November 22, 2019
3 min read

CDK 4/6 inhibitors effective across age groups in breast cancer subset

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Harpreet Singh, MD
Harpreet Singh

Combinations of cyclin-dependent kinase 4/6 inhibitors and aromatase inhibitors appeared effective among older and younger women with hormone receptor-positive, HER2-negative metastatic breast cancer compared with aromatase inhibitors alone, according to results of an FDA pooled analysis published in Journal of Clinical Oncology.

However, women aged older than 75 years experienced higher rates of toxicity, dose modifications and faster declines in quality-of-life measures than younger women.

“[Although] breast cancer affects a large proportion of women older than 70 years, they are underrepresented in clinical trials,” Harpreet Singh, MD, medical oncologist at FDA, told HemOnc Today. “The treatment landscape for advanced hormone receptor-positive breast cancer has evolved to include the use of CDK 4/6 inhibitors, such as palbociclib [Ibrance, Pfizer], abemaciclib [Verzenio, Eli Lilly] and ribociclib [Kisqali, Novartis]. A greater understanding of the efficacy and toxicity of these drugs in older adults was needed.”

Singh and colleagues pooled data from three randomized controlled trials — PALOMA-2, MONALEESA-2 and MONARCH-3 — that examined the use of different combinations of CDK 4/6 inhibitors and aromatase inhibitors vs. aromatase inhibitors alone among 1,827 women with hormone receptor-positive, HER2-negative metastatic breast cancer. Researchers divided women into three age groups: aged younger than 70 years (n = 1,371), aged 70 years and older (n = 456), and aged 75 years and older (n = 198).

Investigator-assessed PFS served as the primary endpoint. Researchers used Kaplan-Meier estimates and Cox proportional hazards regression models to evaluate the effect of age on PFS.

Results of a pooled analysis showed an overall improvement in median PFS, from 14.8 months to 27.7 months (HR = 0.55; 95% CI, 0.48-0.63), with the addition of a CDK 4/6 inhibitor to an aromatase inhibitor.

Estimated median PFS among women aged younger than 70 years was 27.3 months with the combination vs. 14.1 months with an aromatase inhibitor alone (HR = 0.57; 95% CI, 0.48-0.65). Estimated median PFS among women aged 70 years and older was 33.1 months vs. 19.2 months (HR = 0.52; 95% CI, 0.38-0.7), and among those aged 75 years and older was 31.1 months vs. 13.7 months (HR = 0.49; 95% CI, 0.31-0.76).

Moreover, estimated median time to PFS among all women treated with the combination (n = 1,106) was 33.1 months (95% CI, 27.8-not evaluable) for those aged older than 70 years vs. 27.3 months (95% CI, 23.1-27.7) for those aged younger than 70 years (HR = 0.73; 95% CI, 0.58-0.91). For those treated with an aromatase inhibitor only (n = 721), estimated median time to PFS was 19.2 months (95% CI, 14.7-26) among those aged older than 70 years vs. 14.1 months (95% CI, 12.9-15.9) among those aged younger than 70 years (HR = 0.78; 95% CI, 0.63-1).


These results suggest that older patients may have a slower rate of disease progression than their younger counterparts, the researchers wrote.

Incidence of grade 3 or grade 4 adverse events among women treated with CDK 4/6 inhibitors was 88.8% for those aged 75 years and older compared with 73.4% for those aged younger than 75 years. Women aged 75 years or older also experienced higher rates of adverse events leading to dose reduction or interruption (81.6% vs. 71.1%) and discontinuation (32% vs. 12.1%) than those younger than 75 years. These increases were more pronounced than those among women who received aromatase inhibitors alone.

“Our findings suggest that older adults may need additional monitoring and supportive care while taking these agents,” Singh told HemOnc Today. “Older adults should be prospectively studied in the context of clinical trials. Ongoing FDA efforts to modernize eligibility criteria for oncology clinical trials should result in a greater body of data in older women who represent the majority of patients in the U.S. with [hormone receptor]-positive, HER2-negative metastatic breast cancer.”

ASCO also has called for broader clinical trial enrollment criteria due to the limited generalizability of trial results and difficulties interpreting the risk-benefit ratio of regimens in real-world settings, according to University of Alabama at Birmingham assistant professors Gabrielle B. Rocque, MD, MSPH, of the division of hematology and oncology in the department of medicine, and Grant R. Williams, MD, of the university’s Institute for Cancer Outcomes and Survivorship.

“We fully support this sentiment, but would propose to take this a step further,” Rocque and Williams wrote in a related editorial.

“We advocate not only for developing strategies to include older adults in clinical trials, but also for measuring outcomes that are meaningful for this unique patient population,” they wrote. “Without such mechanisms to address the data-free zone and generate high-quality evidence for care delivery, we cannot minimize both the mortality and the morbidity of our older patients.” – by Jennifer Southall

For more information:

Harpreet Singh, MD, can be reached at FDA, 10903 New Hampshire Ave., Building 22, Room 2137, Silver Spring, MD 20993; email:

Disclosures: Singh reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Rocque and Williams report no relevant financial disclosures.