Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are associated with a robust benefit in patients with hormone receptor–positive, HER2-negative breast cancer, but now the monarcHER trial has confirmed their benefit in the HER2-positive population. The new findings were reported at the European Society for Medical Oncology (ESMO) Congress 2019 by Sara M. Tolaney, MD, MPH, of Dana-Farber Cancer Institute, Boston.1
Sara M. Tolaney, MD, MPH
In this study of 237 postmenopausal women with heavily pretreated hormone receptor–positive, HER2-positive advanced breast cancer, the combination of abemaciclib, trastuzumab, and fulvestrant reduced the risk of disease progression or death by 33% (P = .05) and improved response rates, compared with trastuzumab plus chemotherapy.
“This is the first phase II study of a CDK4/6 inhibitor and endocrine therapy vs standard-of-care chemotherapy, together with HER2-directed treatment in hormone receptor–positive, HER2-positive advanced breast cancer, to report positive results,” Dr. Tolaney said.
“Together with previously disclosed data, abemaciclib has now demonstrated activity in both hormone receptor–positive, HER2-negative and hormone receptor–positive, HER2-positive advanced breast cancer,” she added.
Resistance to endocrine therapy remains a challenge in advanced breast cancer. Inhibition of CDK4 and CDK6 has been shown to attenuate resistance to endocrine therapy, Dr. Tolaney noted. In preclinical models, inhibition of these pathways with abemaciclib was shown to enhance the activity of HER2-directed agents and resensitize resistant tumors to HER2 blockade.
MonarcHER enrolled 237 women with hormone receptor-positive, HER2-positive advanced breast cancer who had been previously treated with at least two prior HER2-directed therapies. Prior treatment had to have included trastuzumab emtansine (T-DM1) and a taxane but could not have included a CDK4/6 inhibitor plus fulvestrant.
Patients were randomly assigned 1:1:1 to: abemaciclib at 150 mg twice daily plus trastuzumab every 21 days and fulvestrant every 28 days (arm A); abemaciclib plus trastuzumab (arm B); or trastuzumab plus investigator’s choice of chemotherapy (arm C). The primary endpoint was progression-free survival (arm A vs C, then arm B vs C).
Progression-Free Survival Benefit
The triplet of abemaciclib, trastuzumab, and fulvestrant led to a median progression-free survival of 8.3 months, compared to 5.7 months for arm C (hazard ratio [HR] = 0.673; P = .05). For arm B, median progression-free survival was 5.6 months, similar to arm C (HR = 0.943; P = .77 for arm B vs arm C).
“We saw a significant improvement in progression-free survival, with a delta of 2.6 months favoring abemaciclib/trastuzumab/fulvestrant vs trastuzumab/chemotherapy at a prespecified two-sided alpha of 0.2,” Dr. Tolaney said. “No progression-free survival benefit was observed for abemaciclib/trastuzumab vs trastuzumab/chemotherapy.”
The abemaciclib arm also improved response rates in the intent-to-treat population, from 13.9% in the control arm to 32.9%, with a median duration of response of 12.5 months with the triplet. In the population with measurable disease, response rates were 35.7% and 15.9%, respectively.
An exploratory analysis of overall survival, with only 93 of 158 events expected by year 2021, showed no differences yet in median survival, which is approximately 24 months in arm A and 21 months in arm C.
Tolerability and Safety
Patients in the abemaciclib arm received an average of two additional cycles of treatment, and no new safety signals were observed. Patients on abemaciclib did experience more grade ≥ 3 treatment-emergent adverse events than did those in arm C (56% vs 33%), but this did not lead to more treatment discontinuations (7.7% vs 8.3%). With the abemaciclib regimen, grade ≥ 3 thrombocytopenia was more common (10.3% vs 2.8%), as was diarrhea (9.0% vs 2.8%).
There were four treatment-related deaths due to adverse events: in arm A, cardiopulmonary arrest and adult respiratory distress syndrome; in arm B, pulmonary fibrosis; and in arm C, febrile neutropenia.
DISCLOSURE: The monarcHER trial was funded by Eli Lilly. Dr. Tolaney has consulted or advised for Eli Lilly, Genentech, Novartis, Pfizer, Celldex, Paxman, Seattle Genetics, Nektar, Immunomedics, NanoString, Daiichi Sankyo, Bristol-Myers Squibb, Sanofi, Athenex, AbbVie, AstraZeneca, Eisai, Puma Biotechnology, and Merck.
1. Tolaney SM, Wardley 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. ESMO Congress 2019. Abstract LBA23. Presented September 28, 2019.
Formal discussant Mafalda Oliveira, MD, PhD, of Vall d’Hebron Institute of Oncology in Barcelona, commented that monarcHER was a “well-designed, hypothesis-generating trial that addresses clinically relevant questions,” including whether cyclin-dependent kinase 4 and 6 inhibition now has broader...