Dr Sikov on the Use of CDK4/6 Inhibitors in the First-line Treatment of ER+/HER2- Breast Cancer

William M. Sikov, MD, medical oncologist, Women and Infants Hospital of Rhode Island, member, Lifespan Educational Advisory Committee, Lifespan Cancer Institute, discusses the negative outcome seen with palbociclib (Ibrance) in the phase 3 PALOMA-2 trial (NCT01740427), and compares this to data with other CDK4/6 inhibitors in the first-line treatment of patients with estrogen receptor (ER)–positive, HER2-negative breast cancers.

The PALOMA-2 trial investigated the use of palbociclib in combination with letrazole vs letrozole plus placebo in postmenopausal women with ER-positive, HER2-negative advanced breast cancer. Although this study did demonstrate a progression-free survival (PFS) benefit with the combination, it did not meet its primary end point of overall survival (OS), Sikov reports. Discussion surrounding this negative result is ongoing, and several potential explanations have been proposed, Sikov says. For example, treatment with palbociclib may introduce a less responsive subclone, making the disease less responsive to treatment after a patient has experienced progression, Sikov postulates.

Conversely, the phase 3 MONALEESA-2 (NCT01958021) and MONALEESA-3 (NCT02422615) trials evaluating ribociclib (Kisqali) resulted in a confirmed benefit of both PFS and OS with the addition of this CDK4/6 inhibitor to first-line ovarian function suppression, Sikov continues. The phase 3 MONALEESA-7 trial (NCT02278120 ) investigating ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer showed a similar magnitude of survival benefit carry-over from the initial improvement in median PFS, he adds.

Regarding survival benefit with first-line abemaciclib (Verzenio), interim findings from the phase 3 MONARCH-3 trial (NCT03155997) of abemaciclib plus fulvestrant (Faslodex) show an increase in the median OS by 12.6 months compared with placebo, Sikov says. Despite this positive trend, statistical significance was not reached at the time of interim analysis, and OS data from MONARCH-3 have yet to mature, Sikov explains. Therefore, the comparative benefit of abemaciclib in this space cannot yet be definitively stated, Sikov concludes.

Editor's Note: Dr Sikov reports serving on a speaker’s bureau and receiving honoraria from Seagen, Daiichi Sankyo, AstraZeneca, Lilly Oncology; he received royalty payments from UpToDate.