Abemaciclib Added to Aromatase Inhibitors Allows for PFS Boost in HR+/HER2- Breast Cancer

When abemaciclib was added to a non-steroidal aromatase inhibitor in treatment-naive patients with HER2-negative, HR-positive advanced breast cancer, the combination reduced the risk of progression of disease or death by 46% compared with either anastrozole or letrozole alone, according to findings from the phase III MONARCH 3 trial.

Angelo Di Leo, MD, PhD

When abemaciclib was added to a non-steroidal aromatase inhibitor (NSAI) in treatment-naive patients with HER2-negative, HR-positive advanced breast cancer, the combination reduced the risk of progression of disease or death by 46% compared with either anastrozole or letrozole alone, according to findings from the phase III MONARCH 3 trial.

In the phase III study, the median progression-free survival (PFS) was not yet reached in the abemaciclib arm versus 14.7 months with an NSAI alone (HR, 0.543; 95% CI, 0.409-0.723;P= .000021). In those with measurable disease, the objective response rate (ORR) was 59.2% with the CDK4/6 inhibitor and 43.8% in the control arm (P= .004).

“The results of the MONARCH-3 trial showed that the addition of abemaciclib with a non-steroidal AI improves PFS and ORR when compared with a non-steroidal AI alone for postmenopausal patients with endocrine sensitive HER2-negative advanced breast cancer,” said Angelo Di Leo, MD, PhD, medical oncologist, Sandro Pitigliani Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, during a presentation at the 2017 ESMO Congress in Madrid, Spain. “Abemaciclib, which is dosed on a continuous schedule, was generally well tolerated."

In the phase III MONARCH 3 trial, 493 postmenopausal women with locoregionally recurrent or metastatic breast cancer were randomized in a 2:1 ratio to continuous abemaciclib at 150 mg twice daily (n = 328) or placebo (n = 165). All patients also received either 1 mg of anastrozole or 2.5 mg of letrozole once daily. Patients had not received prior system therapy for metastatic disease, although adjuvant endocrine therapy was permitted. The median follow-up for the ESMO presentation was 17.8 months.

The median age of patients in both groups was 63 years, and approximately 80% had measurable disease at baseline. The majority had a metastatic recurrence (55.5% to 60%), although nearly 40% of patients had de novo metastatic disease. Approximately 54% of patients had visceral disease and nearly 22% had bone-only disease. Nearly half of patients had received a prior neoadjuvant or adjuvant endocrine therapy.

Across all patients in the study, the ORR was 48.2% with abemaciclib versus 34.5% with placebo (P= .002). The complete response rate with the CDK4/6 inhibitor was 1.5% versus 0% with an NSAI alone. At the time of the analysis, data were immature for overall survival. There had been 49 total deaths, with 315 required for the final assessment.

Median PFS consistently favored the abemaciclib arm across preplanned subgroups. An exploratory analysis found that treatment-free interval (TFI), bone-only disease, and liver metastasis could potentially be utilized for treatment selection.

"Looking at our exploratory subgroup analysis, the patients with the worst prognostic factors are those who seem to derive the largest benefit of adding abemaciclib to single-agent endocrine therapy," said Di Leo. "Conversely, in patients with a long treatment-free interval or bone-one disease, we observed, that in this particular group of patients, single agent endocrine therapy could still be considered a valued treatment option."

In the small exploratory analysis, those with a TFI of <36 months (42 patients in abemaciclib arm versus 32 in the placebo group) had a median PFS that was not reached with abemaciclib versus 9.0 months with placebo (HR, 0.48; 95% CI, 0.25-0.91). Those with a TFI ≥36 months (94 in the abemaciclib arm versus 40 in the placebo group), did not experience additional benefit with the addition of the CDK4/6 inhibitor (HR, 0.83; 95% CI, 0.46-1.52).

Additionally, the PFS increase with abemaciclib was not statistically significant in those with bone-only disease (HR, 0.58; 95% CI, 0.27-1.25), and in those without bone-only disease, there was a larger benefit with abemaciclib (HR, 0.51; 95% CI, 0.38-0.70). A benefit for abemaciclib was seen for those with and without liver metastases, although it was more dramatic for patients with visceral metastases (HR, 0.47; 95% CI, 0.25-0.87).

When discussing the findings, ESMO expert Nicholas C. Turner, MD, PhD, noted that abemaciclib could become a standard of care therapy and that the benefits seen in the MONARCH 3 study were consistent with other trials of CDK4/6 inhibitors. He projected that median PFS would be improved by 11 to 12 months, once data were more mature.

"This is practice changing data. We see substantial efficacy with abemaciclib, with a safety profile compatible with long-term dosing," said Turner, from the Royal Marsden and the Institute of Cancer Research. "We're now seeing consistent benefit across studies, suggesting a class effect for CDK4/6 inhibitors."

The most common adverse event (AE) associated with abemaciclib was diarrhea, which occurred in 81.3% of patients treated with the CDK4/6 inhibitor versus 29.8% of those in the control arm. These events were primarily grade 1/2 in both arms. With abemaciclib there was no grade 4 diarrhea and grade 3 diarrhea occurred in 9.5% of patients. "Diarrhea typically occurred within the first 7 to 10 days and was successfully managed with dose reductions and anti-diarrheal medication," said Di Leo.

In addition to diarrhea, neutropenia was also common, which is a known AE associated with CDK4/6 inhibition. This AE was seen in 41.3% of those treated with abemaciclib versus 1.9% in the control arm. Only 1 patient developed febrile neutropenia in the abemaciclib arm.

Di Leo suggested that differences between the potency for each CDK could have resulted in the higher rates of diarrhea and the decrease in neutropenia with abemaciclib compared with other agents. Overall, abemaciclib is 14 times more potent for CDK4 than CDK6, which differentiates it from other approved agents in the class, he said.

"The safety profiles of these compounds are not overlapping. There's more neutropenia with palbociclib and ribociclib and more diarrhea with abemaciclib," said Di Leo. "This can be used to tailor treatment for patients. Those who live farther from the hospital and cannot get their blood counts tested as frequently may take one while those who don't want gastrointestinal problems may take another."

Other common AEs with abemaciclib versus placebo, respectively, included fatigue (40.1% vs 31.7%), nausea (38.5% vs 19.9%), abdominal pain (29.1% vs 11.8%), anemia (28.4% vs 5.0%), vomiting (28.4% vs 11.8%), alopecia (26.6% vs 10.6%), decreased appetite (24.5% vs 9.3%), and leukopenia (20.8% vs 2.5%). Additionally, grade 2 creatinine increase was experienced by 52.9% of those in the abemaciclib arm versus 4.5% with placebo.

"We know now that treating patients with abemaciclib may induce a creatinine rise," said Di Leo. "This creatinine rise observed in patients treated with abemaciclib is not associated with any renal injury or impairment in the renal function."

Overall, 27.5% of patients in the abemaciclib arm experienced a serious AE versus 14.9% of those in the control arm. There were significantly more deaths from AEs in the abemaciclib arm (2.4%) versus placebo group (1.2%). Deaths in the investigational arm were attributed to lung infection (n = 3), embolism (n = 2), cerebral ischemia (n = 1), pneumonitis (n =1), and respiratory failure (n = 1). Additionally, venous thromboembolic events occurred in 4.9% of patients treated with abemaciclib versus 0.6% with placebo.

"Approximately 5% of patients had a venous thromboembolic event on this study, and I think we need further information on this when the study is finally published," noted Turner.

Abemaciclib is also being explored in the adjuvant setting, in the MONARCH-E trial. This phase III trial plans to enroll 3580 patients to receive adjuvant endocrine therapy with or without abemaciclib. The primary endpoint of the study is invasive disease-free survival, and results are not anticipated until 2027 (NCT03155997).


Di Leo A, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract 236O_PR.