Abemaciclib (Verzenio) in combination with fulvestrant and trastuzumab (Herceptin) demonstrated significant improvement in progression-free survival (PFS) and tolerable safety compared with standard of care chemotherapy combined with trastuzumab in patients with hormone receptor (HR)-positive, HER2-positive advanced breast cancer, according to published results from the monarcHER trial (NCT02675231).

Patients in the study were randomized 1:1:1 depending on the number of prior systemic regimens and their disease status. Patients in group A received abemaciclib, trastuzumab, and fulvestrant. In group B, patients received abemaciclib plus trastuzumab. In group C, patients received chemotherapy of the physicians choice plus trastuzumab.

Baseline screening showed that the median age for groups A, B, and C was 55 years (range 47-61 years, 54 years (range, 47-62 years), and 57 (range, 47-62 years), respectively. The majority of patients across the treatment arms were European (n = 111), but there were also 38 patients from Asia, 61 from North America, and 27 from South America.

Disease characteristics were sorted by metastatic site and measurable disease status. The most common site of metastasis in the study was visceral, which was the case for 73% of group A, 71% of group B, and 61% of group C. Respectively, 89%, 86%, and 87% of these patients had measurable disease.

In terms of prior systemic therapy, most patients had 3 or more. Overall, 80% of group A, 76% of group B, and 76% of group C had prior endocrine therapy. In addition, 97% of patients in group A, 96% in group B, and 100% in group C received prior trastuzumab.

In total, 78 from group A, 77 from group B, and 72 from group C received at least 1 dose of treatment during the study. However, at data cutoff, only 20% of the patients in group A remained on the study (n = 16), 11% in group B (n = 9), and 15% in group C (n = 10). Most patients discontinued treatment due to progressive disease, including 51 patients in group A, 58 in group B, and 62 in group C. Additionally, there were 11 deaths across the 3 study arms, and 4 treatment withdrawals based on physicians decision.

In the intention-to-treat population, there were 169 PFS events at the time of data cutoff. Of the PFS events, 56 (33%) occurred in group A, 61 (36%) in group B, and 52 (31%) in group C. At a median follow-up of 19.0 months (interquartile range [IQR], 14.7-25.1 months), the median PFS was 8.3 months (95% CI, 5.9-12.6) in group A compared with 5.7 months (range, 5.4-7.0 months) in group C (HR 0.67; 95% CI, 0.45-1.00;P=.051). PFS in the subgroup analysis of prior systemic treatment was consistent with the overall analysis.

Overall survival data have not yet matured in this study and will be reported at a later date.

In terms of response, group A was superior to group C in the overall analysis and the post-hoc analysis, which evaluated response based on disease status.

To our knowledge, this trial is the first randomized study to report positive results for a CDK4 and CDK6 inhibitor in combination with fulvestrant and trastuzumab versus standard-of-care chemotherapy and trastuzumab. The endocrine combination of abemaciclib plus fulvestrant and trastuzumab showed significant improvements in both progression-free survival and overall response compared with chemotherapy plus trastuzumab and was generally well-tolerated, wrote Sarah M. Tolaney et al. The current study is noteworthy as it directly compared an

the endocrine-based regimen with standard-of-care chemotherapy in combination with trastuzumab, potentially offering a chemotherapy sparing treatment option.

There were multiple post-hoc analyses in monarcHER. First, the patients were assessed according to Blinded Independent Central Review in a post-hoc exploratory analysis. The assessment showed no significant difference in PFS between group A, which had a median PFS of 7.1 months versus group C, which had a PFS of 6.9 months (HR, 0.883; 95% CI, 0.565-1.380; two-sidedP=.56 stratified). The median PFS for groups B versus C were 7.9 months versus 6.9 months (HR, 0.876; 95% CI; 0.5601.368; two-sidedP=.56 stratified), which also showed no significant difference, respectively.

Among patients with brain metastases, another post-hoc analysis was inconclusive based on the fact that 11% of the patient population had progressive disease.

In terms of safety, at least 1 grade 1 to 4 treatment-emergent adverse event (TEAE) was observed in 94% of patients in group A (n = 73), 97% in group B (n = 72), and 93% in group C (n = 72). Grade 3/4 TEAEs were seen in all groups, with a higher percentage observed in group A (68%). The most frequent TEAE in patients was grade 3/4 neutropenia, which occurred in 27% of patients in group A, 22% in group B, and 26% in group C.

In higher than 1% of the safety population of monarcHER, the most common serious AEs in group A were pyrexia (4%), diarrhea (3%), urinary tract infection (3%), and acute kidney injury (3%). In group B, the most common serious AEs were diarrhea (3%), and pneumonitis (3%). Finally, in group C, the most common serious AEs were neutropenia (6%) and pleural effusion (3%).

A total of 6 patients from group A, 11 from group B, and 6 from group C discontinued treatment due to AEs. Across the 3 treatment arms, dose reductions were required for 50% of group A, 42% of group B, and 28% of group C. Mostly, diarrhea was the AE that led to treatment discontinuation.

MonarchHER is an ongoing phase 2, randomized, multicenter, open-label study. Participants of monarchHER received 150 mg of abemaciclib every 12 hours on a 21-day cycle, along with 8 mg/kg of intravenous trastuzumab, and 500 mg of intramuscular fulvestrant. Trastuzumab is administered for 90 minutes on day 1 of cycle 1 and then at 6 mg /kg on day 1 of all subsequent cycles. Fulvestrant is administered on days 1 and 12 of cycle 1 and on day 8 of cycle 2, followed by once every 4 weeks. All study treatments were continued until disease progression as per RECIST v 1.1. criteria or unacceptable toxicity.

MonarchHER was conducted based on prior research from the MONARCH-1 (NCT02102490), MONARCH-2 (NCT02107703), and MONARCH-3 (NCT02246621) clinical trials, which provided evidence of activity with CDK4/CDK6 inhibition in combination with endocrine therapy and chemotherapy.

This study provides clinical validation of the preclinical hypothesis suggesting that treatment with a CDK4 and CDK6 inhibitor might overcome acquired resistance to trastuzumab. Furthermore, together with previously published data, abemaciclib has now shown activity in both HR-positive, HER2-negative and hormone receptor-positive, HER2-positive advanced breast cancer, Tolaney et al concluded in the published report.

Reference:

Tolaney SM, Wardley AW, Zambelli S, et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020. Published Online April 27, 2020. doi: 10.1016/S1470-2045(20)30112-1

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