In a March 2017 press release, the pharmaceutical company Lilly Oncology announced results of its phase III MONARCH 2 trial. The final study results have now been published in the Journal of Clinical Oncology.

The study found that abemaciclib plus the hormonal therapy medicine fulvestrant (Faslodex) worked better than fulvestrant plus a placebo. This article was originally published in April and reviewed by Shannon Puhalla, MD; it has been updated with information from the full published study and the recent application for FDA approval.

Background

Abemaciclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor. Cyclin-dependent kinases 4 and 6 are two proteins that cause tumor cells in some breast cancers to grow. CDK 4/6 inhibitors like abemaciclib work by blocking CDK 4 and 6 from telling cancer cells to multiply. This can slow the growth or spread of cancer cells. These medicines are typically given in combination with hormonal therapies.

CDK 4/6 inhibitors are fairly new treatments. Two have been approved by the FDA to treat metastatic breast cancer when paired with hormonal therapies. Those CDK 4/6 inhibitors are

• palbociclib (Ibrance), approved in February 2016, in combination with an aromatase inhibitor or fulvestrant
• ribociclib, approved in March 2017, in combination with an aromatase inhibitor

The MONARCH 2 Trial

The MONARCH 2 trial recruited 669 women with hormone receptor-positive, HER2-negative advanced breast cancer who experienced the disease growing or spreading during or after treatment with hormonal therapy. The women were randomly chosen to be treated with fulvestrant and a placebo or fulvestrant and abemaciclib. The trial’s main goal was to see which group of women would have longer progression-free survival, the length of time during and after treatment that a person lives without the disease growing. It found progression-free survival was longer in the women who got abemaciclib.

The women taking abemaciclib and fulvestrant went a median of 16.4 months without disease progression, a statistically significant improvement over the placebo and fulvestrant group. In the placebo and fulvestrant group, participants went a median of 9.3 months without the disease getting worse.

The group taking abemaciclib also had a better overall response rate, with 48.1 percent of measurable tumors showing a response to treatment compared to 21.3 percent in the placebo group.                                                                        

In the abemaciclib group diarrhea was the most common side effect, with 86.4 percent of women experiencing it. Most cases were minor and usually happened during the first cycle of treatment, but 13.4 percent had more serious cases of diarrhea. A total of 2.9 percent of women stopped taking abemaciclib because of this side effect.

Despite some women needing to stop the treatment, the researchers say diarrhea was controlled well with antidiarrheal medicines and dose changes in most people. Diarrhea and other side effects were less severe after researchers decided to lower the dose of abemaciclib for everyone in the treatment group from a 200 milligram pill taken twice a day to a 150 milligram pill taken twice a day.

Other common side effects of abemaciclib, including neutropenia, nausea and fatigue, appeared at the same rates seen in treatment with other CDK 4/6 inhibitors, but more often than in women taking placebo.

There was also a phase II MONARCH 1 trial that looked at the effect of abemaciclib alone in 132 women with hormone receptor-positive, HER2-negative metastatic breast cancer that grew or spread after multiple treatments, including hormonal therapy and at least one regimen of chemotherapy. Results of that study were released in 2016. The results showed tumors responded to this medicine taken alone in almost 20 percent of the women.

In July, Lilly announced that it had submitted a new drug application to the FDA for abemaciclib to be approved for use in people with hormone receptor-positive, HER2-negative metastatic breast cancer for two uses:

• As a single therapy, based on the findings of the MONARCH 1 trial
• In combination with fulvestrant, based on the findings of the MONARCH 2 trial

The FDA has given the application priority review status to move it through the review process faster. Under priority review, the agency plans to release its decision within 8 months, instead of the normal deadline of 12 months. The FDA will evaluate and approve the two proposed treatment options separately.

Abemaciclib is the subject of other current trials. MONARCH 3 is a phase III trial of abemaciclib plus aromatase inhibitors.  There is also monarcHER, a phase II trial of abemaciclib plus trastuzumab (Herceptin) with or without fulvestrant in women with hormone receptor-positive, HER2-positive advanced breast cancer. And the company recently announced the phase III monarchE study of abemaciclib with standard hormonal therapy in high-risk, early-stage breast cancer.  

What This Means for You

In just the last 18 months, two CDK 4/6 inhibitors have gained FDA approval, and a third, abemaciclib, has shown positive results in a major clinical trial. While abemaciclib is still largely only available through clinical trials, that could change soon. The results of this study show a statistically significant improvement in both how long women lived without the cancer growing and how many women with cancer responded to the treatment overall. If approved by the FDA this would give another treatment option to women with hormone receptor-positive, advanced breast cancer that has grown despite hormonal therapy. And more treatment options mean more chances at a longer life for people with metastatic breast cancer.

Talk to your doctor about CDK 4/6 inhibitors and whether this type of medicine is a good option for you.

Sledge, G; Toi, M; Neven, P; et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. Journal of Clinical Oncology. Published online before print June 3, 2017. DOI: 10.1200/JCO.2017.73.7585