The combination of abemaciclib and fulvestrant has demonstrated a statistically significant improvement in overall survival compared with fulvestrant and placebo in women with HR–positive, HER2-negative advanced or metastatic breast cancer who have previously received endocrine therapy, according to updated interim results from the phase III MONARCH 2 trial.
Maura Dickler, MD
The combination of abemaciclib (Verzenio) and fulvestrant (Faslodex) has demonstrated a statistically significant improvement in overall survival (OS) compared with fulvestrant and placebo in women with hormone receptor (HR)positive, HER2-negative advanced or metastatic breast cancer who have previously received endocrine therapy, according to updated interim results from the phase III MONARCH 2 trial.1
In a news release, Lilly, the developer of the CDK4/6 inhibitor, noted that this is the first CDK4/6 inhibitor to demonstrate a statistically significant improvement in OS in combination with fulvestrant, which was a secondary endpoint of the trial.
"This definitive overall survival analysis from MONARCH 2 showed significant improvement in overall survival for women living with HR-positive, HER2-negative metastatic breast cancer, a complex disease that remains incurable," said Maura Dickler, MD, vice president, late stage development, Lilly Oncology, in the news release. "For many doctors and patients, overall survival is the most important endpoint. It's been difficult in the past to achieve meaningful improvements in this endpoint for women with advanced breast cancer, including those whose cancer progressed after prior endocrine therapy."
The trial, which included both pre/peri- and postmenopausal women, previously demonstrated a statistically significant improvement in progression-free survival (PFS) as well, which was the primary endpoint of the MONARCH 2 trial.2
"I believe we must continue to fight this devastating disease because the women who are living with metastatic breast cancer want to do everything they can to lead more fulfilling lives and be there for those who need them most," said Anne White, president, Lilly Oncology, in the news release. "While Verzenio had already shown an impressive benefit for progression-free survival, we are delighted that Verzenio is the first and only CDK4 & 6 inhibitor in combination with fulvestrant that has significantly extended life for both pre/peri- and postmenopausal women."
The initial approval for abemaciclib in combination with fulvestrant as a treatment for patients with HR-positive, HER2-negative breast cancer was supported by the PFS results from the MONARCH 2 trial.
Lilly announced that the company plans to submit these data later in the year to regulatory authorities and present the findings at an upcoming medical meeting.
The randomized, double-blind, placebo-controlled phase III trial enrolled 669 patients with HR-positive, HER2-negative metastatic breast cancer who had progressed on prior endocrine therapy. The patients were randomized 2:1 to receive fulvestrant with either abemaciclib (n = 446), which was given on a continuous dosing schedule, or placebo (n = 223).
All of the patients had experienced disease progression on endocrine therapy or within 12 months of treatment in the neoadjuvant or adjuvant setting, or while receiving first-line endocrine therapy for metastatic disease. Those who had received chemotherapy or more than 1 line of prior endocrine therapy for metastatic disease were excluded from the trial.
Abemaciclib was given at 150 mg twice daily, after an adjustment from the initial dose of 200 mg twice daily due to diarrhea-related toxicity concerns, plus 500 mg of fulvestrant. A gonadotropin releasing hormone agonist was also given to all pre/perimenopausal patients (82%).
The median PFS with abemaciclib and fulvestrant was 16.4 months compared with 9.3 months with fulvestrant alone (HR< 0.553; 95% CI, 0.449-0.681;P<.001) after a median follow-up of 19.5 months. A blinded central analysis and a post-dose adjustment sensitivity analysis both demonstrated similar PFS benefits with added abemaciclib. The benefit was also consistent across patient subgroups.
In the intention-to-treat population, the objective response rate (ORR) was 35.2% (95% CI, 30.8%-39.6%) in the abemaciclib arm compared with 16.1% (95% CI, 11.3%-21.0%) in the fulvestrant-alone arm. Among the patients with measurable disease, the ORR was 48.1% (95% CI, 42.6%-53.6%) in the abemaciclib arm versus 21.3% (95% CI, 15.1%-27.6%) in the fulvestrant arm (P<.001). In the abemaciclib arm, 3.5% of patients achieved a complete response.
Frequent all-grade treatment-related adverse events (AEs) with abemaciclib and fulvestrant versus fulvestrant alone were diarrhea (86.4% vs 24.7%), neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%).
The most commonly reported grade 3 AEs in the abemaciclib/fulvestrant versus fulvestrant-alone arms were neutropenia (23.6% vs 1.3%) and diarrhea (13.4% vs 0.4%). Grade 4 neutropenia occurred in 2.9% versus 0.4% of patients in the abemaciclib and fulvestrant-alone groups, respectively. There were 3 deaths in the abemaciclib arm linked to treatment-related AEs, compared with none in the control arm.
Updated data did not demonstrate any new safety signals from the established safety profile of abemaciclib.