Trastuzumab-Pertuzumab Plus Eribulin or Taxane as First-Line Chemotherapy for Human Epidermal Growth Factor 2-Positive Locally Advanced/Metastatic Breast Cancer: The Randomized Noninferiority Phase III EMERALD Trial

Abstract

Purpose: Trastuzumab-pertuzumab (HP) plus taxane is a current standard first-line therapy for recurrent or metastatic human epidermal growth factor 2 (HER2)+ breast cancer (BC). We investigated noninferiority of eribulin to a taxane when combined with dual HER2 blockade as first-line systemic treatment for locally advanced/metastatic HER2+ BC.

Methods: In the phase III EMERALD trial (target sample size, 480; ClinicalTrials.gov identifier: NCT03264547/UMIN000027938), patients were randomly assigned (1:1) to receive eribulin 1.4 mg/m² once daily on days 1 and 8 (eribulin group) or a taxane (docetaxel 75 mg/m² once on day 1 or paclitaxel 80 mg/m² once daily on days 1, 8, and 15; taxane group) intravenously in a 21-day cycle, each with HP on day 1. The primary end point was progression-free survival (PFS; intention-to-treat population). Secondary end points included objective response rate, overall survival (OS), patient-reported quality of life (QoL), and safety. Noninferiority was tested using the stratified Cox proportional hazards model to estimate hazard ratios (HRs) for PFS events, with a noninferiority HR margin of 1.33.

Results: Between August 2017 and June 2021, 446 patients (median age, 56.0 years) were enrolled. The median PFS was 14.0 and 12.9 months in the eribulin group (n = 224) and taxane group (n = 222 [docetaxel/paclitaxel, n = 186/36]), respectively (HR, 0.95 [95% CI, 0.76 to 1.19]), which confirmed the noninferiority of the study regimen. The median OS was 65.3 months in the taxane group but has not been reached in the eribulin group. Median time to QoL deterioration was numerically longer with eribulin than with taxane. Adverse event (AE) rates were similar, despite the longer duration of eribulin use. Infusion reaction, skin-related AEs, diarrhea, and edema were more common with taxane, whereas neutropenia was more common with eribulin.

Conclusion: The results suggested that eribulin + HP is an option for first-line treatment of locally advanced/metastatic HER2+ BC.

FIG 1.

CONSORT diagram for the JBCRG-M06/EMERALD trial. FAS, full analysis set; H, trastuzumab; ITT, intention-to-treat; P, pertuzumab.

FIG 2.

(A) Kaplan-Meier curves and (B) subgroup analysis data for PFS. Generated from data for the intention-to-treat population (N = 446). HR and 95% CI were calculated using the stratified Cox proportional hazards model. The primary end point results met the criterion for noninferiority (ie, upper limit of 95% CI <1.33). In the subgroup analysis, the HR (95% CI) for each variable (study group v control group) was estimated using the Cox proportional hazards model, with the treatment groups as covariates. ^aRandom assignment stratification factors (revised). HER2, human epidermal growth factor 2; HR, hazard ratio; IHC, immunohistochemistry; PFS, progression-free survival; T-DM1, trastuzumab emtansine.

FIG 3.

(A) Kaplan-Meier curves and (B) subgroup analysis data for OS. Generated from data for the intention-to-treat population (N = 446). HR and 95% CI were calculated using the stratified Cox proportional hazards model. In the subgroup analysis, the HR (95% CI) for each variable (study group v control group) was estimated using the Cox proportional hazards model, with the treatment groups as covariates. ^aRandom assignment stratification factors (revised). HER2, human epidermal growth factor 2; HR, hazard ratio; IHC, immunohistochemistry; OS, overall survival; T-DM1, trastuzumab emtansine.

FIG 4.

Kaplan-Meier curves for patient-reported QoL, showing time to QoL deterioration, defined as ≥10-point decrease from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Module C30. Generated from data for the QoL analysis set (n = 437). HR and 95% CI were calculated using the stratified Cox proportional hazards model. HR, hazard ratio; QoL, quality of life.

FIG A1.

Study design for JBCRG-M06/EMERALD, a multicenter, randomized, noninferiority phase III trial. ^aH: 8 mg/kg loading dose, 6 mg/kg subsequent doses + P: 840 mg/body loading dose, 420 mg/body subsequent doses (intravenously, once daily). Treatment continued to disease progression or unmanageable toxicity. ECOG, Eastern Cooperative Oncology Group; H, trastuzumab; HER2, human epidermal growth factor 2; LABC, locally advanced breast cancer; LVEF, left ventricular ejection fraction; MBC, metastatic breast cancer; P, pertuzumab; QoL, quality of life; T-DM1, trastuzumab emtansine; R, random assignment.