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CDK4/6 Inhibitor Boosts Overall Survival in Advanced, Premenopausal Breast Cancer Subgroup


CHICAGO (Precision Oncology News) – Members of an international team have identified an overall survival advantage associated with adding the CDK4/6 inhibitor ribociclib (Kisqali from Novartis) to endocrine therapy in premenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer, according to clinical trial data presented at the American Society for Clinical Oncology annual meeting here this weekend.

Sarah Hurvitz, a medicine, hematology, oncology, and internal medicine specialist at the UCLA Jonsson Comprehensive Cancer Center shared results from a phase III MONALEESA-7 trial during a press briefing on Saturday.

That trial included 672 pre- or peri-menopausal women younger than 60 with advanced HR-positive, HER2-negative breast cancer who were randomized to receive a non-steroidal aromatase inhibitor (NSAI) or tamoxifen in combination with ribociclib or the NSAI or tamoxifen alone. All of the patients received goserelin (marketed as Zoladex by TerSera Therapeutics) to turn off ovarian estrogen production.

Patients were not eligible for the trial if they had received endocrine therapy for advanced breast cancer in the past. Women who had already received one line of chemotherapy for metastasis could enroll, though Hurvitz noted that that was the case for just 15 percent or so of patients.

After nearly 35 months of follow up, on average, the investigators saw a statistically significant surge in overall survival in the group that had the CDK4/6 inhibitor added to their treatment — marking the first time that a CDK4/6 inhibitor had shown this sort of overall survival effect in younger advanced hormone receptor-positive, HER2-negative patients.

She and her colleagues reported 83 deaths in the 335 cases treated with ribociclib and endocrine therapy, compared with 109 deaths in the group of 337 patients who received the endocrine therapy and placebo.

"We demonstrated an approximately 29 percent relative reduction in the risk of death with this treatment, ribociclib," Hurvitz said.

Nearly one-third of the ribociclib-treated patients remained on treatment at the data cutoff time. The team's Kaplan-Meier estimate put the 42-month survival just beyond 70 percent in the ribociclib and endocrine therapy arm versus 46 percent in the arm that received endocrine therapy and placebo.

When investigators focused in on patient subgroups who received either NSAI or tamoxifen in conjunction with ribociclib, meanwhile, they found that the results for both groups were similar to those reported across the full ribociclib-treated population.

Even so, most patients opted to get NSAI, rather than tamoxifen, in combination with the ribociclib, Hurvitz said, noting that tamoxifen is no longer given in conjunction with ribociclib due to prolonged QT interval complications reported after the MONALEESA-7 trial closed, which showed that the combination therapy could place patients at increased arrhythmia risk.

Ribociclib was initially approved for treating advanced HR-positive, HER2-negative breast cancers in combination with fulvestrant (AstraZeneca's Faslodex) in post-menopausal patients initially or after the disease has already progressed.

"There are three drugs on the market that all inhibit CDK4/6 and they have slight differences in toxicities, but they are all equally effective in the post-menopausal situation, with hormonal therapies of various sorts," noted Larry Norton, senior vice president of Memorial Sloan Kettering Cancer Center's Office of the President and medical director of the Evelyn H. Lauder Breast Center, who was not involved in the MONALEESA-7 trial.

The US Food and Drug Administration expanded its approval of ribociclib last July, based on the MONALEESA-7 trial's primary endpoint of progression-free survival, which was reported in The Lancet Oncology that month. The CDK4/6 inhibitor can now be used in pre- and perimenopausal women with HR-positive, HER2-negative breast when combined with aromatase inhibitor.

The latest findings may bolster the use of the CDK4/6 inhibitor in a larger population of breast cancer patients, Hurvitz suggested, not only because a significant proportion of breast cancers are fueled by estrogen, but also because around on-fifth of breast cancers are diagnosed in women under 50 years old.

"Compared with older women, younger women with breast cancer tend to have poorer prognoses and more aggressive behaving disease biology, even when it's hormone receptor-positive," she told reporters. "Yet, premenopausal patients are underrepresented in clinical trials."

Commenting on the presentation, ASCO-designated expert Harold Burstein, a medical oncologist affiliated with the Dana-Farber Cancer Institute, Harvard Cancer Center, and Brigham and Women's Hospital, said that the study "shows that a class of drugs — the CDK4/6 inhibitors — which we are widely using and have been shown to delay the time to treatment progression and delay the time to chemotherapy for advanced breast cancer … now also translates into a significant survival benefit for women who have [estrogen receptor] metastatic breast cancer."

Burstein added that "this is the largest study in recent memory that has focused exclusively on premenopausal women and shows that they, too, benefit from this class of drugs."

In advance of the presentation, MSK's Norton said that "superficially it seems like a really major advance, and I think the odds are that it is."

Still, he cautioned that there are outstanding questions to address, including the issue of whether the effect might be specific to ribociclib, or whether it carries over to the other CDK4/6 inhibitors.

"For hormone receptor-positive patients that are HER2-negative, in general, we now have an abundance of therapies that potentially can help them," Norton added, citing the three CDK4/6 inhibitors, the mTOR inhibitor Afinitor, and a PI3-kinase inhibitor that was recently approved in women with PIK3CA-mutant breast cancer.

But, those successes bring questions, he said. "We've got a lot of data showing the efficacy of each individual [treatment], but we don't necessarily have the data comparing them, we don't have the data showing the right sequence."

An oral presentation of the MONALEESA-7 premenopausal ribociclib trial data is scheduled for a session on metastatic breast cancer at ASCO on Tuesday.