Abemaciclib plus endocrine therapy improves outcomes for certain women with advanced breast cancer
MADRID — The addition of abemaciclib to endocrine therapy extended PFS and improved response rates among postmenopausal women with hormone receptor-positive, HER-2-negative advanced breast cancer, according to results of a randomized phase 3 study presented at the European Society for Medical Oncology Congress.
Although most women derived considerable benefit from the combination, approximately one-third of women may not a cyclin-dependent kinase (CDK) 4/6 inhibitor like abemaciclib (Eli Lilly) as part of their initial treatment, Angelo Di Leo, MD, PhD, head of the Sandro Pitigliani Medical Oncology Unit and chair of the oncology department at Hospital of Prato at Istituto Toscano Tumori in Italy, told HemOnc Today.
“The major implication of this study is it [shows] some patients may start with endocrine therapy alone,” Di Leo said in an interview. “Until now, we didn’t have this information. The feeling was that, because of the striking results in favor of the combination therapy, all patients — or at least the vast majority — needed to start with it. Our data suggest this is not entirely true.”
Abemaciclib, an oral selective CDK 4/6 inhibitor, has appeared efficacious and well tolerated as monotherapy and combined with fulvestrant for patients with hormone receptor-positive, HER-2-negative advanced breast cancer.
In the MONARCH 3 trial, Di Leo and colleagues evaluated the addition of abemaciclib to the nonsteroidal aromatase inhibitors 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.
The double-blind study included 493 women who either were endocrine naive or had relapsed more than 12 months after neoadjuvant endocrine therapy. The majority of women had visceral disease (52.9%) and measurable disease (80.5%). Slightly more than one-quarter (27.4%) received a prior aromatase inhibitor, and 39.8% had de novo advanced breast cancer.
Researchers randomly assigned 328 women to abemaciclib 150 mg twice daily plus a nonsteroidal aromatase inhibitor (anastrozole 1 mg daily or letrozole 2.5 mg daily). The other 165 women received a nonsteroidal aromatase inhibitor plus placebo.
Investigator-assessed PFS served as the primary objective. Secondary objectives included objective response rate and safety.
Researchers stratified results by metastatic site (visceral, bone only or other) and prior endocrine therapy (aromatase inhibitor vs. other therapy vs. no therapy).
Interim analysis performed at 18 months showed the addition of abemaciclib to endocrine therapy significantly extended median PFS (not reached vs. 14.7 months; HR = 0.54; 95% CI, 0.4-0.72).
Among patients with measurable disease, researchers observed a higher ORR in the abemaciclib group (59% vs. 44%; P = .004).
Exploratory analyses suggested patients with indicators of poor prognosis — such as liver metastases — derived substantial benefit from abemaciclib. However, patients with bone metastases only, as well as those with indolent disease — relapsing 3 or 4 years after stopping adjuvant endocrine therapy — demonstrated excellent prognosis with endocrine therapy alone, Di Leo said.
“These patients accounted for approximately one-third of the trial population,” Di Leo told HemOnc Today. “This is not a niche group. It is a significant number of patients for whom, apparently, you may start just with endocrine therapy.”
This approach could help some patients avoid the toxicity of first-line CDK 4/6 inhibitors and also save money, Di Leo said. For these patients, CDK 4/6 inhibitors possibly could be reserved for next-line treatment of metastatic disease.
“This idea warrants further study given our data,” Di Leo said.
The most frequent adverse events were diarrhea (all-grade, 81.3% for abemaciclib vs. 29.8% for endocrine therapy alone; grade 3, 9.5% vs. 0%), neutropenia (all-grade, 41.3% vs. 1.9%; grade 3/grade 4, 21.1% vs. 1.2%), and fatigue (all-grade, 40.1% vs. 31.7%; grade 3/grade 4, 1.8% vs. 0%).
Abemaciclib is the third CDK 4/6 inhibitor to be evaluated for patients with advanced breast cancer.
“The MONARCH3 trial confirms the role of this new class of agents in combination with endocrine therapy in the treatment of metastatic breast cancer,” Giuseppe Curigliano, MD, PhD, director of the division of new drug development at European Institute of Oncology at University of Milan in Italy, said in an ESMO-issued press release.
“Many patients with metastatic disease still receive chemotherapy, despite guidelines and data from clinical trials,” Curigliano said. “This study confirms that we should avoid chemotherapy in hormone receptor-positive, HER-2-negative metastatic breast cancer if visceral crisis is not present.”
The ideal sequence for treatment in the era of CDK 4/6 inhibitors has not yet been determined, Curigliano added.
“Should we use these agents in the first-line setting, or is there a space to start with endocrine therapy alone and to add CDK 4/6 inhibitors at progression?” he said. “An academic-driven trial should be designed to address this question.” – by Mark Leiser
Di Leo A, et al. Abstract 2360_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.
Disclosures: Eli Lilly funded this study. Di Leo reports honoraria, consultant fees and travel funds from Eli Lilly, Daiichi-Sankyo, Roche, Novartis, Pfizer, AstraZeneca, Genomic Health, Eisai, Pierre Fabre, Bayer and Celgene; consultant and travel funds from Puma Biotechnology; and research funding from Novartis, Pfizer and AstraZeneca. Please see the abstract for a list of all researchers’ relevant financial disclosures.