-2: Overall Survival Benefit

MONALEESA-2 randomly assigned 668 patients in a 1:1 ratio to receive either ribociclib and letrozole or placebo and letrozole. As previously mentioned, the study met its primary endpoint of improving progression-free survival (hazard ratio [HR] = 0.56, 95% confidence interval [CI] = 0.43–0.72, P = 3.29 × 10−6 for superiority). It also increased objective response rates and had a manageable safety profile, which besides neutropenia, included a less than 10% rate of high-grade abnormalities in liver function and QT prolongation that required monitoring when starting therapy.

Now, after more than 6.5 years of follow-up, the data set has matured, and we see a clinically and statistically significant improvement in overall survival with the combination. Median overall survival with the combination was 63.9 months vs 51.4 months in the control arm (HR = 0.76, 95% CI = 0.63–0.93, two-sided P =.008). This improvement occurred despite a significant number of patients on the control arm receiving a CDK4/6 inhibitor after disease progression on front-line therapy—34.4% in the control arm vs 21.7% in the ribociclib group. Almost all patients received some therapy after study treatment, including 87.8% in the ribociclib group and 90.2% in the control group. With extended follow-up, there were no new safety signals observed.

Comparing MONALEESA-2 With Other Trials

MONALEESA-2 is the first of three trials combining CDK4/6 inhibitors with nonsteroidal aromatase inhibitors in the first-line postmenopausal population to report overall survival data. It builds on other ribociclib studies: MONALEESA-7, in premenopausal women with ovarian suppression and endocrine therapy, and MONALEESA-3, in postmenopausal women in combination with fulvestrant. Both studies met their primary endpoints of improving progression-free survival but also demonstrated consistent improvements in overall survival as well.

Recently, survival data from the PALOMA-2 study with palbociclib and letrozole in the first-line treatment of postmenopausal women were presented at the 2022 ASCO Annual Meeting.6 Survival data from the MONARCH-3 study evaluating abemaciclib and endocrine therapy in this setting are still awaited. With a median follow-up of 90 months (7.5 years), there was a numerical improvement in overall survival with palbociclib and letrozole in PALOMA-2, but it was not statistically significant.

Although there may be inherent differences between the two drugs, the analysis of overall survival in PALOMA-2 is limited. Patients were randomly assigned 2:1 to the combination vs the control arms, and there was a large and disproportionate number of patients who were censored for overall survival (13% in the combination arm vs 21% in the control arm) because of patients’ withdrawing consent for ongoing follow-up or being lost to follow-up. As in the ­MONALEESA-2 study with ribociclib, the long-term safety of palbociclib was confirmed, with no evidence of cumulative toxicity. In addition, there was a similar significant delay in the time to starting chemotherapy, which is an important quality-of-life factor in this population of patients.

The study designs and populations of MONALEESA-2 and ­PALOMA-2 did have differences. Both PALOMA-2 and MONALEESA-2 met their progression-free survival endpoints with a similar magnitude of benefit (HR = 0.58 and HR = 0.56, respectively). The control arm in PALOMA-2 did have a shorter median progression-free survival vs that in MONALEESA-2 (14.5 months vs 16 months), perhaps representing a higher-risk population. This is reflected in the percent of patients reported to have a disease-free interval from prior ­(neo)adjuvant therapy of less than 12 months, which was about 22% in each arm of PALOMA-2 and less than 5% in each arm of MONALEESA-2. Nevertheless, the progression-free survival benefit was consistent across subgroups in both studies. As previously mentioned, PALOMA-2 used a 2:1 randomization design vs a 1:1 design in the MONALEESA-2 study. Given its early approval, there is now a large data set with real-world experience with palbociclib and aromatase inhibitors that demonstrates an improvement in overall survival in that population.7

Closing Thoughts

The introduction of CDK4/6 inhibitors in estrogen receptor–positive/HER2-negative advanced, and now early, breast cancer has changed the natural history of the disease. MONALEESA-2 was a well-designed and conducted study that adds additional evidence. Women are living longer because of the incorporation of these agents into their treatment paradigms. 

Dr. Finn is Professor of Medicine, Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center.

DISCLOSURE: Dr. Finn has served as a consultant or advisor to AstraZeneca, Bayer, Bristol Myers Squibb, CStone Pharmaceuticals, Eisai, Exelixis, Genentech/Roche, Hengrui Therapeutics, Lilly, Merck, Novartis, and Pfizer; and has received institutional research funding from Bayer, Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, and Roche/Genentech.


1. Finn RS, Dering J, Conklin D, et al: PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11:R77, 2009.

2. Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 16:25-35, 2015.

3. McAndrew NP, Finn RS: Clinical review on the management of hormone receptor-positive metastatic breast cancer. JCO Oncol Pract 18:319-327, 2022.

4. Broglio KR, Berry DA: Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst 101:1642-1649, 2009.

5. Hortobagyi GN, Stemmer SM, Burris HA, et al: Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med 386:942-950, 2022.

6. Finn RS, Rugo HS, Dieras V, et al: Overall survival with first-line palbociclib plus letrozole versus placebo plus letrozole in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer: Analyses from PALOMA-2. 2022 ASCO Annual Meeting. Abstract LBA1003. Presented June 4, 2022.

7. DeMichele A, Cristofanilli M, Brufsky A, et al: Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2– metastatic breast cancer in US real-world clinical practice. Breast Cancer Res 23:37, 2021.