Interim data from the MONARCH3 study indicate that abemaciclib is an effective first-line therapy for advanced ER-positive, HER2-negative breast cancer. Adding the investigational CDK4/6 inhibitor to letrozole significantly improved patients' progression-free survival, compared with those given a placebo alongside endocrine therapy.

Having shown strong second-line efficacy for advanced ER-positive, HER2-negative breast cancer, abemaciclib (Eli Lilly) appears also to benefit patients as part of initial treatment. Adding the investigational CDK4/6 inhibitor to letrozole up front significantly improved progression-free survival (PFS), according to an interim analysis of the MONARCH3 trial.

The findings were presented by Angelo Di Leo, MD, PhD, of Istituto Toscano Tumori in Prato, Italy, during the ESMO 2017 Congress, the annual meeting of the European Society for Medical Oncology, in Madrid, Spain. In this global phase III study, 493 postmenopausal women with locally advanced or metastatic disease were randomized 2:1 to receive abemaciclib or placebo, plus letrozole.

Di Leo reported that abemaciclib reduced the risk of disease progression by about 46%. At the time of analysis, the median PFS was not reached in this cohort, versus 14.7 months in the placebo arm. Among patients with measurable disease, the objective response rates were 59.2%—including five complete responses—and 43.8%, respectively. Diarrhea, a main side effect with abemaciclib, typically occurred early during treatment and was managed with dose reductions and antidiarrheal agents.

The reduced risk of disease progression seen with abemaciclib was “remarkably consistent” with that of palbociclib (Ibrance; Pfizer) as well as ribociclib (Kisqali; Novartis), noted Nicholas Turner, MD, PhD, of the Institute of Cancer Research in London, UK. “It's clear that we have a class effect of CDK4/6 inhibitors here.”

International guidelines have long recommended first-line endocrine therapy for ER-positive, HER-negative breast cancer, but “out in the real world, a sizable number of women still get chemotherapy instead,” Turner added. “I think we'll start to shift away from this approach as practice-changing studies like MONARCH3 emphasize that CDK4/6 inhibition alongside endocrine therapy is much better.”

Whether all women with this disease subtype should receive a CDK4/6 inhibitor up front remains a matter of debate. For instance, based on a subgroup analysis of MONARCH3′s data, Di Leo suggested that patients with bone-only rather than visceral metastases might not initially require the addition of abemaciclib to endocrine therapy. Turner, though, cautioned that this exploratory probe involved a relatively small number of patients, adding that “it will be interesting to see if a similar finding is made” in analyses of data from the palbociclib and ribociclib studies.

“At this time, I think it's very difficult to say that we have any clinical subgroups who benefit more or less from this class of drugs,” he commented.

Besides testing it in metastatic breast cancer, researchers are evaluating abemaciclib as adjuvant therapy for women with early-stage disease who are at high risk for recurrence, Turner said. Results from this study, MonarchE, are keenly awaited. As well, CDK4/6 inhibitors were recently shown to promote antitumor immunity by enhancing antigen presentation and suppressing the proliferation of regulatory T cells. These are preclinical findings, Turner observed; nonetheless, “we look forward to data from clinical trials combining these agents with immunotherapy, in future years.” –Alissa Poh