Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial

Abstract

Summary Background The antibody–drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. Methods EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m2 self-administered orally twice daily on days 1–14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1–21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166. Findings Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months [95% CI 26·3–34·1] vs 25·9 months [95% CI 22·7–28·3]; hazard ratio 0·75 [95% CI 0·64–0·88]). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5–26·1]). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control gr...

Late Administration of Trastuzumab Emtansine Might Lead to Loss of Chance for Better Outcome in Patients with HER2-Positive Metastatic Breast Cancer

“…With a median follow-up of 19 months, treatment with T-DM1 improved PFS from 6.4 months to 9.6 months in the control arm with an absolute gain of 3.2 months (hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.55-0.77; p < 0.001). Most importantly, patients in the T-DM1 arm experienced prolonged OS of 4.0 months (29.9 vs. 25.9 months; HR 0.75; p < 0.001) [25]. Moreover, the ORR was also improved with T-DM1 (44 vs. 31%; p < 0.001), mainly due to the greater number of partial responses.…”

“…Originally, the primary endpoint of the study was PFS assessed by an independent review panel, but later with data still masked, overall survival (OS) was included as a co-primary efficacy endpoint [25]. With a median follow-up of 19 months, treatment with T-DM1 improved PFS from 6.4 months to 9.6 months in the control arm with an absolute gain of 3.2 months (hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.55-0.77; p < 0.001).…”

Advances in the management of HER2-positive early breast cancer

“…One such example is in breast cancer, where the antibody-drug conjugate T-DM1, a combination of the HER2-targeting antibody trastuzumab with the microtubule-inhibiting chemotherapeutic agent DM1 (emtansine), has been used to deliver cytotoxic therapy directly to breast cancer cells while avoiding the severe adverse event profile often associated with chemotherapy (Verma et al, 2012). In patients with metastatic breast cancer who were resistant to trastuzumab, T-DM1 significantly prolonged time to progression and resulted in an improvement in OS of 4 months compared to lapatinib and capecitabine (29.9 months vs 25.9 months; HR 0.75) (Diéras et al, 2017). T-DM1 is now approved as a treatment for metastatic breast cancer that has progressed on first-line trastuzumab-based therapy.…”

A prognostic 10‐lncRNA expression signature for predicting the risk of tumour recurrence in breast cancer patients

“…Patients with luminal breast cancer often have a better prognosis, whereas those with HER2‐enriched or basal‐like types have a poorer prognosis. For HER2‐positive breast cancers, the monoclonal antibody, trastuzumab and the dual tyrosine dual kinase inhibitor, lapatinib, were approved . Because of the heterogeneity of breast cancer, multiple gene prognostic signatures could provide further prognostic information, and several molecular prognostic profiles have been validated for clinical use .…”