Matthew Ellis, MD, PhD
Endocrine therapy has long been a staple for treatment of patients with hormone receptor (HR)–positive breast cancer; however, most patients will develop acquired resistance or harbor intrinsic resistance to the treatment, said Matthew J. Ellis, MD, PhD.
Nevertheless, CDK4/6 inhibitors have been an impactful addition to this landscape over the past few years.
In September 2017, abemaciclib (Verzenio) became the third CDK4/6 inhibitor to be FDA approved for the treatment of patients with HR-positive, HER2-negative breast cancer following endocrine therapy. The indication was expanded to the frontline setting in February 2018; the decision was based on data from the phase III MONARCH 3 trial. In the study, the addition of abemaciclib to anastrozole or letrozole decreased the risk of progression or death by 46% compared with a nonsteroidal aromatase inhibitor (AI) alone.1
In March 2017, the FDA approved frontline ribociclib (Kisqali), another CDK4/6 inhibitor, in combination with an AI for patients with HR-positive, HER2-negative advanced or metastatic breast cancer. The indication was expanded in July 2018 for use in combination with an AI for the treatment of pre-, perimenopausal, or postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer. The FDA also approved ribociclib for use in combination with fulvestrant for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy.
The expanded approvals for ribociclib in combination with an AI and fulvestrant were announced following the results of the phase III MONALEESA-7 and MONALEESA-3 trials, respectively. The combination of ribociclib and an AI induced a 14-month improvement in median progression-free survival (PFS) versus AI monotherapy (27.5 vs 13.8 months; HR, 0.569; 95% CI, 0.436- 0.743).2
The median PFS with ribociclib and fulvestrant versus fulvestrant and placebo was 20.5 months and 12.8 months, respectively (HR, 0.593; 95% CI, 0.480-0.732; P
In 2017, palbociclib (Ibrance) received FDA approval in combination with letrozole as a frontline treatment for postmenopausal women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. The approval followed the results of the phase III PALOMA-2 trial, which demonstrated a 42% reduction in the risk of disease progression compared with letrozole alone and a 10-month improvement in median PFS.4
In an interview during the 2018 OncLive®
State of the Science Summit™ on Breast Cancer, Ellis, professor and director, Lester and Sue Smith Breast Center; associate director of Precision Medicine, Dan L. Duncan Comprehensive Cancer Center; and professor of medicine and cellular and molecular biology, Baylor College of Medicine, explained that although these agents have shown strong signals of activity, demonstrating efficacy is merely the first aspect in overcoming resistance to endocrine therapy in patients with HR-positive breast cancer.
OncLive: How have CDK4/6 inhibitors impacted the landscape of HR-positive metastatic breast cancer?
The landscape of endocrine therapy for advanced disease has been a settled question for a long period of time. Major forms of therapy have been anti-estrogens and estrogen deprivation therapy. These drugs have relatively low toxicity. Patients do well on them for various periods of time, but resistance is the problem. Except in rare circumstances, most patients will meet an endocrine therapy resistance “wall” in their treatment between the first few months on therapy when it doesn’t work at all to progression—that could be 3 to 5 years down the line.
When we think about resistance, we think about it in 2 broad phases—intrinsic resistance and acquired resistance. We have been studying the molecular biology of acquired resistance to endocrine therapy for some time, and it’s clear that recurring events within ER itself are a cause of acquired resistance. As many as 30% to 40% of patients who become resistant to AIs and tamoxifen have mutations in ER that cause ligand independent activity. We have recently discovered another recoding event in the ER involving ER translocations. [These translocations] are really interesting. When those events occur, all endocrine therapies are off the table because there’s no drug-binding domain. It’s replaced with a chunk of coding sequence from another gene.
Interestingly, experimental systems and patients who have ER mutations or fusions can respond to CDK4/6 inhibitors. These drugs block the cell cycle downstream of the ER. Even if the ER is constitutive or translocated, CDK4/6 inhibitors can block proliferation.