Yelena Novik, MD
FDA approvals of the 3 novel CDK4/6 inhibitors– palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) have given oncologists a tool in their armamentarium against metastatic estrogen receptor (ER)-positive breast cancer, according to Yelena Novik, MD.
The agents have demonstrated efficacy in combination with endocrine therapy or an aromatase inhibitor (AI) in the first-line setting for patients with metastatic and advanced disease in studies such as PALOMA-2, MONALEESA-3, and MONARCH 2.
Updated findings from the PALOMA-2 study showed the superiority in median progression-free survival (PFS) with frontline palbociclib and letrozole in patients with metastatic ER-positive disease compared with placebo (24.8 vs 14.5 months; HR, 0.58; 95% CI, 0.46-0.72; P
Additionally, women with advanced hormone receptor (HR)-positive breast cancer experienced a 41% reduction in the risk of disease progression (P
= .00000041) when ribociclib was added to fulvestrant (Faslodex) in the first- or second-line setting. The combination led to an improved median PFS of 20.5 months versus 12.8 months with placebo in the phase III MONALEESA-3 trial.2
Data from the phase III MONARCH 2 trial showed that the addition of abemaciclib to fulvestrant versus fulvestrant alone led to an improvement in median PFS of 7.1 months in pretreated patients with advanced HR-positive/HER2-negative disease (HR, 0.553; 95% CI, 0.449-0.681; P
More recently, the combination plus a GnRH agonist was found to improve PFS and overall response rates in a subgroup analysis in both pre- and perimenopausal women with HR-positive advanced breast cancer.4
Abemaciclib is also approved in the frontline setting in combination with an aromatase inhibitor for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.
Additionally, Novik said, ongoing adjuvant trials could even further enhance the impact of CDK4/6 inhibitors in breast cancer.
In an interview during the 2018 OncLive®
State of the Science Summit™ on Breast Cancer, Novik, associate professor, NYU Langone’s Perlmutter Cancer Center, discussed the application of CDK4/6 inhibition and methods to overcome resistance in ER-positive breast cancer.
OncLive: Please provide an overview of your presentation.
: We discussed overcoming hormone resistance in the treatment of [patients with] advanced and metastatic breast cancer. Over the last few years, we've been lucky to have access to new targeted agents of cell-cycle inhibitors. Currently, we have 3 FDA-approved agents–palbociclib, ribociclib, and abemaciclib. They have been shown in randomized controlled studies to be superior to hormonal agents in improving PFS, as well as responses in women with advanced breast cancer.
I discussed the PALOMA, MONALEESA, and MONARCH randomized studies. PALOMA-2 compared palbociclib versus placebo in combination with letrozole. MONALEESA-3 combined ribociclib versus placebo. MONARCH 2 examined abemaciclib versus placebo in both the first-line and second-line treatment of metastatic breast cancer with fulvestrant. These drugs work through the D1 cycle mechanism to significantly improve PFS in advanced breast cancer. We are very lucky to be able to offer these options to our patients.
What is the impact of the MONALEESA-7 trial?
Most of the trials in advanced breast cancer specifically target women who are menopausal or postmenopausal. It's much more difficult to conduct trials that specifically target premenopausal women. The MONALEESA-7 trial was directed to premenopausal women.
Premenopausal women were randomized to receive either hormonal therapy alone–which is ovarian suppression and either tamoxifen or an AI–or the combination of hormonal therapy and ribociclib. The women were followed for a number of years and followed for PFS as well as overall responses. Not surprisingly, the PFS was significantly superior in the combination group with ribociclib compared with standard therapy.
Are there any preemptive means of overcoming resistance?
Now that we have the FDA approval of those first-line therapies, we can offer them to women at the first presentation of metastatic disease. However, a patient who presents with advanced cancer may already have resistance. We are also studying these agents in adjuvant trials, so we may be able to potentially increase the time before metastatic disease can develop.