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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
Reference:
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.
Perspective
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Abemaciclib does have a different toxicity profile than the other two compounds — palbociclib (Ibrance, Pfizer) and ribociclib (Kisqali, Novartis) — with higher rates of diarrhea and lower rates of neutropenia. This toxicity might affect its use in patients with breast cancer, for whom therapies are noncurative, as effects on quality of life play an important role in making treatment decisions with patients.
One interesting finding, although always difficult to interpret when comparing different trials, is that — in both the MONARCH 3 and MONARCH 2 trials — the combinations with abemaciclib induced higher response rates than those observed in similar patient populations treated with palbociclib or ribociclib combinations. Whether this finding truly differentiates abemaciclib from other CDK 4/6 inhibitors will have to be determined by further investigations.
The proper sequencing of therapies continues to be a hotly debated topic among breast oncologists. The MONARCH 3 data confirm that a large population of patients can get durable responses from single-agent aromatase inhibitor treatment without the need for CDK 4/6 inhibition. The full trial data will have to be reviewed if characteristics other than bone-only disease and time to progression from adjuvant therapy would help us identify this patient population.
The CDK 4/6 inhibitors have firmly established themselves as an option for patients with hormone receptor-positive breast cancer, and they have resulted in prolongation of response to hormonal treatments and delay of initiation of chemotherapy. Patients are able to live longer before experiencing toxicities associated with chemotherapy. Further studies to help us determine best sequencing and choice of agents for individual patients will result in increasingly personalized care and better results with less toxicity.
Perspective
Back to TopER-positive, HER-2-negative breast cancer is the most common subtype of breast cancer. It represents about 70% of patients with advanced disease. The standard first-line management for postmenopausal women with metastatic ER-positive, HER-2 negative breast cancer has been aromatase inhibitors, because studies approximately 20 years ago showed letrozole and anastrozole were substantially better than tamoxifen.
There have been further studies showing incremental improvement by adding fulvestrant to first-line therapy. But what we have really wanted is targeted therapies that understand and target the biology of ER-positive, HER-2 negative breast cancer. We’ve known for a long time that cyclin D1 and cyclin-dependent kinase (CDK) 4 are potentially critical to breast cancer genesis.
The MONARCH3 study randomly assigned women with metastatic postmenopausal ER-positive HER-2-negative breast cancer between the standard of care — which is an aromatase inhibitor, mostly letrozole — and the addition of abemaciclib. What we would like to ask is: “Is this a practice-changing study?” and “Do these results change who we give this therapy to?”
We have seen a substantial improvement in progression-free survival with the addition of abemaciclib, with a hazard ratio of 0.54. At the moment, abemaciclib hasn’t bridged the median PFS, but we can anticipate that, with further follow-up, we will see approximately a year improvement in median PFS with the addition of abemaciclib, which is really quite a substantial improvement for these patients.
Of course, we have to be careful comparing studies, but what is remarkable is the consistency of the hazard ratio across studies of different CDK4/6 inhibitors (PALOMA2: palbociclib [Ibrance, Pfizer], HR = 0.58; MONALEESA2: ribociclib [Kisqali, Novartis], HR = 0.58; MONARCH3: abemaciclib, HR = 0.54). But there are differences between abemaciclib and the other CDK4/6 inhibitors. There’s less grade 3/grade 4 neutropenia than the others (palbociclib, 66%; ribociclib, 59%; abemaciclib, 22%) but there is more diarrhea (1.4% vs. 1.2% vs. 9.5%). And, as a consequence of having less neutropenia, abemaciclib can be continuously administered, whereas the others are given intermittently. It is worth noting that approximately 5% of patients had a venous thromboembolic event on abemaciclib, and we all need more information when the study is finally published.
This study also may potentially change who we give endocrine therapy to. Across all international guidelines, endocrine therapy is the preferred option — even in the presence of visceral disease — as the first treatment in these patients with metastatic cancer, unless there is evidence of visceral crisis. What we know out in the real world is that a substantial number of women who have visceral disease get chemotherapy instead of hormone therapy, with all of the associated side effects chemotherapy brings, and with only a 5-month median PFS.
MONARCH3 emphasizes that endocrine therapy with an aromatase inhibitor in combination with abemaciclib is potentially substantially better for patients than chemotherapy. I think this will lead a shift more toward guidelines and away from chemotherapy. So, yes, I believe these are practice-changing data.