Novel Agents Improve Outcomes in HR+ Breast Cancer

William J. Gradishar, MD

Adding CDK4/6 and mTOR inhibitors to standard endocrine therapy has significantly improved outcomes in patients with hormone receptor (HR)—positive, HER2-negative advanced breast cancer, William J, Gradishar, MD, explained in a presentation at the 34th Annual Miami Breast Cancer Conference.

Palbociclib (Ibrance), ribociclib, and abemaciclib are the 3 key CDK4/6 agents that have emerged. The FDA granted an accelerated approval in February 2015 to palbociclib as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, based on findings from the phase II PALOMA-1 trial. In the open-label phase II study, treatment with the novel CDK4/6-inhibitor palbociclib plus letrozole reduced the risk of disease progression by 51% compared with letrozole alone. The median progression-free survival (PFS) with palbociclib was 20.2 versus 10.2 months for letrozole alone.

These data were confirmed in the follow-up phase III PALOMA-2 study, in which adding palbociclib to letrozole reduced the risk of disease progression by 42% compared with letrozole alone. The median PFS was improved by more than 10 months with the addition of palbociclib. Based on the PALOMA-2 data, an application has been submitted to the FDA to convert the accelerated approval of palbociclib into a full approval, with a final decision expected by the end of April 2017.

The CDK4/6 inhibitor ribociclib was granted a priority review from the FDA in November 2016 for use in combination with letrozole as a frontline therapy for patients with HR-positive, HER2-negative advanced breast cancer. The application for ribociclib is primarily based on findings from the phase III MONALEESA-2 trial, in which combining ribociclib with letrozole reduced the risk of progression or death by 44% compared with letrozole alone in the first-line setting for HR+/HER2- advanced breast cancer. As with palbociclib’s full approval application, the FDA is scheduled to make its final decision on ribociclib by the end of April 2017.

The third key agent in the CDK4/6 class, abemaciclib, demonstrated potential as a single agent in heavily pretreated patients with refractory, HR-positive, HER2-negative advanced breast cancer in the phase II the MONARCH 1 trial. Results of the single-arm trial presented at the 2016 ASCO Annual Meeting showed that abemaciclib induced a response rate of nearly 20% in this patient population. The ongoing MONARCH 2 trial is assessing abemaciclib plus fulvestrant or fulvestrant alone in patients with HR-positive, HER2-negative advanced breast cancer.

With several options emerging, Gradishar predicts “CDK4/6 wars” for supremacy in the space will emerge. Key questions that remain, according to Gradishar, include, “How will we be using these CDK4/6 inhibitors in sequence and what will the optimal sequence be for targeted therapies and endocrine therapies?”

The efficacy of mTOR inhibition in the HR-positive space was definitively established in the phase III BOLERO-2 trial, which led to the FDA approval of the mTOR inhibitor everolimus for use in combination with exemestane after the failure of treatment with letrozole or anastrozole.

The other area of “intense interest” with targeted agents in HR+ breast cancer is PI3 kinase inhibitors; however, according to Gradishar, “We have some signals that are positive for preoperative studies, some in the metastatic setting, but, thus far, there hasn’t been a home run with respect to PI3 kinase inhibitors.”

Going forward, Gradishar said that in addition to optimizing use of these doublet regimens, it is also critical to use biomarkers and other tools of precision medicine to identify those patients who can be exceptional responders with endocrine therapy alone. Avoiding doublet regimens can reduce toxicities and other complications for these patients.

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