SAN ANTONIO – Treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6) appears to have the same efficacy in older breast cancer patients, as compared to younger ones, according to new findings presented at the San Antonio Breast Cancer Symposium.
Women aged 65 years and older with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer who received CDK4/6 inhibitors achieved a rate of progression-free survival (PFS) similar to that which has been reported in younger patients. Importantly, combining a CDK4/6 inhibitor with endocrine therapy led to superior PFS as compared to endocrine therapy alone.
However, older patients appeared to be less tolerant of associated adverse events and were more likely to discontinue treatment for that reason.
“Older patients with breast cancer benefit from treatment with CDK4/6 inhibitors ... for HR-positive, HER2-negative, metastatic breast cancer,” said the study’s lead author, Harpreet Singh, MD, scientific liaison for the FDA’s Cancer in Older Adults and a medical officer in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, at the Food and Drug Administration.
“The severity of adverse events and rates of dose modifications and interruptions were higher in those 65 years of age and older and those 70 years and older,” Dr. Singh said. “Rates of selected adverse events were similar across pooled trials.”
Breast cancer is a disease of aging, and 72,000 breast cancers occur annually in women aged 70 years or older, she explained. “Most cancers in older women are lower risk tumors and most older patients will die of other causes, but approximately 40% of breast cancer related deaths are in women over the age of 70.
“But the accrual of older individuals in trials has been a persistent challenge,” said Dr. Singh. “Older patients traditionally have been underrepresented in oncology clinical trials, so pooling outcomes of older patients across clinical trials in the same drug class allows us to gain insight into how these patients may benefit.”
In the current study, which was an FDA-conducted review of FDA registration trials over a 10 year period, the authors found that fewer than 60% of new cases of breast cancer are diagnosed in women under the age of 65 years.
“But these women make up about 80% of the clinical trial populations even though they are only 57% of cases,” said Dr. Singh.
Only 17% of clinical trial populations comprised individuals aged 65-74 years – even though patients aged 75 years and older make up about 20% of new cases, they comprise only 4% of the clinical trial population.
The FDA has issued several guidances that encourage investigators to enroll older women into trials but does not require them to. Only 22% of patients over 70 received adjuvant or neoadjuvant therapy compared to close to 50% of younger patients, and as a result, very little is known about the safety and efficacy of these agents in older adults.
To assess the efficacy and safety of CDK4/6 inhibitors in an older population, Dr. Singh and her colleagues pooled and analyzed data from prospective, randomized, controlled trials that evaluated three different CDK4/6 inhibitors in combination with an aromatase inhibitor, as the first-line treatment for postmenopausal patients with HR-positive metastatic breast cancer. The cohort included 1,334 patients, (intention-to-treat population, 1,992), of whom 42% were aged 65 years or older, and 24% were 70 years or older.
The primary endpoint was PFS in patients aged 70 years and older, and in control groups.
For patients 70 years or older who received a CDK4/6 inhibitor in combination with an aromatase inhibitor, the estimated PFS was not reached (25.1 months, not reached), versus 16.8 months (13.7, 21.9) for those who received an aromatase inhibitor only.
For patients younger than 70 years of age, PFS also was superior among those who received a CDK4/6 inhibitor, compared with treatment with an aromatase inhibitor alone: 23.75(21.9, 25.4) months versus an estimated 13.8 months (12.9, 14.7).
There were no treatment differences across age subgroups and similar results with alternate age cut-offs (greater than 65 years, greater than 75 years, etc.).
When looking at safety, the authors found that older patients were more likely to stop treatment because of adverse events. Among those 70 years and older, 20% discontinued treatment as compared with 17% of those 65 years or older, and 8% of those under the age of 65 years. Virtually all patients in the three age groups experienced grade 1-2 events (younger than 65, 98%; greater than or equal to 65 years, 98%; greater than or equal to 70 years, 99%), and the majority experienced grade 3-4 events (76%, 83%, 85%, respectively), with the rate higher in the older age groups. More than three quarters of all patients experienced neutropenia (76%, 77%, 80%), and two-thirds or higher grade 3-4 neutropenia (65%, 69%, 72%). Adverse events leading to dose interruption and/or reduction were also higher in the older age groups (66%, 75%, 77%).
“But there are many signs of progress,” said Dr. Singh, referring to efforts in enrolling more older breast cancer patients in clinical trials. “There are ongoing efforts to modernize eligibility criteria which will include greater inclusion of older adults, and specifically, taking a rational approach to organ dysfunction and prior malignancies.”
The increased use of patient-reported outcomes will provide further information on the tolerability of therapy. “Also the acquisition of real-world data from more diverse oncology practices will help inform data on efficacy and safety of novel therapies in older adults,” concluded Dr. Singh.
SOURCE: Singh et al., SABCS 2017 Abstract GS5-06.