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CDK4/6 inhibitors may benefit older patients with metastatic breast cancer
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SAN ANTONIO — Patients with breast cancer aged 70 years or older tolerated treatment with CDK4/6 inhibitor therapy, according to results of a retrospective pooled analysis conducted by the FDA and presented at the San Antonio Breast Cancer Symposium.
Further, CDK4/6 inhibitors appeared as effective among older women as younger women.
Older patients traditionally are underrepresented in clinical trials, Harpreet Singh, MD, scientific liaison for Cancer in Older Adults and a medical officer in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research at the FDA, said during a press conference.
“Breast cancer is a disease of the aging,” she said, suggesting that as many as 40% of breast cancer-related deaths occur among women aged older than 70 years. “Upward of 20% of new cases diagnosed are among women older than 75, but they comprise only 4% of trial populations.”
The FDA has approved three CDK4/6 inhibitors in the past 2 years — palbociclib (Ibrance, Pfizer), ribociclib (Kisqali, Novartis) and abemaciclib (Verzenio, Eli Lilly). These drugs — which block the function of proteins CDK4 and CDK6, both of which drive cell multiplication, fueling tumor growth — are indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with hormone receptor-positive, HER-2-negative advanced or metastatic disease. Thus, an increasing number of older adults will be treated with these drugs.
“However, we know very little about the safety and efficacy of these agents in older adults,” Singh said.
Researchers evaluated data from 716 women aged younger than 65 years, 555 women aged 65 years or older, and 329 women aged 70 years or older who were enrolled on registration trials submitted to the FDA for CDK4/6 inhibitors.
The effect of age on PFS served as the main study outcome.
Among women treated with a CDK4/6 inhibitor plus an aromatase inhibitor, median PFS for women aged 70 years or older was not reached (95% CI, 25.1-not reached), whereas the PFS among younger women was 23.75 months (95% CI, 21.9-25.4).
“We looked for differences in treatment across subgroups and found that there appears to be a benefit whether the patient is aged 70 years or younger than 70 years,” Singh said.
By comparison, women aged 70 years or older treated with only an aromatase inhibitor had a median PFS of 16.8 months (95% CI, 13.7-21.9), and those aged younger than 70 years in this treatment group showed a median PFS of 13.8 months (95% CI, 12.9-14.7).
Thus, there were no significant differences across age subgroups.
Safety and tolerability data showed that low-grade adverse event rates were similar among patients in the three age groups.
“However, patients aged older than 65 and 70 years of age experienced higher rates of grade 3 or grade 4 adverse events,” Singh said, noting rates of 80% and 82% in the two older age groups, compared with 66% in the younger age group.
Dose reductions or interruptions also occurred more frequently among the two older age groups than the younger age group (< 65 years, 66%; 65 years, 75%; 70 years, 77%).
Adverse events lead to discontinuation among 16% of the 65 years and older group, 17% of the 70 years and older group and 8% of those aged younger than 65 years.
The most commonly reported adverse events included neutropenia, infections, hepatotoxicity, fatigue and diarrhea.
“Older patients with breast cancer benefit from treatment with CDK4/6 inhibitors as initial endocrine-based therapy for hormone receptor-positive, HER-2-negative, metastatic breast cancer,” Singh said.
However, she noted a limitation of the study highlights a limitation in breast cancer research in general: an underrepresentation of older patients in clinical trials.
“Availability of prospective data in these patients is limited,” she said.
The nature of patients in clinical trials also may be problematic.
“We know that older adults enrolled in clinical trials are often more fit and have a better performance status than those seen in clinical practice,” she said.
Modernizing eligibility criteria to assess physiologic age and not chronologic age may allow clinicians to better assess patients, according to Singh. Promoting greater inclusion of older patients in trials also may be useful. – by Rob Volansky
Reference:
Singh H, et al. Abstract GS5-06. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio.
Disclosures: The researchers report no relevant financial disclosures.
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Jennifer K. Litton, MD
Singh and colleagues evaluated CDK4/6 inhibitors for postmenopausal women with metastatic breast cancer. We now have three phase 3 trials that have been presented showing these drugs can provide benefit in terms of PFS. Because usage of this therapy is increasing among patients with hormone receptor-positive breast cancer, the researchers looked specifically at older patients.
The take-home message for this is that for older individuals, we are still seeing the preserved improvement in PFS. However, there are toxicities — specifically hematologic toxicities — that are increased among patients who had discontinued the drug. In particular, more patients aged older than 65 years, rather than those aged younger than 65 years, are discontinuing the drug. But, the survival outcome still makes this a very viable drug in this population. We should continue to follow this drug in these patients for toxicity and management.
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