• Trastuzumab and pertuzumab in combination with eribulin mesylate or a taxane as first-line chemotherapeutic treatment for HER2-positive, locally advanced or metastatic breast cancer: Results of a multicenter, randomized, non-inferiority phase 3 trial in Japan (JBCRG-M06/EMERALD).

Background: Trastuzumab (H) + pertuzumab (P) + taxane is a current standard first-line therapy for recurrent or metastatic human epidermal growth factor 2–positive (HER2+) breast cancer (BC). However, taxane-induced toxicities, which reduce patient quality of life (QoL), necessitate development of less toxic but at least equally effective taxane alternatives. We investigated the non-inferiority of eribulin to taxane when used in combination with dual HER2 blockade (HP). Methods: The multicenter randomized open-label parallel-group phase 3 EMERALD trial (UMIN000027938, NCT03264547) was carried out to test the non-inferiority of eribulin + HP (study regimen) against docetaxel/paclitaxel + HP (control regimen) as first-line chemotherapeutic treatment in patients with locally advanced or metastatic HER2+ BC. The study design has been published (doi: 10.1186/s13063-020-04341-y). Patients were randomized (1:1) to receive, by intravenous infusion in a 21-day cycle, either (i) eribulin 1.4 mg/m2 on days 1 and 8, or (ii) a taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8 and 15), each being administered in combination with HP on day 1. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), QoL and safety. Non-inferiority was tested using the Cox proportional hazards model to estimate hazard ratios (HRs) for PFS events. The upper limit of acceptance of non-inferiority HR margins (1.33 and 1.25) was tested in a stepwise manner. Results: Between August 2017 and June 2021, 446 patients (224 and 222 in the study and control groups, respectively) were enrolled: median age was 56.0 (29–70) years, 244 (54.7%) had ER-positive BC, 285 (63.9%) had visceral metastasis. While 247 patients (55.4%) had de novostage 4 disease, 199 (44.6%) underwent radical surgery and 138 (30.9%) received taxanes perioperatively. Both groups’ baseline characteristics were well balanced. Median PFS was 14.0 mos in the study group and 12.9 mos in the control group (HR, 0.96; 95% CI, 0.77–1.20), confirming non-inferiority of the study regimen. Median OS was 65.3 mos in the control group but has not been reached in the study group. Incidences of adverse drug reactions including grade ≥3 febrile neutropenia, edema and diarrhea were numerically lower in the study group than in the control group (4.9% vs 8.7%, 8.5% vs 42.2% and 36.6% vs 54.1%, respectively). Conclusions: This is the first study to show non-inferiority of eribulin to taxane when used in combination with dual HER2 blockade. As a less toxic but equally effective alternative to the taxane-containing regimen, eribulin combined with HP could be first-line treatment of locally advanced or metastatic HER2+ BC. Clinical trial information: UMIN000027938, jRCTs021180027.