The addition of abemaciclib to trastuzumab and fulvestrant prolonged progression-free survival (PFS) compared with trastuzumab plus fulvestrant or standard of care chemotherapy among women with advanced hormone receptor (HR)-positive, HER2-positive breast cancer after progression with at least 2 HER2-targeted therapies, according to results from a phase 2 study published in Lancet Oncology.

“Patients with heavily pretreated HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options,” the authors wrote. “In this setting, HER2-targeted therapy combined with cytotoxic chemotherapy agents offer modest clinical benefit with associated toxicities.”

Abemaciclib is a CDK4/6 inhibitor, and demonstrated antitumor activity in a phase 1 trial among a subset of patients with HR-positive, HER2-positive disease. The purpose of the phase 2 monarcHER trial was to determine if abemaciclib plus trastuzumab with or without fulvestrant could improve efficacy compared with the standard of care in this setting.

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The international, multicenter, open-label trial randomly assigned 237 women with unresectable, locally advanced, recurrent, or metastatic HR-positive, HER2-positive breast cancer to receive abemaciclib plus trastuzumab and fulvestrant, trastuzumab plus fulvestrant, or chemotherapy plus trastuzumab. The primary endpoint was investigator-assessed PFS, and secondary endpoints included overall survival (OS), tumor response, duration of response, disease control, and safety.

At baseline, the median age was 55 years and 87% had measurable disease. More patients in the abemaciclib group received  more than 3 prior systemic therapies for their disease at 56%, compared with 44% in the trastuzumab-fulvestrant group and 49% in the chemotherapy-trastuzumab group. There were 44%, 56%, and 51% of patients who received 2 to 3 prior therapies in the abemaciclib, trastuzumab-fulvestrant, and chemotherapy-trastuzumab groups, respectively. Nearly all patients had previously received trastuzumab and trastuzumab emtansine, and about half of patients had received pertuzumab followed by lapatinib.

After a median follow-up of 19 months, abemaciclib plus trastuzumab and fulvestrant significantly prolonged PFS compared with trastuzumab plus fulvestrant, with a median of 8.3 months (95% CI, 5.9-12.9 months) compared with 5.7 months (95% CI, 5.4-7 months) with chemotherapy plus trastuzumab (hazard ratio [HR], 0.67; 95% CI, 0.45-1.00; P =.051). There was no difference between the trastuzumab plus fulvestrant and chemotherapy plus trastuzumab arms, with a median PFS of 5.7 months in both arms (HR, 0.94; 95% CI, 0.64-1.38; P =.77).

OS data were immature and were not reported.

Abemaciclib plus trastuzumab and fulvestrant also increased the overall response rate to 33% compared with 14% with trastuzumab plus fulvestrant and 14% with chemotherapy plus trastuzumab (P =.0042). The duration of response was 12.5 months in the abemaciclib group compared with 9.5 months in the trastuzumab-fulvestrant group and was not yet reached in the chemotherapy-trastuzumab group.

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The most common grade 3 to grade 4 treatment-emergent adverse event (TEAE) reported was neutropenia, which occurred in over a quarter of patients in each treatment group. The most common serious adverse events in the abemaciclib arm included pyrexia, diarrhea, urinary tract infection, and acute kidney injury.

Dose reductions due to adverse events were most common in the abemaciclib group at 47%, followed by 39% in the trastuzumab-fulvestrant arm and 28% in the chemotherapy-trastuzumab arm.

These monarcHER results demonstrated that “the combination of abemaciclib, fulvestrant, and trastuzumab significantly improved PFS versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile,” the authors wrote.

However, the authors also acknowledged that “the question remains: what is the optimal role for CDK4 and CDK6 inhibitors in patients with HR-positive, HER-positive breast cancer?”


Tolaney SM, Wardley AM, 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 [published online April 27, 2020]. Lancet Oncol. doi: 10.1016/S1470-2045(20)30112-1.