By David Douglas
NEW YORK (Reuters Health) - 2/10/2019
Abemaciclib in combination with fulvestrant can increase overall survival in patients with HR-positive, ERBB2-negative (HER2-negative) advanced breast cancer that has progressed on endocrine therapy (ET), according to the Monarch 2 trial.
The study "is one of a suite of trials demonstrating that the addition of CDK 4/6 inhibitors to endocrine therapy in the metastatic setting leads to a meaningful improvement in overall survival," said Dr. George W. Sledge of Stanford University School of Medicine, in California.
"As such these agents can be considered part of the standard of care for ER-positive HER2-negative metastatic breast cancer," he told Reuters Health by email.
In a paper online September 29 in JAMA Oncology, Dr. Sledge and colleagues note that although ET is an efficacious and well-tolerated therapy in most patients, resistance and disease progression are major challenges.
Abemaciclib, they add, is currently the only inhibitor of CDK4 and CDK6 approved in the U.S. for the treatment of such patients.
In order to examine its performance in combination with the selective estrogen-receptor antagonist fulvestrant, versus treatment with placebo and fulvestrant, the researchers did a global phase-3 trial including 669 women.
The participants were randomized 2:1 to receive abemaciclib 150 mg or placebo every 12 hours on a continuous schedule plus fulvestrant 500 mg by IM injection on days 1 and 15 of the first cycle and on day 1 of each cycle thereafter. Treatment continued until progressive disease, death, or withdrawal for any other reason.
In all, 446 women (median age, 59) received the abemaciclib combination and 223 (median age, 62) received the placebo combination. Most had visceral disease or bone-only disease. Median follow-up was for 47.7 months.
At a prespecified interim analysis in the intent-to-treat population, at which point 338 deaths had occurred, overall survival (OS) was significantly greater in the combination group (46.7 months) than in the placebo combination group (37.3 months).
The overall improvement in OS (hazard ratio, 0.757) was consistent across all stratification factors, although more pronounced effects were seen in patients with visceral disease (HR, 0.675) and primary resistance to prior ET (HR, 0.686).
There were also significant improvements in the median time to second disease progression (23.1 vs. 20.6 months), to chemotherapy (50.2 vs. 22.1 months), and for chemotherapy-free survival (25.5 months vs. 18.2 months).
The researchers conclude that their "data constitute the largest absolute OS benefit reported so far in a phase 3 clinical trial for HR-positive, ERBB2-negative advanced breast cancer."
Oncologist Dr. Aditya Bardia of Massachusetts General Hospital, in Boston, who was not involved in the trial, told Reuters Health by email, "Improvement in overall survival is the best clinical outcome one could hope for, and the results of MONARCH 2, along with the trials investigating CDK 4/6 inhibitors, demonstrate the transformative potential of CDK 4/6 inhibitors and impact on modulating the natural history of disease."
"Endocrine therapy with CDK 4/6 inhibitor should be considered the first-line therapy for hormone-receptor-positive metastatic breast cancer and we eagerly await the results of the adjuvant trials," she concluded.
The study was funded by Eli Lilly, which markets abemaciclib as Verzenio. A number of authors have relationships with the company and four are employees.
JAMA Oncol 2019.
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