CDK 4/6 Inhibitors Improve Overall Survival in 2 More Clinical Trials

Makers of the CDK 4/6 inhibitors ribociclib (Kisqali) and abemaciclib (Verzenio) announced in late July that these medicines improved overall survival for women with certain advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer in phase III clinical trials.

These announcements come less than 2 months after the first data to show a CDK 4/6 inhibitor’s lengthened overall survival were presented at the American Society of Clinical Oncology Annual Meeting in June.

Background

Ribociclib, abemaciclib, and palbociclib (Ibrance) belong to a class of targeted therapies called cyclin-dependent kinase 4/6 inhibitors. Cyclin-dependent kinases 4 and 6 are two proteins that lead to cell growth. CDK 4/6 inhibitors block these proteins and keep cancer cells from growing. CDK 4/6 inhibitors are usually prescribed with hormonal therapy, such as an aromatase inhibitor or fulvestrant (Faslodex).

CDK 4/6 inhibitors are relatively new treatment options. Palbociclib was the first medicine of this type approved by the U.S. Food and Drug Administration in February 2015 Like many medicines for advanced and metastatic breast cancers, these CDK 4/6 inhibitors were approved based on how much they improved progression-free survival, how long people went without cancer growing or spreading, compared to hormonal therapy alone. Overall survival (how long people lived after starting this treatment) takes longer to determine in trials but is also an important measure. It tells us if the medicine really leads to people living longer.

In June, updated results from the MONALEESA-7 trial were presented at the ASCO Annual Meeting. In the study, women who had not yet gone through menopause were treated with hormonal therapy, goserelin (Zoladex) to suppress the function of the ovaries, and either ribociclib or a placebo. The results presented at ASCO showed women given ribociclib lived longer than those given the placebo. This was the first study to show that adding a CDK 4/6 inhibitor to standard hormonal therapy led to longer overall survival.

In late July, pharmaceutical companies announced that two other studies found CDK 4/6 inhibitors to lengthen overall survival.

MONARCH 2 Trial — Abemaciclib

MONARCH 2 is a phase III trial that included women of any menopausal status with advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer. Participants had cancer grow during or after treatment with hormonal therapy, either for early-stage or metastatic breast cancer. They were assigned to get either

• abemaciclib with the hormonal therapy fulvestrant
• placebo with fulvestrant

The study reached its primary endpoint in 2017, showing that women given abemaciclib and fulvestrant stayed on that treatment longer without the cancer growing than those given a placebo and fulvestrant. This contributed to the FDA approval of abemaciclib later that year.

Eli Lilly and Company, the maker of abemaciclib, announced on July 30 that the results for overall survival for MONARCH 2 had been determined. The press announcement says that abemaciclib with fulvestrant showed a statistically significant improvement in overall survival compared to placebo and fulvestrant. Statistically significant means the longer survival was likely not a result of chance.

The release did not include specifics on how much longer women in the abemaciclib group lived compared to those in the standard treatment group, only that it was statistically significant.

MONALEESA-3 — Ribociclib

MONALEESA-3 is the second trial to find that adding ribociclib to treatment led to longer overall survival. The trial included 726 postmenopausal women — women who have stopped having their periods — with advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer. Participants had cancer grow during or after treatment with hormonal therapy, either for early-stage or metastatic breast cancer. They were assigned to get either

• ribociclib with fulvestrant
• placebo with fulvestrant

Initial findings from MONALEESA-3 showed that women given ribociclib with fulvestrant stayed on that treatment longer without the cancer growing than women given a placebo with fulvestrant. This led to the FDA adding this use to ribociclib’s approved uses in 2018.

Ribociclib’s maker, Novartis, announced on July 31 that updated results from MONALEESA-3 found ribociclib and fulvestrant led to postmenopausal women living longer than those getting placebo and fulvestrant. Like the abemaciclib announcement, the press release did not share specific data about the overall survival numbers, but said the results will be shared at a future medical conference.

What This Means for You

In less than 2 years, three CDK 4/6 inhibitors were approved by the FDA and quickly brought into standard care for women with metastatic hormone receptor-positive breast cancer. These medicines produced exciting results that led to FDA approvals. Staying on a treatment longer without cancer growing is a good sign that you will live longer thanks to this treatment, which is why the FDA approves medicines based on those results. But trials are expected to eventually confirm that treatments lengthen overall survival.

These results are not likely to change your treatment options. Ribociclib and abemaciclib have already been approved for this use and are used in practice. The overall survival results confirm the value of adding these medicines to treatment:  they not only keep you on one treatment longer, but their use also results in more people living longer. There is still more to learn when the data is released to the public, but if you have been given one of these medicine, or are being given them now, you may be pleased to know that the long-term effects seem to line up with the benefits doctors have already seen in earlier research and clinical practice.