Matthew P. Goetz
CHICAGO — The addition of abemaciclib to initial treatment with a nonsteroidal aromatase inhibitor appeared effective for women with hormone receptor-positive, HER-2-negative advanced breast cancer, according to results of the double-blind, phase 3 MONARCH 3 study presented at American Association for Cancer Research Annual Meeting.
The combination significantly improved PFS and objective response rate compared with NSAI therapy alone. The regimen also exhibited a tolerable safety profile.
“Estrogen is known to enhance cyclin D1 expression and leads to the activation of CDK4/6, resulting in cell cycle progression in hormone receptor-positive breast cancer,” Matthew P. Goetz, MD, associate professor of oncology at Mayo Clinic in Rochester, Minnesota, said during his presentation. “Continuous inhibition of CDK 4/6 leads to prolonged cell cycle arrest with initiation of apoptosis or senescence.”
However, there is concern that short-term inhibition of CDK 4/6 in tumor cells may cause a rebound effect that triggers increased cellular proliferation upon withdrawal of the drug.
Abemaciclib (Eli Lilly) is an oral selective CDK 4/6 inhibitor.
In the MONARCH 1 trial, abemaciclib demonstrated clinical activity as monotherapy for patients with hormone receptor-positive, HER-2-negative advanced breast cancer. In the MONARCH 2 trial, the agent appeared effective and also exhibited a generally tolerable safety profile when combined with fulvestrant.
In the MONARCH 3 trial, Goetz and colleagues evaluated the addition of abemaciclib to the NSAI anastrozole (Arimidex, AstraZeneca) or letrozole (Femara, Novartis) as initial therapy for postmenopausal women with hormone receptor-positive, HER-2-negative advanced breast cancer. Study participants had received no prior systemic therapy in the metastatic setting. They either were endocrine therapy naive or had disease relapse more than 12 months after neoadjuvant endocrine therapy.
Researchers randomly assigned patients 2:1 to abemaciclib or placebo 150 mg twice daily on a continuous schedule, plus 1 mg anastrozole or 2.5 mg letrozole daily. Investigators stratified patients by metastatic site (visceral, bone only, or other) and prior endocrine therapy (aromatase inhibitor, no endocrine therapy, or other).
Investigator-assessed PFS served as the primary endpoint. Additional objectives included ORR, clinical benefit rate, duration of response, OS, safety and tolerability.
Results of an interim analysis, presented last fall at European Society for Medical Oncology Congress in Madrid, showed the addition of abemaciclib to an NSAI significantly improved PFS (HR = 0.54; 95% CI, 0.4-0.72) and ORR (59.2% vs. 43.8%; P = .004).
At AACR, Goetz presented results from the preplanned final analysis.
The analysis — performed after 246 events had occurred — included 493 patients, of whom 328 received abemaciclib and 165 received placebo.
Results showed the addition of abemaciclib to NSAI significantly extended median PFS (28.1 months vs. 14.7 months; HR = 0.54; 95% CI, 0.41-0.69).
Researchers observed the PFS benefit in all patient subgroups.
Among patients with measurable disease, abemaciclib appeared associated with a higher ORR (61% vs. 45.5%; P = .003) and complete benefit rate (79% vs. 69.7%; P = .037).
Abemaciclib-treated patients achieved a longer median duration of response (27.3 months vs. 17.4 months).
OS data were immature at the time of analysis, and adverse events appeared consistent with prior reports. – by Mark Leiser
Goetz MP, et al. Abstract CT040. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
Disclosure: Goetz reports financial relationships with Biotheranostics, Biovica, Eisai, Eli Lilly and Myriad Genetics. Please see the abstract for all other authors’ relevant financial disclosures.