Angelo Di Leo, MD, PhD
The addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with the non-steroidal aromatase inhibitor (NSAI) alone for previously untreated patients with HER2-negative, HR-positive advanced breast cancer, according to findings from the phase III MONARCH3 study presented at the 2017 ESMO Congress.
In the phase III study, the median progression-free survival (PFS) was not yet reached in the abemaciclib arm versus 14.7 months with the 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
“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. “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-only 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."