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.

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.

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William M. Sikov, MD, discusses the negative outcome seen with palbociclib in the phase 3 PALOMA-2 trial, and compares this to data on other CDK4/6 inhibitors in the first-line treatment of estrogen receptor–positive, HER2-negative breast cancers.

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 benefit of CDK4/6 inhibitors in the treatment of hormone receptor (HR)–positive/HER2-negative breast cancers.

Hormones, such as estrogen, stimulate the growth of HR-positive/HER2-negative breast cancer, and these hormones activate genes that lead to increased cell proliferation, Sikov explains. Cyclin D1 is a consistent hallmark of cell proliferation, working with the CDK4/6 to phosphorylate the retinoblastoma (Rb) protein, leading to the release of the E2F transcription factor, which aids in the ability of cancer cells to continue to grow and divide, Sikov notes.

Treatment with endocrine therapy causes cyclin D1 levels to fall when patients; however, if patient still develop to an endocrine therapy, cyclin D1 levels will rise, leading to cancer cells to growing and dividing. This is where CDK4/6 inhibitors can be beneficial, Sikov says. By binding to CDK4/6, these inhibitors prevent the uptake of cyclin D1 and the phosphorylation of Rb protein. When the Rb protein is not phosphorylated, it will bind to E2F and prevent the cell from going through a cell cycle, Sikov expands.

This mechanism of action of CDK4/6 inhibitors has been shown to enhance and extend the effectiveness of anti-hormone therapies to potentially delay the development of resistance to endocrine therapy, Sikov explains. The use of these agents in the HR-positive/HER2-negative breast cancer space has led to improvements in progression-free survival, and in some settings, improvements in overall survival, Sikov adds. By delaying the onset of resistance to endocrine therapy, CDK4/6 inhibitors can also delay the need for patients to switch from endocrine therapy to a more toxic treatments, such as chemotherapy, Sikov concludes.

William M. Sikov, MD, discusses the benefit of CDK4/6 inhibitors in the treatment of hormone receptor–positive/HER2-negative breast cancers.

William M. Sikov, MD

Articles

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

Dr Sikov on the Benefit of CDK4/6 Inhibitors in HR+/HER2-Negative Breast Cancer