August 20, 2018, by NCI Staff

A breast cancer cell undergoing cell division.

Credit: National Cancer Institute

The Food and Drug Administration (FDA) has expanded the approval for ribociclib (Kisqali) for some women with advanced breast cancer.

Under the July 18 approval, ribociclib can now be used in combination with some types of hormone therapy for the treatment of advanced hormone receptor–positive (HR+), HER2-negative (HER2-) cancer in women who haven’t yet reached menopause. Most breast cancers are HR+ and HER2-.

FDA also expanded ribociclib’s approval for use in postmenopausal women with this type of advanced breast cancer. Previously, it had been approved for use in combination with a type of hormone therapy called an aromatase inhibitor. With the expanded approval, ribociclib can now also be used with fulvestrant (Faslodex), a different type of hormone therapy.

The approval for premenopausal and perimenopausal women was based on results from a randomized clinical trial called MONALEESA-7. The expanded approval for postmenopausal women was based on results of a related trial, called MONALEESA-3. Both trials were sponsored by Novartis, the maker of ribociclib.

The new approvals for ribociclib were the first granted through a new FDA pilot program launched earlier this year called Real-Time Oncology Review. The program allows FDA to begin reviewing a drug after results from trials are first available but before a company has officially submitted an approval application.

Under the pilot program, the expanded approval of ribociclib was granted less than a month after Novartis filed its formal approval application, FDA Commissioner Scott Gottlieb, M.D., explained in a statement.

Slowing Disease Progression

Ribociclib works by inhibiting molecules called CDK4 and CDK6 that help control cell division. These enzymes are commonly activated by a variety of molecular mechanisms in breast cancer cells. Other FDA-approved CDK4/6 inhibitors include palbociclib (Ibrance) and abemaciclib (Verzenio).

MONALEESA-7 enrolled 672 pre- and perimenopausal women with recurrent or metastatic breast cancer. Women who had previously received hormone therapy for early-stage breast cancer, but not for advanced disease, could enroll in MONALEESA-7. Women who had received a single course of chemotherapy for advanced disease were also eligible to participate.

The researchers randomly assigned participants to receive ribociclib plus hormone therapy or a placebo plus hormone therapy. The type of hormone therapy used was based on factors such as patient and doctor preference and previous treatments, and it could be letrozole (Femara), anastrozole (Arimidex), or tamoxifen. All participants also received a monthly injection of goserelin (Zoladex), which suppresses hormone production in premenopausal women and allows hormone therapy to work better. Goserelin is usually given with standard hormone therapy for premenopausal women with breast cancer.

Women who received ribociclib plus hormone therapy lived longer without their disease progressing (progression-free survival) than women who received placebo plus hormone therapy: a median of 24 months compared with 13 months. The improvement in progression-free survival in women treated with ribociclib was about the same regardless of what type of hormone therapy was used.

Earlier trials of other CDK4/6 inhibitors had included some premenopausal women but weren’t exclusively designed for them, explained Jairam Krishnamurthy, M.D., from the University of Nebraska Medical Center, who was not involved in MONALEESA-7.

Based on results from the earlier trials, many doctors were already using CDK4/6 inhibitors in premenopausal women (with ovarian suppression), said Dr. Krishnamurthy. “MONALEESA-7 is a confirmation for that [practice],” he added.

A similar relative improvement in progression-free survival was seen in the MONALEESA-3 trial, which tested the combination of ribociclib and fulvestrant in postmenopausal women with advanced or metastatic disease.

In MONALEESA-7, more cases of a potentially dangerous change in the heart’s electrical conduction (called QT interval prolongation) were seen in women who received tamoxifen, even without ribociclib, than in women who received the other forms of hormone therapy, explained Debu Tripathy, M.D., of the University of Texas MD Anderson Cancer Center, who led the trial. As a precaution the new approval does not include the use of ribociclib in combination with tamoxifen, he added.

Some of the most common side effect seen in women in both trials included a drop in the number of white blood cells, infection, fatigue, and nausea. Quality of life remained higher for longer in the ribociclib group.

What Therapy for Which Patients?

Follow-up for both trials is still ongoing, to see if a difference in overall survival emerges over time.

“Typically, in HR+, HER2- disease, it has been difficult to show an overall survival advantage because these patients have so many other lines of therapy available” if their disease progresses, explained Dr. Krishnamurthy. “[Improved] overall survival is something that’s been kind of the holy grail” in advanced breast cancer, he added.

In both trials, patients’ quality of life remained high during treatment. This is important for advanced cancer, said Dr. Krishnamurthy.

“A common misconception among patients [with advanced disease] and their families is they feel that we should administer chemotherapy, because we have to be ‘aggressive.’

“On the contrary, for HR+, HER2- disease, you have to target the estrogen receptor,” for as long as possible, he added. This strategy has the potential to be both more effective and produce fewer side effects than chemotherapy, he explained.

Two trials in progress (PEARL and PASIPHAE) are testing whether giving a CDK4/6 inhibitor and hormone therapy instead of chemotherapy as an initial, or first-line, treatment for women with metastatic breast cancer improves progression-free survival.

Other questions about the best way to use CDK4/6 inhibitors remain to be answered. For instance, further studies are needed to understand which patients with advanced or metastatic breast cancer may do just as well with a hormone therapy alone and which patients have tumors that are resistant to CDK4/6 inhibition, explained Dr. Tripathy. Neither of these groups would benefit from a combination of CDK4/6 inhibitors and hormone therapy.

And for tumors that are resistant to CDK4/6 inhibitors, more research is needed to tease out “what the mechanisms of resistance are and how we can use this information—not only to make better choices for our patients, but also to discover newer drugs that might reverse resistance or perform better in these patients,” Dr. Tripathy said.

But “clinicians should at least discuss the possibility of adding a CDK4/6 inhibitor with everybody who’s getting first-line or second-line hormone therapy [for advanced disease],” he concluded. “Because, for most patients, CDK4/6 inhibitors appear to be of benefit in terms of delaying progression. . .and may also delay the time that they need to go on more aggressive treatment, like chemotherapy.”