In the single-arm phase II MONARCH 1 trial, the investigational cyclin-dependent kinase 4/6 (CDK4/6) inhibitor abemaciclib achieved an objective response in about 20% of heavily pretreated patients with metastatic hormone receptor–positive, HER2-negative breast cancer and a disease control rate of more than 40%. Responses were durable, lasting for a median of almost 9 months. Updated results of this single-agent trial were presented at the 2017 American Association for Cancer Research (AACR) Annual Meeting.1
Based on these results, two phase III trials are evaluating abemaciclib in combination with a hormonal agent: MONARCH 2 -(abemaciclib plus fulvestrant [Faslodex] in endocrine-pretreated hormone receptor–positive HER2-negative breast cancer), and MONARCH 3 (abema-ciclib plus a nonsteroidal aromatase inhibitor as first-line treatment for metastatic hormone receptor–positive or HER2-negative breast cancer). Both trials have met their primary endpoint, and data will be released this year (including a presentation of MONARCH 2 at the ASCO Annual Meeting).
Hope S. Rugo, MD
Two other CDK4/6 inhibitors are already U.S. Food and Drug Administration (FDA)-approved for the treatment of breast cancer—palbociclib (Ibrance) and ribociclib (Kisqali). Abemaciclib was awarded Breakthrough Therapy designation by the FDA in October 2015. Other CDK4/6 inhibitors are in various stages of development.
According to MONARCH 1 lead author Hope S. Rugo, MD, of the University of California Helen Diller Family Comprehensive Cancer Center, San Francisco, abemaciclib has properties that distinguish it from both palbociclib and ribociclib. Unlike its competitors, abemaciclib is 14 times more potent against CDK4 than CDK6, it has single-agent activity, neutropenia is not a dose-limiting toxicity, and it can be continuously administered.
“Single-agent activity is not observed with other CDK4/6 inhibitors [in metastatic breast cancer]. Abemaciclib -demonstrated single-agent activity in heavily pretreated patients with metastatic hormone receptor–positive/HER2-negative breast cancer. Few patients discontinued treatment due to adverse events,” Dr. Rugo said.
MONARCH 1 enrolled 132 women with hormone receptor–positive/HER2-negative breast cancer previously treated for metastatic disease with at least 2 prior chemotherapy regimens, 1 of them taxane-based. Patients were treated with oral abemaciclib until evidence of progressive disease or unacceptable toxicity.
The median age was 58 years, with an upper age limit of 89 years. About 50% of patients had three or more sites of metastatic disease. The median number of prior systemic regimens was five for all settings and three for metastatic disease (including endocrine therapy).
Prior to study entry, 67% of patients had received treatment with fulvestrant and 37% with everolimus (Afinitor). About 91% had received 2 prior lines of chemotherapy for metastatic disease (69% got a taxane, and 65% received capecitabine).
The overall response rate was 19.7%, all of them partial responses. The clinical benefit rate (response plus stable disease) was 42.4%. Median duration of response was 8.9 months. In a subgroup analysis, overall response rate and clinical benefit rate were comparable regardless of the number of prior therapies, the number of endocrine therapies, prior fulvestrant, prior capecitabine, and prior anthracycline.
Previous studies with FDA-approved chemotherapy in the metastatic hormone receptor–positive/HER2-negative breast cancer setting (capecitabine, ixabepilone [Ixempra], and eribulin [Halaven]) showed overall response rates ranging from 11% to 25%. Progression-free survival was 3 to 4 months, and overall survival was 8.6 to 13.1 months. Although not a head-to-head comparison, single-agent abemaciclib surpassed that in MONARCH 1; median progression-free survival was 6 months, and median overall survival was 22.3 months.
The most common investigator-assessed adverse event was diarrhea of all grades. Grade 3 diarrhea was reported in 20%, and grade 3 fatigue, in 13.6%. No grade 4 events were reported.
The most common laboratory abnormality of all grades was increased serum creatinine. Dr. Rugo emphasized that this increase did not affect renal function adversely, according to assessment of glomerular filtration rate with cystatin C. During the question-and-answer session after the presentation, Dr. Rugo told the audience that cystatin C is a readily available, inexpensive test. “If cystatin C is in the normal range, you don’t need to check glomerular filtration rate,” she said.
Other laboratory effects included decreased white blood cell counts (92.3%), decreased neutrophil counts (87.7%), anemia (69.2%), decreased lymphocyte count (42.3%), and decreased platelet count (41.4%). The most common grade 3 abnormalities were decreased white blood cell count (27.7%) and decreased neutrophil count (22.3%).About 50% of patients required dose reductions of abemaciclib, mainly for neutropenia. Serious adverse events were reported in 25% of patients, and 7.6% discontinued therapy due to serious adverse events.
No Biomarkers Identified
Fabrice Andre, MD
In a related presentation following Dr. Rugo’s talk, Fabrice Andre, MD, of the Institut Gustave Roussy, Université-Paris-Sud, Villejuif, France, and colleagues were unable to identify biomarkers of response to ribociclib in an analysis of fresh or archival tumor samples from participants in the -MONALEESA-2 trial. These investigators presented data on the first six biomarkers they studied: Rb and p16 protein levels, Ki67 cell proliferation, and CDKN2A, CCND1, and ESR1 gene expression.2 Further analyses of additional biomarkers using these tumor samples are under study. ■
Disclosure: Dr. Rugo disclosed relationships (through her institution) with GlaxoSmithKline, Genentech/Roche, Novartis, Pfizer, Merck, Amgen, Eisai, Plexxikon, Macrogenics, Lilly, OBI, BioMarin, and Genomic Health. Dr. Andre disclosed relationships with AstraZeneca, Lilly, Novartis, and Pfizer.
Filipa Lynce, MD
Formal discussant of the MONARCH 1 trial and the MONALEESA-2 biomarker analysis, Filipa Lynce, MD, of Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, noted that this is the first study to evaluate a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in patients...