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Abemaciclib reduces Ki67 expression in certain postmenopausal women with breast cancer
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SAN ANTONIO — Neoadjuvant therapy with abemaciclib alone or in combination with significantly reduced Ki67 expression after 2 weeks compared with anastrozole alone among postmenopausal patients with hormone receptor–positive, HER-2–negative breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
The majority of patients treated with abemaciclib (LY2835219, Eli Lilly) — an inhibitor of cyclin dependent kinases (CDK) 4 and 6 — and anastrozole achieved an objective response, and continuous dosing of abemaciclib in combination with anastrozole generated no new safety signals.
“Abemaciclib did induce profound cell cycle arrest defined by a decrease in Ki67,” researcher Sara A. Hurvitz, MD, associate professor of medicine at University of California, Los Angeles, and medical director of UCLA’s Jonsson Comprehensive Cancer Center Clinical Research Unit, said during a press conference.
“Treatment with this combination therapy may induce immune cell infiltration, characterized by an increase in total T cells, but that is not seen until after 4 months of therapy,” Hurvitz added. “These data support further evaluation of abemaciclib in early-stage breast cancer.”
Neoadjuvant treatment for patients with hormone receptor–positive, HER-2–negative breast cancer typically consists of chemotherapy or endocrine therapy.
Agents that target CDK4 and CDK6 primarily have been evaluated for this population when disease reaches an advanced stage, and one such drug — palbociclib (Ibrance, Pfizer) — is approved for use in this setting.
In the phase 2 neoMONARCH trial, Hurvitz and colleagues evaluated the activity of abemaciclib in patients with early-stage disease.
The analysis included 220 postmenopausal women with stage I through stage IIIB disease suitable for neoadjuvant endocrine therapy.
All patients underwent core biopsy at baseline.
Researchers then randomly assigned patients to one of three regimens: anastrozole 1 mg daily; abemaciclib 150 mg twice daily; or combination therapy with anastrozole 1 mg daily plus abemaciclib 150 mg twice daily.
Patients underwent another core biopsy at 2 weeks of treatment. After that, all patients underwent combination therapy with abemaciclib and anastrozole for 14 weeks. A final core biopsy was performed at the end of that regimen.
Subsequent surgery was optional.
Change in Ki67 — a marker of cell proliferation that may predict DFS — after 2 weeks of therapy served as the primary endpoint.
Secondary and exploratory endpoints included safety; clinical, radiologic and pathological response; and cell cycle–associated gene expression.
The final analysis included 54 evaluable patients assigned anastrozole alone, 51 assigned abemaciclib alone, and 56 assigned the combination.
At week 2, results showed significantly greater reductions in Ki67 expression among patients assigned the combination regimen (92.6%) and those assigned abemaciclib monotherapy (90.6%) than those assigned anastrozole alone (63.2%; P < .001).
Also at week 2, researchers also reported higher levels of complete cell arrest in the combination group (66.1%) and abemaciclib monotherapy group (58.8%) than those assigned anastrozole alone (14.8%; P < .001).
When Hurvitz and colleagues analyzed RECIST response data over time — after all study participants had received 14 weeks of combination therapy — they reported a 54.7% radiologic response rate and a 56.6% caliper response rate in the entire cohort.
Three of 95 (3.2%) patients who underwent surgery achieved complete pathologic response. One patient discontinued therapy due to progressive disease.
The most common all-grade treatment-related adverse events included diarrhea (55.2%), constipation (39%), nausea (36.8%), fatigue (35%), abdominal pain (19.7%) and decreased appetite (18.4%).
No grade 4 treatment-related adverse events occurred. The most common grade 3 events were diarrhea (4%), abdominal pain (3.1%), nausea (2.2%) and decreased appetite (1.8%).
The most common all-grade laboratory abnormalities were increased creatinine (95.9%), decreased neutrophil count (66.7%) and decreased white blood cell count (61.6%).
“Even though the results of this study were positive and promising, they will not change the standard of care because this was a proof-of-concept study,” Hurvitz said. “The duration of therapy was relatively short and did not allow us to robustly assess pathologic responses, nor were we able to follow patients to evaluate long-term outcome. Nonetheless, the data generated are important and support continued evaluation of this drug in early-stage breast cancer.” – by Mark Leiser
Reference:
Hurvitz SA, et al. Abstract S4-06. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio.
Disclosure: Eli Lilly funded this study. Hurvitz reports research funding or travel expenses from Amgen, Bayer, Biomarin, Boehringer Ingelheim, Dignitana, Eli Lilly, Genentech, GlaxoSmithKline, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.