In findings from the phase II next MONARCH 1 trial, single-agent abemaciclib continued to be safe and effective for patients with hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on or following endocrine therapy.
Erika P. Hamilton, MD
In findings from the phase II next MONARCH 1 trial, single-agent abemaciclib (Verzenio) continued to demonstrate positive safety and efficacy findings for patients with hormone receptor (HR)positive, HER2-negative advanced breast cancer who have progressed on or following endocrine therapy.
“[It’s clear that] abemaciclib has single-agent activity. For women who have not seen a CDK4/6 inhibitor, and have already progressed through our standard endocrine options, this is a very reasonable approach. It's also reasonable for those women who cannot tolerate endocrine therapy,” said lead study author Erika P. Hamilton, MD.
The multicenter, open-label study, included patients with HR-positive, HER2-negative advanced breast cancer who were randomized to 1 of 3 treatment arms: 150 mg of abemaciclib twice daily and 20 mg of tamoxifen (Arm A; n = 78); 150 mg of abemaciclib monotherapy twice daily (Arm B; n = 79); or 200 mg of abemaciclib twice daily and prophylactic loperamide (Arm C; n = 77).
To be eligible for the trial, patients must have received ≥2 prior lines of chemotherapy, 1 of which had to be given in the advanced setting; measurable disease; and no prior exposure to a CDK4/6 inhibitor. Progression-free survival (PFS) served as the primary endpoint of the study; secondary endpoints were objective response rate (ORR), clinical benefit rate (CBR), and safety.
Although the addition of tamoxifen to abemaciclib did not translate to a statistically significant improvement in PFS, it did show prolonged benefit compared with the other treatment arms. The median PFS was 9.1 months, 6.5 months, and 7.4 months, in arms A, B, and C, respectively, with confirmed objective response rates of 25.6%, 19%, and 28.6%, respectively. Additionally, the clinical benefit rates were 61.5%, 49.4%, and 51.9%, respectively.
Though the addition of loperamide did not reduce the incidence of diarrhea relative to arms A and B, it showed a significant reduction in the rate of grade 3 diarrhea (7.8%) compared with what the rate observed in the MONARCH 1 trial (19.7%), which was the basis for the FDA’s approval of single-agent abemaciclib in patients with metastatic HR-positive, HER2-negative advanced breast cancer who have previously received endocrine therapy and chemotherapy.
“This study gives us more reassuring data that [abemaciclib monotherapy] can be a well-tolerated regimen if we’re proactive about counseling patients about diarrhea and instituting loperamide,” added Hamilton.
In an interview withTargeted Oncology, Hamilton, director, Breast and Gynecologic Research Program, Sarah Cannon Research Institute, discussed the findings from the phase II nextMONARCH 1 study of abemaciclib in HR-positive, HER2-negative advanced breast cancer.
TARGETED ONCOLOGY:What was the rationale for the study?
Hamilton:The goal of this study was to take a more proactive approach compared with the precursor study, MONARCH 1. In that study, prophylactic loperamide or a prophylactic dose reduction was not looked at for diarrhea. Knowing what we know about abemaciclib now, we wanted to answer the question of whether going down to 150 mg of abemaciclib or using prophylactic loperamide once daily with 200 mg of abemaciclib would increase tolerability, decrease diarrhea, and ultimately increase compliance.
TARGETED ONCOLOGY:What was the rationale for studying abemaciclib specifically of the 3 CDK4/6 inhibitors?
Hamilton:Abemaciclib is a CDK4/6 inhibitor that we believe has single-agent activity. It's been shown in previous studies, as well as in this phase II study. We wanted to know whether adding tamoxifen and endocrine therapy to abemaciclib boosts the duration of response, or whether abemaciclib alone is sufficient as a monotherapy.
TARGETED ONCOLOGY:What was the design of the trial?
Hamilton:It was a 3-arm trial. In arm A, patients were given tamoxifen in combination with 150 mg of abemaciclib. In arm B, patients received 150 mg of abemaciclib monotherapy. In arm C, patients got 200 mg of abemaciclib monotherapy in combination with 2 mg of loperamide once daily.
TARGETED ONCOLOGY:What were the findings?
Hamilton:We discovered a number of things. First, the PFS ranged from 6.5 months to 9.1 months, though this was not statistically significant across the arms. It looked like abemaciclib monotherapy had equal activity, as far as PFS was concerned, to the combination with tamoxifen. As far as the ORR, the highest response rate was in arm C, in which abemaciclib was given at a dose of 200 mg; the ORR in that arm was 29%. In the original MONARCH 1 trial, the response rate was about 19%, so [the increased dose] did improve the response by about 10%.
What we all really wanted to see was the tolerability. It looked like it was much more tolerable than what we saw in the [MONARCH 1] study. Grade 3 diarrhea was extremely low; it was less than 8% across all the arms. What's perhaps more clinically meaningful is the percentage of patients who had to dose reduce the abemaciclib because of diarrhea. That rate was around 1% to 5% of patients who received 150 mg of abemaciclib and about 9% for those who received 200 mg of abemaciclib. It was certainly low enough to be a reasonable starting dose for patients.
TARGETED ONCOLOGY:What are the next steps?
Hamilton:We have 3 CDK4/6 inhibitors on the market. We're able to use them in combination with aromatase inhibitors in the first-line setting and in combination with fulvestrant in the second-line setting. We have quite a body of evidence that shows that abemaciclib has single-agent activity in later lines of therapy. What was particularly unusual compared with most HR-positive metastatic breast cancer studies is that these women were required to have 2 prior lines of chemotherapy, at least one of which had to be given in the advanced setting. As far as the estrogen receptorpositive [population is concerned], these women were very heavily pretreated. To see a 29% response rate is quite impressive.
Hamilton E, Cortes J, Dieras V, et al. nextMONARCH 1: phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer. In: Proceedings from the 2018 San Antonio Breast Cancer Symposium, December 1-4, 2018; San Antonio, TX. Abstract PD1-11.