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CHICAGO -- Progression-free survival (PFS) in advanced hormone receptor (HR)-positive breast cancer improved by 7 months with the addition of the investigational CDK4/6 inhibitor abemaciclib to fulvestrant (Faslodex), a large randomized trial dubbed MONARCH-2 showed.

The median PFS increased from 9.3 months with fulvestrant alone to 16.4 months when abemaciclib was added. The difference represented a 45% reduction in the hazard for disease progression or death. Subgroup analysis showed a consistent advantage for the combination across all prespecified demographic and clinical factors.

Most patients had some degree of tumor shrinkage with the combination, George Sledge, MD, of Stanford University, reported here at the meeting.

"Abemaciclib plus fulvestrant was an effective treatment for women with hormone receptor-positive, HER2-negative advanced breast cancer whose disease progressed on prior endocrine therapy," said Sledge. "Abemaciclib dosed on a continuous schedule was generally well tolerated."

On the basis of the positive results in advanced disease, a randomized trial of abemaciclib and endocrine therapy in the adjuvant setting will begin enrollment during the third quarter of 2017, Sledge added.

The results make abemaciclib the third CDK4/6 inhibitor -- following palbociclib (Ibrance) and ribociclib (Kisqali) -- to demonstrate a significant PFS advantage when added to endocrine therapy for progressive, HR-positive/HER2-negative breast cancer. Invited discussant Ingrid Mayer, MD, of Vanderbilt University in Nashville, Tenn., said the agents achieved similar benefits, leaving the choice in the clinic to individual clinicians.

Reviewing how the CDK4/6 inhibitors might be used, Mayer said the evidence to date suggests that the total gain in PFS is similar whether a CDK4/6 inhibitor combination is used upfront or in second line. The agents probably do not have a role as monotherapy. Whether a CDK4/6 inhibitor combination should be used to prolong survival in metastatic HR-positive breast cancer remains unclear, pending overall survival data from pivotal trials of palbociclib and ribociclib.

Without question, however, patients with HR-positive metastatic breast cancer should receive a CDK4/6 inhibitor-endocrine agent combination at some point in their treatment, said Mayer: "The overall good quality of life, long duration of clinical benefit, and delay in chemotherapy initiation are clear reasons to do so."

But despite the consistent PFS benefits across the drug class, the lack of an overall survival benefit -- so far -- should temper enthusiasm about the agents' potential impact on advanced breast cancer, said Charles Shapiro, MD, of Mount Sinai Medical Center in New York City.

"I was struck by the lack of survival advantage in multiple studies the CDK4/6 inhibitors," Shapiro told 番茄社区app. "When the doubling of median progression-free survival came out with palbociclib in combination with letrozole (Femara), I think the world got excited about the possibility that we had a 'Herceptin' for ER-positive disease.

"But the lack of survival advantage should make us pause, because we've seen this before -- drugs that increase PFS but don't have a survival advantage. Bevacizumab (Avastin) is one example. There are more trials to come, but it gives me pause about how worthwhile these drugs are, really, if they don't have a survival advantage."

Study Details

Sledge presented results from the phase III , which included 669 patients with HR-positive/HER2-negative, advanced breast cancer with demonstrated resistance to endocrine therapy. Eligible patients had received no chemotherapy for metastatic breast cancer and no more than one endocrine therapy in the metastatic setting.

Investigators at 142 centers in 19 countries randomized patients 2:1 to abemaciclib plus fulvestrant or to fulvestrant and placebo. The primary endpoint was investigator-assessed PFS.

The results showed a significant reduction in the risk of disease progression or death in the abemaciclib group (P<0.0000001). A review of the data by an independent committee confirmed the PFS benefit, showing a 52% reduction in the hazard for the combination versus fulvestrant and placebo (HR 0.480, 95% CI 0.363-0.584, P<0.000001).

By intention-to-treat analysis, the combination led to a doubling of average reduction in tumor size, from 16.1% with fulvestrant and placebo to 35.2% with abemaciclib. Among patients with measurable tumors, the average reduction in tumor size increased from 21.3% with fulvestrant alone to 48.1% with abemaciclib and fulvestrant (P<0.001).

Responses to fulvestrant had a median duration of 25.6 months, whereas the median had yet to be reached with the abemaciclib-fulvestrant combination.

The combination was associated with more toxicity, including diarrhea, neutropenia, nausea, fatigue, abdominal pain, anemia, leukopenia, decreased appetite, and vomiting. The most common grade 3/4 adverse events with the combination were neutropenia (26.5%) and diarrhea (13.4%).

Abemaciclib's developer, Eli Lilly, has said it plans to begin . The agent is also in trials for a variety of other tumor types including lung and pancreatic cancer and brain metastases.

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