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Expert Discusses Emerging Agents in ER+ Metastatic Breast Cancer

Andrew J. Roth
Published: Wednesday, Mar 23, 2016

Joyce A. O’Shaughnessy, MD

Joyce A. O’Shaughnessy, MD

As the management of patients with estrogen receptor (ER)–positive metastatic breast cancer continues to evolve, Joyce O’Shaughnessy, MD, provides an update on existing research and a look toward the future.

In an interview with OncLive, O’Shaughnessy, the co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center in Dallas and for The US Oncology Network, highlights four agents: palbociclib (Ibrance), pembrolizumab (Keytruda), abemaciclib (LY2835219), and buparlisib (BKM120). This group of agents is worth examining, O’Shaughnessy says, because it encompasses entirely new ideas and new options for patients as well as novel avenues from follow-up data from clinical trials.


In February 2015, the CDK 4/6-inhibitor palbociclib was approved by the FDA in combination with letrozole for the treatment of postmenopausal women with ER-positive, human epidermal growth factor receptor 2 (HER2)- negative advanced breast cancer as initial therapy for metastatic disease.

The approval for the combination of letrozole and palbociclib was based on a 10-month benefit in progression- free survival (20.2 months with the combination compared with 10.2 months with letrozole alone) in the phase II PALOMA-1 trial. Data also showed a reduction in the risk of disease progression by 51% with the addition of palbociclib. Palbociclib has already changed practice, according to O’Shaughnessy, and should be used by all breast cancer physicians in its approved setting.

The agent also received a priority review designation in December 2015 in combination with fulvestrant for pretreated patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. Based on findings from the phase III PALOMA-3 trial, the combination doubled progression-free survival (PFS) and delayed disease progression by over 5 months compared with fulvestrant alone. These data were presented at the 2015 at the 2015 ASCO Annual Meeting and published in The New England Journal of Medicine.1,2

O’Shaughnessy sees palbociclib as the standard of care now in the frontline setting, but says that another CDK4/6 inhibitor, abemaciclib, could make its way into later lines of therapy.


In early October 2015, abemaciclib received a breakthrough therapy designation from the FDA as monotherapy for heavily pretreated patients with refractory hormone- receptor (HR)-positive advanced breast cancer. The designation was granted based on data from the phase I JPBA trial, which included 36 patients with HR-positive disease. In the single-arm trial, abemaciclib elicited an objective response rate of 33.3%. The clinical benefit rate with abemaciclib was 61.1% when including those with stable disease for ≥24 weeks. O’Shaughnessy says she is eagerly anticipating the release of updated data from MONARCH-1, which she says could change practice. “It’s possible that abemaciclib could be available by the end of the year if the data are good,” O’Shaughnessy said. “I don’t know if they’ll meet FDA requirements or not.”

With regard to the advanced setting of metastatic disease, O’Shaughnessy also plans to highlight the potential for immunotherapy — a class of drugs that received a lot of attention in 2015.


Most of the research done to date with the PD-1 inhibitor pembrolizumab in breast cancer has been in the setting of triple-negative disease. Most immunotherapies have been eliciting response rates around 20% in breast cancer, O’Shaughnessy said, but it’s still somewhat unknown how long these responses will last. In the phase Ib KEYNOTE- 028 trial presented at the 2015 San Antonio Breast Cancer Symposium (SABCS), pembrolizumab elicited an overall response rate of 12% in PD-L1–positive patients with ER+/HER2- advanced breast cancer.3 Data from the KEYNOTE-012 trial, conversely, showed that pembrolizumab had an ORR of 18.5% in patients with PD-L1–positive TNBC.4

In order to improve response rates with pembrolizumab and immunotherapies as a whole in breast cancer, O’Shaughnessy said, more research needs to be done in the area of patient selection. “We’re going to need a better way to select patients, I think, than PD-L1,” she said. “One of the leading hypotheses is that cancers with heavier mutational loads may benefit and so, we may need to explore that particular hypothesis in breast cancer.”

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Community Practice Connections™: How Do We Leverage PARP Inhibition Strategies in the Contemporary Treatment of Breast Cancer?May 31, 20191.5
Community Practice Connections™: A Better Way to Stop Pain: Paths Toward Responsible Postsurgical Pain Management for Patients With Breast CancerMay 31, 20191.5
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