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Advanced Breast Cancer Patients Benefit From Combination Therapy Including CDK4/6 Inhibitors

BARCELONA – Two new breast cancer studies presented at the annual meeting of the European Society for Medical Oncology in Barcelona on Sunday showed that the addition of CDK4/6 inhibitors to fulvestrant therapy led to higher overall survival in HR-positive, HER2-negative breast cancer patients.

The MONARCH-2 study evaluated the combination regimen of abemaciclib (Eli Lilly's Verzenio) plus fulvestrant in patients with advanced breast cancer after failure of endocrine therapy and regardless of menopausal status. The MONALEESA-3 study, meanwhile, investigated the addition of ribociclib (Novartis' Kisqali) to fulvestrant as first- or second-line treatment in postmenopausal patients.

MONARCH-2 was a global, randomized, double-blind phase III trial of abemaciclib plus fulvestrant, or placebo plus fulvestrant in perimenopausal and postmenopausal women with advanced HR-positive, HER2-negative breast cancer that had grown resistant to endocrine therapy.

According to Stanford University School of Medicine's George Sledge, 669 patients were randomized in a 2-to-1 ratio to receive either the combination therapy or the placebo with fulvestrant. The patients were stratified based on site of metastasis (visceral, bone-only, or other), and either primary or secondary resistance to prior endocrine therapy. The study's primary objective was to increase progression-free survival (PFS), and the researchers measured overall survival (OS) as a secondary endpoint.

Abemaciclib is a selective CDK4/6 inhibitor, but it is 14 times more potent against CDK4 than CDK6, Sledge said.

At the interim analysis, median OS for the experimental arm was 46.7 months compared to 37.3 months for the control arm. The benefit was consistent across all patient subgroups, he added, though the benefit was more pronounced in patients with visceral metastasis and those with primary resistance to endocrine therapy. However, Sledge also said this particular data was not yet mature.

Median PFS was 16.9 months for the experimental arm compared to 9.3 months in the control arm. Further, approximately three times as many patients taking the combination treatment survived compared to the placebo group.

In addition, 17 percent of the patients in the placebo arm crossed over to the experimental arm, while only 5.4 percent of patients in the experimental arm crossed over to take fulvestrant and placebo.

Median time to chemotherapy was 50.2 months for the experimental arm compared to 22.1 months for the control group, results Sledge called "highly significant."

The overall results met the predefined boundary for significance, he said, noting that the combination of abemaciclib and fulvestrant provided a statistically significant and clinically meaningful OS benefit for these patients.

"CDK4/6 inhibitors significantly prolong the time patients remain in remission and significantly improve overall survival," Sledge added. "Therefore, it is very reasonable to think of these as standard-of-care options for patients with metastatic breast cancer."

The researchers plan to continue the study to further characterize the OS benefit.

Meanwhile, the phase III MONALEESA-3 study investigated the combination of ribociclib and fulvestrant as first-line or second-line treatment for postmenopausal patients with advanced HR-positive, HER2-negative breast cancer. Dennis Slamon, director of Clinical/Translational Research at the University of California Los Angeles, reported on OS and first-line PFS results.

Some data has suggested that CDK4 is more important in breast cancer than CDK6, Slamon noted. He also pointed to his group's MONALEESA-7 study, which was reported at the American Society for Clinical Oncology's annual meeting in Chicago this June, which showed that adding ribociclib to endocrine therapy in premenopausal women with HR-positive, HER2-negative advanced breast cancer conferred an overall survival advantage.

MONALEESA-3, meanwhile, showed that the combination of ribociclib plus fulvestrant significantly increased OS compared to fulvestrant plus placebo, with a 28 percent reduction in the relative risk of death among these breast cancer patients.

The OS benefit with the combination therapy was consistent across all subgroups, including the first-line subgroup and the early-relapse/second-line subgroup, Slamon reported. In patients receiving first-line treatment, the median PFS for the experimental arm was 33.6 months compared to 19.2 months for the control arm.

Time to progression on next-line therapy or death (referred to in the study as PFS2) was also longer with the combination therapy, with a median of 39.8 months compared to 29.4 months in the control group, suggesting that the benefit of ribociclib extended beyond the study's treatment regimen.

The combined data from MONALEESA-3 and MONALEESA-7 came from about 1,400 patients, Slamon noted, which represents the largest body of evidence of OS benefit for any CDK4/6 inhibitor.

The data demonstrates a "consistent, meaningful prolongation of survival" with ribociclib, regardless of menopausal status and line of therapy, he said. "This is a significant, practice-changing report, in that we are now saying that patients with advanced breast cancer will have an overall survival benefit if they get the CDK4/6 inhibitor ribociclib upfront at the time of their recurrence, even if they have not had any prior endocrine therapy at the time of presenting with metastatic disease."

Commenting on the new studies, Professor Nadia Harbeck of the University of Munich said the data was "highly clinically meaningful for patients," especially because clinicians sometimes struggle with whether to give patients CDK4/6 inhibitors in the first or second line of treatment. These studies set a new standard of care for treating metastatic breast cancer, she added, and these drugs should be first-line therapies in the metastatic setting.

Harbeck further noted that the MONARCH-2 and MONALEESA-3 results bode well for upcoming studies of CDK4/6 inhibitors in early breast cancer, adding that there's a possibility these drugs could be curative in that setting.