Abemaciclib Data Show Benefit Across Breast Cancer Subgroups

Gina Columbus

Maura Dickler, MD

Maura Dickler, MD

A handful of abstracts involving the CDK4/6 inhibitor abemaciclib (Verzenio) presented at the 2018 ASCO Annual Meeting demonstrated the agent’s efficacy and impact on quality of life (QOL) across subpopulations of patients with hormone receptor (HR)–positive, HER2-negative breast cancer.

The FDA approved abemaciclib in February 2018 as a frontline therapy in combination with a nonsteroidal aromatase inhibitor for postmenopausal patients with HR-positive, HER2-negative breast cancer. The approval was based on data from the phase III MONARCH 3 trial, which also showed that the CDK4/6 inhibitor improved outcomes in patients with concerning clinical characteristics, including visceral metastases.1

Abemaciclib was initially approved in September 2017 for use in combination with fulvestrant (Faslodex) to treat patients with advanced disease that has progressed on endocrine therapy, as well as for single-agent use for patients with HR+/HER2- breast cancer with metastatic disease who have previously received endocrine therapy and chemotherapy.

A subgroup analysis of the MONARCH 2 study presented at the 2018 ASCO Annual Meeting showed that the combination of abemaciclib and fulvestrant plus a GnRH agonist was found to improve progression-free survival (PFS) and overall response rates (ORRs) in both pre- and perimenopausal women with HR-positive, HER2-negative advanced breast cancer.2 The median PFS was not reached for the abemaciclib/fulvestrant arm and was 10.5 months for the placebo with fulvestrant arm (HR, 0.446; 95% CI, 0.264-0.754; P = .002). In those with measurable disease, the ORR was higher in the abemaciclib arm versus placebo at 60.8% versus 28.6%.

A second analysis from the MONARCH 2 trial presented at the 2018 ASCO Annual Meeting, evaluated the health-related QOL in those who received abemaciclib plus fulvestrant following progression on endocrine therapy.3 Findings showed that while there were higher rates of gastrointestinal-related adverse events in early visits, there was no statistically significant decline in patient-reported global health or symptoms versus fulvestrant/placebo.

Moreover, an analysis of dose-reduction strategies in the MONARCH 1, MONARCH 2, and MONARCH 3 studies demonstrated that there was no difference in PFS for patients who required dose reductions with abemaciclib due to diarrhea or neutropenia versus those who did not.4 Additionally, efficacy was still observed in patients regardless of whether they experienced events of neutropenia or diarrhea early in treatment.

Overall, CDK4/6 inhibitors have created “a tremendous advance in the first- and second-line settings,” said Maura Dickler, MD, adding, “we have not seen improvements in PFS as we have with this class of drugs.”

In an interview with OncLive during ASCO, Dickler, vice president, Late Phase Oncology Development, Eli Lilly and Company expanded on the findings with abemaciclib presented at this year’s meeting and what some of the next steps are for the CDK4/6 inhibitor.

OncLive: We saw interesting data presented with abemaciclib at the 2018 ASCO Annual Meeting. Can you discuss the findings with pre- and perimenopausal women?

Dickler: Dr Patrick Neven presented the data for abemaciclib in a pre- and perimenopausal group of women who participated in the MONARCH 2 trial. MONARCH 2 was a large, randomized phase III study where about 114 women were pre- and perimenopausal. But, everyone was given an GnRH agonist to make sure they were in menopause while they were receiving abemaciclib on study.

For that subgroup of 114 women, what this presentation nicely demonstrated was that there was a clear benefit of abemaciclib when added to fulvestrant in all patient subgroups, including the pre- and perimenopausal women included on this study. Therefore, it is reassuring to see that these data add to the evidence showing that abemaciclib specifically works in all subgroups of women. The MONARCH 2 data really are strong data showing that abemaciclib adds to the benefit of fulvestrant in this population of patients.

Have any differences between the 3 FDA-approved CDK4/6 inhibitors been identified?

There are no head-to-head studies of the CDK4/6 inhibitors, so we really can’t make inferences about the differences between the agents or the comparative effectiveness of each drug. We can really only comment on the trials that have been reported to date.

There really aren’t data to help guide the [decision] on which [drug] you would use. There are first-line trials with all 3 agents [as well as] second-line trials. Looking at each study, there are benefits in the first- and second-line settings with hazard ratios that are very similar. But, you can’t compare trials.

What is very interesting about abemaciclib is with the MONARCH 1 data, [which is] in a more heavily pretreated patient population—so a cohort of postmenopausal women who already have progressed on endocrine therapy and have had at least 1 prior chemotherapy for metastatic disease. There was single-agent activity with abemaciclib with a response rate of almost 20%. In that more heavily pretreated group of patients, that response rate is pretty comparable to that of chemotherapy in that setting. One differentiating factor is that abemaciclib is FDA approved as a monotherapy in a more heavily pretreated population of patients.

We have also reported data looking at abemaciclib in both the MONARCH 2 and MONARCH 3 populations in a group of patients who had more concerning clinical characteristics, such as visceral metastases—like liver metastases. In the group of patients who had more concerning characteristics, abemaciclib plus endocrine therapy performed very well.

Please discuss the QOL with abemaciclib.

At the 2018 ASCO Annual Meeting, there was a poster by Dr Peter Kaufman, who reported health-related QOL data in the MONARCH 2 study. Although patients do experience diarrhea with abemaciclib, women who [experience] it do not have a statistically significant decline in their patient-reported QOL. That was very reassuring—that although there are some side effects to this drug, it did not reduce QOL in that setting.

Dr Hope Rugo presented data at the meeting, which clearly showed that women who experience diarrhea and then required dose reductions because of that did as well as women who did not require dose reductions. Therefore, women who could be experiencing diarrhea and neutropenia early, and were managed with a hold or a dose reduction, had similar outcomes as women who did not require any modifications of their dose.

Abemaciclib is approved for use in combination with a nonsteroidal aromatase inhibitor in the frontline setting. How has that changed the landscape?

Those are very exciting data, in which abemaciclib added to either anastrozole or letrozole improved median PFS in a very significant way, with a hazard ratio in the 0.5 range. These drugs really had a significant impact on the first-line [setting] for women with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer. [The data from] these trials clearly show that all subgroups of patients do derive benefit, and the addition of CDK4/6 inhibitors as first-line treatment has been one of the major advances in the treatment of ER-positive metastatic disease.

What are some next steps planned for abemaciclib?

Another study that was reported at the 2018 ASCO Annual Meeting was with first author Dr Sara Tolaney. It looked at a cohort of patients on a phase I/Ib study of abemaciclib plus pembrolizumab (Keytruda). Updated data at 24 weeks showed a response rate of 28%, so although this is a relatively small cohort of women who were treated with abemaciclib and pembrolizumab, it is a very exciting early signal that is actually better than the 19% that was reported with abemaciclib alone as monotherapy in the MONARCH 1 study. Again, we can’t compare across trials, but it is a positive and interesting early signal for adding immunotherapy to abemaciclib in this setting.

Are there any other studies with abemaciclib you would like to share?

There are studies looking at abemaciclib in the HER2-positive population of patients in the metastatic setting. One of those trials is the monarcHER study that is yet to be reported but exciting in that, so far to date, there has been no studies yet reported in the HER2-positive population of the CDK4/6 inhibitors. We eagerly await those results.

How would you capture the significance of CDK4/6 inhibitors for the treatment of these patients?

CDK4/6 inhibitors add [a significant benefit] in the first-line setting in combination with aromatase inhibitors, as well as in the second-line setting in combination with what we call the selective estrogen receptor degraders, like fulvestrant. There have been tremendous improvements in PFS that will hopefully translate into improvements with overall survival, though that has yet to be reported. There are studies ongoing in the adjuvant setting to see if we can bring the advances that have been proven in metastatic disease to patients with earlier stages of breast cancer, so that we can actually hope to bring more cures to women with breast cancer.


  1. Di Leo A, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract 236O_PR.
  2. Neven P, Rugo HS, Tolaney SM, et al. Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer. J Clin Oncol. 2018;36 (suppl; abstr 1002).
  3. Kaufman PA, Toi M, Neven P, et al. Health-related quality of life (HRQoL) in MONARCH 2: Abemaciclib plus fulvestrant in women with HR+, HER2- advanced breast cancer (ABC) who progressed on endocrine therapy. J Clin Oncol. 2018;36 (suppl; abstr 1049).
  4. Rugo HS, Sledge GW, Johnston SRD, et al. The association of early toxicity and outcomes for patients treated with abemaciclib. J Clin Oncol. 2018;36 (suppl; abstr 1053).
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