The triplet combination of abemaciclib, trastuzumab, and fulvestrant showed a significant statistical improvement in progression-free survival compared with chemotherapy and trastuzumab in patients with heavily pretreated, hormone receptor–positive, HER2-positive breast cancer, according to the results of the phase II monarcHER trial.
Sara Tolaney, MD, MPH
The triplet combination of abemaciclib (Verzenio), trastuzumab (Herceptin), and fulvestrant (Faslodex) showed a significant statistical improvement in progression-free survival (PFS) compared with chemotherapy and trastuzumab in patients with heavily pretreated, hormone receptor (HR)positive, HER2-positive breast cancer, according to the results of the phase II monarcHER trial.
MonarcHER was designed to highlight signals of response with the addition of abemaciclib to fulvestrant-based chemotherapy and trastuzumab, as seen in preclinical studies using abemaciclib in this disease state.
The study of 225 patients randomized them into 3 arms, 1:1:1 to either abemaciclib plus trastuzumab, and fulvestrant (arm A), abemaciclib and trastuzumab (arm B), or chemotherapy of the physician's choice plus trastuzumab (arm C). Each arm was treated in 21-day cycles.
The 3-arm analysis showed that the median PFS was longer in arm A at 8.3 months versus arm C, which was 5.7 months (HR, 0.673; 95% CI, 0.451-1.003;P= .0253), meeting the primary endpoint of the trial. No difference in PFS was seen between arms B and C. A secondary endpoint, objective response rate (ORR) was also highest in arm A (35%) compared with arms B (16.5%) and C (22.8%).
These data suggest synergy between endocrine therapy, CDK4/6 inhibition, and anti-HER2 therapy, Sara Tolaney, MD, MPH, stated.
The investigators are considering a phase III confirmatory study of the triplet combination to have an option for this heavily pretreated patient population other than chemotherapy.
“As we get further on into treatment for HER2-positive disease, we're looking at giving further chemotherapy and trastuzumab where we know the PFS starts becoming more limited. We're looking to see if we can get away from chemotherapy and start using a targeted agent and see if we can do better than chemotherapy does in this setting,” said Tolaney.
In an interview withTargeted Oncologyat the 2019 ESMO Congress, Tolaney, senior physician, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School, discussed the results of the monarcHER trial of abemaciclib plus trastuzumab with or without fulvestrant, compared with chemotherapy plus trastuzumab for patients with HR-positive, HER2-positive breast cancer.
TARGETED ONCOLOGY: What does the population of patients with HR-positive, HER2-positive breast cancer look like that is being treated in the monarcHER trial?
Tolaney: We know in general that HER2-positive breast cancer represents about 15% to 20% of all breast cancers, and more than half of those cases are HR-positive/HER2-positive cases. It is a large area of our HER2-positive population, and it's nice to think about being able to develop a non-chemotherapy option for these patients.
TARGETED ONCOLOGY: Can you explain the rationale for the monarcHER trial?
Tolaney: The rationale for the trial was that we had some initial data to suggest that abemaciclib may have activity in advanced HR-positive, HER2-positive breast cancer.
This initial clinical data came from a dose-finding phase I study where there was a small subset of 11 patients who had HR-positive, HER2-positive disease. In this cohort, we saw a response rate that was on the order of 30% with a PFS that was a little over 7 months. That certainly suggested that there was a signal for activity.
We also had some preclinical data suggesting that in a trastuzumab-resistant patient-derived xenograft model, that the combination of abemaciclib and trastuzumab had better activity than abemaciclib alone, also suggesting that the CDK4/6 inhibitors could potentially restore sensitivity to HER2-directed therapy.
TARGETED ONCOLOGY: What was the study design?
Tolaney: The monarcHER trial was a randomized phase II study of abemaciclib plus trastuzumab with or without fulvestrant compared to chemotherapy of physician's choice plus trastuzumab for patients with HR-positive, HER2-positive disease, who were allowed to have had at least 2 prior lines of anti-HER2 based therapy for their advanced disease. They were also required to have had T-DM1 (trastuzumab emtansine; Kadcyla) and a taxane in any disease setting. They could not have had prior fulvestrant or a prior CDK4/6 inhibitor, and they were then randomized 1:1:1 to one of 3 treatment arms.
Arm A was a triplet combination of abemaciclib, trastuzumab, and fulvestrant. Arm B was abemaciclib and trastuzumab, and arm C was chemotherapy of physician's choice with trastuzumab.
The trial was designed to look at PFS and compare arm A, which was the triplet combination, to arm C, the chemotherapy/trastuzumab combination. If positive, then there would be a comparison of arm B, the doublet of abemaciclib/trastuzumab to arm C.
This particular trial was also designed to treat patients who progressed on multiple lines of HER2-directed therapy. These were patients who had a median of 4 prior lines of therapy. As we get further on into treatment for HER2-positive disease, we're looking at giving further chemotherapy, and trastuzumab where we know the PFS starts becoming more limited. We're looking to see if we can get away from chemotherapy and start using a targeted agent and see if we can do better than chemotherapy does in this setting.
TARGETED ONCOLOGY: What were the results of this study?
Tolaney: The study demonstrated that arm A had a median PFS of 8.3 months. This was significantly longer than the median PFS in arm C, which was 5.6 months. There was a 2.6-month absolute difference in the PFS between the 2 arms. This was statistically significant, suggesting the trial did meet its primary endpoint. There was no difference though in PFS between arm B and arm C. We also saw that there was a more than doubling in the objective response rates with arm A having an ORR of 33% compared with 14% in arm C. That suggested that using fulvestrant, abemaciclib, and trastuzumab not only improves PFS but also improves ORRs.
TARGETED ONCOLOGY: What is it about fulvestrant that is adding to that response?
Tolaney: This particular trial can't answer the question about what the exact addition of fulvestrant is doing here. We didn't have an arm that was just fulvestrant and trastuzumab to fully address that question.
I think it's hard to imagine that you would have seen this level of activity from fulvestrant and trastuzumab because this a very heavily pretreated population with about 4 prior lines of therapy and over 50% of patients had already progressed on endocrine therapy for their HER2-positive disease. We also saw that abemaciclib and trastuzumab performed just as well as chemotherapy. Adding on the fulvestrant is likely showing that you probably are getting synergistic activity between endocrine therapy and CDK4/6 inhibition with anti-HER2 therapy to allow for this benefit to be seen.
TARGETED ONCOLOGY: Can you discuss the safety profile?
Tolaney: There were no new safety signals that were found with the abemaciclib-containing arms. Generally, the regimen was well tolerated. Numerically, there were more adverse events in arm A compared with arm C, but there were no differences in dose discontinuations between arm A or arm C.
TARGETED ONCOLOGY: How will these results be used to conduct further research for targeting HR-positive, HER2-positive breast cancer?
Tolaney: Right now, there are ongoing discussions about what the next trial design should be. These data are the first randomized data that are available looking at CDK4/6 inhibition with anti-HER2 therapy and endocrine therapy comparing it with chemotherapy and trastuzumab. Seeing this significant improvement in PFS and ORR is very promising and suggests that this could be an option for patients in a later-line setting.
The question is, do we now need to do a phase III confirmatory trial? That's where further discussions are ongoing.
Tolaney SM, Wardly AM, Zambelli S, et al. MonarcHER: A randomized phase II study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer (ABC). Presented at 2019 ESMO Congress; September 27-October 2, 2019; Barcelona, Spain. Abstract LBA23.