1. Goodwin, Peter M.

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MADRID-"CDK 4/6 inhibitors plus endocrine therapy are definitely more active than endocrine therapy alone in endocrine-sensitive HER2-negative advanced breast cancer," noted Angelo Di Leo, MD, PhD, Head of the Sandro Pitigliani Medical Oncology at the Hospital of Prato Istituto Toscano Tumori in Italy at the ESMO 2017 Congress (Abstract 236O_PR).

breast cancer; ESMO ... - Click to enlarge in new windowbreast cancer; ESMO 2017 Congress. breast cancer; ESMO 2017 Congress

He reported data from the MONARCH 3 trial showing that adding the cyclin-dependent kinase (CDK) 4/6 inhibitor abemaciclib to initial endocrine therapy for postmenopausal patients improved progression-free survival compared to using endocrine therapy alone.

Angelo Di Leo, MD, P... - Click to enlarge in new windowAngelo Di Leo, MD, PhD. Angelo Di Leo, MD, PhD

"We have a new CDK 4/6 inhibitor-abemaciclib-that combined with endocrine therapy is now a new treatment option as an initial therapy for patients who are menopausal who have endocrine-sensitive HER2-negative advanced breast cancer," Di Leo said.


The study also found that patients with metastases confined to bone only, and those with longer periods of disease-free survival since the end of their adjuvant endocrine therapy, had good responses to endocrine therapy alone and could potentially avoid or defer adding a CDK 4/6 inhibitor.


"Our data suggest that you may start treatment with only endocrine therapy [in] patients with favorable prognostic factors. In patients with bad prognostic factors, the combination therapy should be considered the best treatment option," he explained.


Study Details

MONARCH 3 was a phase III, randomized, double-blind trial of abemaciclib or placebo in addition to endocrine therapy with a non-steroidal aromatase inhibitor (anastrozole or letrozole) as initial therapy in postmenopausal women with hormone-receptor positive HER2-negative advanced breast cancer. The study recruited 493 patients from 22 countries who had not been treated previously for metastatic disease. The primary endpoint was progression-free survival.


The investigators found that the combination of abemaciclib and endocrine therapy significantly prolonged progression-free survival with a hazard ratio of 0.543 (p = 0.000021) compared to single agent endocrine therapy. Fifty-nine percent of patients with measurable disease who were treated with abemaciclib had objective responses compared to 44 percent in the placebo arm (p = 0.004).


Among patients receiving abemaciclib, 81.3 percent had diarrhea compared with 29.8 percent of those on placebo. And the drug was also associated with more neutropenia than endocrine therapy alone: 29.8 percent as compared with 1.9 percent.


"This is the third study demonstrating that the combination of endocrine therapy with a CDK4/6 inhibitor is better than endocrine therapy alone," stated Di Leo. "Abemaciclib reduced the risk of disease progression by 46 percent."


This finding was consistent with benefits observed with other CDK 4/6 inhibitors, he said, but this agent had a different mechanism of action. "It is 14 times more potent on CDK 4 than on CDK 6. The clinical consequence of this is that with abemaciclib you have less neutropenia but you may have diarrhea."


Giuseppe Curigliano, MD, PhD, Director of the Division of New Drug Development at the European Institute of Oncology at the University of Milan, Italy, said the MONARCH 3 trial confirmed the role of this new class of agent in combination with endocrine therapy in the treatment of metastatic breast cancer.


"Many patients with metastatic disease still receive chemotherapy, despite guidelines and data from clinical trials," he said. "This study confirms that we should avoid chemotherapy in hormone-receptor positive, HER2-negative metastatic breast cancer if visceral crisis is not present."


But Curigliano was still concerned about the optimal sequencing of treatment in the era of CDK 4/6 inhibitors. "Should we use these agents in the first-line setting or is there a space to start with endocrine therapy alone and add CDK 4/6 inhibitors at progression? An academic driven trial should be designed to address this question," he concluded.


Commenting on the findings, Evandro de Azambuja, MD, PhD, Medical Director at the Breast European Adjuvant Study Team (BrEAST) Data Centre at the Jules Bordet Institute in Brussels, Belgium, said that selecting patients for therapy with abemaciclib was a big outstanding issue.


"What is interesting here is that even some control arm patients do very well. So we still have to identify those patients who do not require CDK 4/6 inhibitors from the beginning-but you could use [them] later. But we still don't know who these patients are."

Evandro de Azambuja,... - Click to enlarge in new windowEvandro de Azambuja, MD, PhD. Evandro de Azambuja, MD, PhD

But he was satisfied there was a clear role for these agents, noted they could also find a role in other settings, too. "The guidance for clinicians is to use endocrine therapy with CDK 4/6 inhibitors in metastatic [disease] first-line," he said. And we have data on the second line as well. These drugs have [also] been tested in the adjuvant setting now-after surgery-together with endocrine therapy," de Azambuja concluded.


Peter M. Goodwin is a contributing writer.