Pooled Study Analysis Explores the Use of CDK4/6 Inhibitors in Metastatic Breast Cancer

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RESEARCH TO DATE has not been able to identify a subgroup of patients with estrogen receptor–positive HER2-negative metastatic breast cancer who do not derive benefit from the addition of inhibitors of cyclin-dependent kinases 4/6 (CDK4/6) to endocrine therapy, according to a study by the U.S. Food and Drug Administration (FDA). 

Jennifer Gao, MD

Jennifer Gao, MD

“Our analysis of the raw data from five registration trials of CDK4/6 inhibitors showed that, contrary to what we had thought, every patient benefits about equally from the addition of CDK4/6 inhibitors—even the patients we thought to have had more indolent disease biology,” said Jennifer Gao, MD, a medical oncologist on the breast cancer team in the Division of Oncology Products 1 at the FDA, who presented a poster on this pooled analysis at the 2018 ASCO Annual Meeting.1


Angelo Di Leo, MD, PhD

Angelo Di Leo, MD, PhD

The addition of a CDK4/6 inhibitor conferred a progression-free survival benefit for all the studied subsets of patients, with hazard ratios comparable to those of the intent-to-treat pooled population. The benefit was seen in both the first-line and second-line metastatic treatment settings. Exploratory statistical analyses within subset variables found no evidence of a treatment effect interaction, she reported. 

Differing Conclusions in ESMO Presentation 

THIS FINDING stands in contrast to discussions arising from the 2017 European Society for Medical Oncology (ESMO) Annual Conference presentation by Angelo Di Leo, MD, PhD, on abemaciclib (Verzenio) in MONARCH-3.2 Although the treatment effect of abemaciclib was consistently observed across subgroups, based on hazard ratios, Dr. Di Leo said combination therapy is probably not warranted in all patients. 


  • Researchers from the Division of Oncology Products 1 at the FDA conducted a pooled analysis of the five registration trials of CDK4/6 inhibitors in metastatic breast cancer.
  • They found no particular subsets of patients with greater or lesser benefit from the addition of CDK4/6 inhibitors to endocrine therapy, either in the first-line or second-line setting.
  • The suggested conclusion is that all patients with hormone receptor–positive, HER2-negative metastatic breast cancer may benefit from this class of agents.

“For the first time, we have insights suggesting that patients with certain clinical characteristics may benefit differently from treatment with a CDK4/6 inhibitor…. Our exploratory subgroup analyses suggest that the largest benefit was observed in patients with adverse prognostic factors, such as liver metastases or relapse only a few years after adjuvant therapy,” Dr. Di Leo said at a press conference during that meeting. 

Dr. Di Leo and other experts maintained that patients with good-prognosis factors, such as bone-only disease or a long treatment-free interval—about one-third of patients—can be treated adequately with endocrine therapy alone. 

FDA Analysis of Five Trials 

AS THE INVESTIGATORS noted at the ASCO meeting, limited data are available on the benefit and value of adding CDK4/6 inhibitors to endocrine therapy in certain patients with breast cancer who may have greater or lesser degrees of endocrine sensitivity compared with the general population. This includes patients with lobular tumors, bone-only metastases, and disease-free intervals of more than 1 year—a presumably indolent group—and those with de novo metastatic disease or progesterone receptor–positive tumors—a presumably more aggressive tumor subset. The hypothesis of the study was that the former would derive less benefit, whereas the latter would derive more, as compared with the overall populations in the trials. 

“We thought there may be a subset of patients, based on tumor biology, that would benefit more from CDK4/6 inhibitors added to the endocrine therapy backbone and a subset that may do just as well with hormonal therapy alone and for whom we could save the CDK4/6 inhibitor for a subsequent line of therapy,” Dr. Gao said. 


TABLE 1 : CDK4/6 Inhibitors in Advanced Breast Cancer: Median Progression-Free Survival by Disease Subset 


AI or fulvestrant 

CDK4/6 inhibitor 


Hazard ratio 

ITT pooled population (n = 3,002) 


20.5 mo 

11.8 mo 


ITT pooled population (n = 1,817) 


26.5 mo 

15.1 mo 


PR-negative (n = 490) 


16.5 mo 

7.4 mo 


Lobular cancer (n = 264) 


16.1 mo 

9.2 mo 


Bone-only metastases (n = 875) 


27.9 mo 

15.5 mo 


De novo metastatic (ie, stage IV at diagnosis; n = 617) 


27.8 mo 

16.8 mo 


Disease-free interval > 12 months (n = 929) 


25.7 mo 

14.2 mo 



To learn whether these thoughts were correct, she and her colleagues pooled raw data from five phase III randomized, controlled registration trials of CDK4/6 inhibitors with an aromatase inhibitor in the first-line or fulvestrant (Faslodex) in the second-line setting. They calculated the median progression-free survival and hazard ratios for these less common subgroups and found that the benefit was similar across the board (Table 1). The natural history of disease and the magnitude of the CDK4/6 benefit are similar for certain subsets previously thought to have different behavior, said the investigators, who considered the results “hypothesis-generating.” ■

DISCLOSURE: Dr. Gao is a consultant for WorldCare International, Inc. Dr. Di Leo is on advisory committees for AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health, Lilly, Novartis, Pfizer, Roche; has been a consultant for Amgen, AstraZeneca, Bayer HealthCare Pharmaceuticals, Celgene, Eisai, Genentech BioOncology, Genomic Health, Lilly, Novartis, Pfizer, and Roche; and has done contracted research for AstraZeneca, Novartis, and Pfizer. 


1. Gao JJ, Cheng J, Bloomquist E, et al: Benefit of CDK 4/6 inhibition in less common breast cancer subsets: A U.S. Food and Drug Administration pooled analysis. 2018 ASCO Annual Meeting. Abstract 1024. Presented June 2, 2018. 

2. di Leo A, Toi M, Campone M, et al: MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2– advanced breast cancer. 2017 ESMO Congress. Abstract 236O_PR. Presented September 10, 2017.