The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial

Abstract

Importance: Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated.

Objective: To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET.

Design, setting, and participants: MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019.

Interventions: Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary).

Main outcomes and measures: The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02.

Results: Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib.

Conclusions and relevance: Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy.

Trial registration: ClinicalTrials.gov identifier: NCT02107703.

Figure 1.. CONSORT Diagram

Figure 2.. Kaplan-Meier Curve of Overall Survival in the Intent-to-Treat Population

The number of events in the abemaciclib plus fulvestrant arm was 211 vs 127 in the placebo plus fulvestrant arm. Median overall survival in the abemaciclib plus fulvestrant arm was 46.7 months vs 37.3 months in the placebo plus fulvestrant arm. HR indicates hazard ratio.

Figure 3.. Subgroup Analysis of Overall Survival

The hazard ratios (HRs) are for the abemaciclib arm vs placebo arm. The HRs are unstratified except for the overall survival (OS), which was stratified by metastatic site and endocrine therapy (ET) resistance. Overall survival HRs are indicated by diamonds, and 95% CIs are indicated by the crossing horizontal lines. The diamond size is proportional to patient subgroup population size. ECOG PS indicates Eastern Cooperative Oncology Group performance status.

Figure 4.. Kaplan-Meier Curves of Overall Survival by Metastatic Site

A, In patients with visceral disease, the median overall survival (mOS) was 40.3 months vs 32.2 months in the abemaciclib and placebo arms, respectively. B, The mOS in patients with bone-only disease was 47.3 months in the placebo arm and was not reached in the abemaciclib arm. C, In those with other sites of metastasis, mOS was 48.5 months vs 40.7 months in the abemaciclib and placebo arms, respectively. HR indicates hazard ratio.

Figure 5.. Kaplan-Meier Curves of Overall Survival by Resistance to Endocrine Therapy

A, The median overall survival (mOS) in patients with primary endocrine therapy resistance was 38.7 months vs 31.5 months in the abemaciclib arm vs placebo arm. B, In patients with secondary endocrine therapy resistance, mOS was 48.8 months vs 40.7 months in the abemaciclib vs placebo arms. HR indicates hazard ratio.