The combination of antiestrogen therapy and ribociclib, an investigational CDK4/6 inhibitor, led to improved outcomes in women with metastatic HR-positive, HER2-negative breast cancer, according to findings presented at a meeting of the European Society for Medical Oncology. The combination significantly increased progression-free survival compared with letrozole alone in a large phase III trial—data that could lead to FDA approval.

The combination of antiestrogen therapy and ribociclib (Novartis), an investigational CDK4/6 inhibitor, prolonged progression-free survival (PFS) in women with metastatic HR-positive HER2-negative breast cancer, according to findings presented at the European Society for Medical Oncology's 2016 Congress in Copenhagen, Denmark. Data from the large phase III trial, which were published concurrently in The New England Journal of Medicine, may lead to FDA approval of the second CDK4/6 inhibitor for this disease (N Engl J Med 2016;375:1738–48).

A planned interim analysis of the MONALEESA-2 trial, which included almost 700 postmenopausal women, found that first-line therapy with ribociclib in addition to the aromatase inhibitor letrozole significantly improved outcomes. After 18 months of treatment, median PFS was not reached in the ribociclib arm compared with 14.7 months in the control group—a 44% improvement.

“The majority of patients treated with ribociclib completed therapy and received significant benefit,” notes the study's lead investigator Gabriel Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center in Houston. “We are now trying to identify markers of response because we don't yet know why these drugs work better in some patients than others.”

Researchers are also exploring whether ribociclib may be effective in second- or third-line settings or in combination with inhibitors of other signaling pathways involved in breast cancer, adds Hortobagyi.

Ribociclib, which has been submitted for FDA approval, is one of three CDK4/6 inhibitors either approved or being tested in combination with antiestrogen therapy for advanced HR-positive, HER2-negative breast cancer. Palbociclib (Ibrance; Pfizer) received FDA approval last year and abemaciclib (Eli Lilly) is in early clinical trials.

Identification of biomarkers is critical, considering that CDK4/6 inhibitors are known to cause significant side effects, notes V.K. Gadi, MD, PhD, of the University of Washington and a clinical researcher at Fred Hutchinson Cancer Research Center in Seattle. In the MONALEESA-2 trial, neutropenia and leukopenia were far more common in the intervention versus the control group (59.3% vs. 0.9% and 21.0% vs. 0.6%, respectively). However, severe (grade 4) neutropenia was relatively uncommon (9.6% vs. 0%) and could be managed with dose interruptions or reductions.

Although ribociclib appears to have a similar toxicity profile to palbociclib, abemaciclib may be less toxic than either drug, notes Gadi. For example, a recent phase I study found that single-agent abemaciclib triggered neutropenia in just 9% of 173 patients with breast cancer, non–small cell lung cancer, and other solid tumors (Cancer Discov 2016;6:740–53).

“The high rate of neutropenia seen with ribociclib and palbociclib makes treating these patients very challenging,” he says. “What we really need is a good marker of response so we can decide who actually needs this therapy and who could be spared the toxicity.” –Janet Colwell

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©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.