Abstract P5-19-01: Randomized Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1
Authors: Harbeck Nadia , Huang Chiun-Sheng , Hurvitz Sara , Yeh Dah-Cherng , Shao Zhimin , Im Seock-Ah , Jung Kyung Hae , Shen Kunwei , Ro Jungsil , Jassem Jacek , Zhang Qingyuan , Im Young-Hyuck , Wojtukiewicz Marek , Sun Qiang , Chen Shin-Cheh , Goeldner Rainer-Georg , Lahogue Annick , Uttenreuther-Fischer Martina , Xu Binghe , Piccart-Gebhart Martine ,   on Behalf of the LUX-Breast 1 Study Group
Published: May 2015

Abstract
Background: Afatinib is an oral, irreversible ErbB family blocker with anti-tumour activity in patients (pts) with HER2-positive metastatic breast cancer (MBC) after failure on trastuzumab.1 Preclinically, afatinib + vinorelbine (AV) showed an additive effect; clinically, the AV combination had a manageable safety profile and showed activity in two Phase I trials.2,3 This randomized, open-label, Phase III trial (LUX-Breast 1) compared AV with trastuzumab + vinorelbine (TV) in pts with HER2-positive MBC who had progressed on a prior T-based regimen.
Methods: Pts with HER2-positive MBC and failure of one T-based regimen (adjuvant/first-line) were randomized 2:1 to AV (40 mg/day oral + 25 mg/m2/week iv) or TV (2 mg/kg/week iv after 4 mg/kg loading dose + 25 mg/m2/week iv). Treatment continued until progressive disease (PD) or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) by investigator review; secondary endpoints included objective response rate (ORR), overall survival (OS) and safety. Planned accrual was 780 pts.
Results
Between August 2010 and April 2013, 508 patients were randomized (AV:339, TV:169). Baseline characteristics were balanced in both arms (mean age 52 yrs, Asian 50.6%, White 41.6%, ER/PR positive 28.7%). 41.1% of pts failed on prior adjuvant and 58.9% on 1st line T-based treatment. A pre-planned risk/benefit assessment was found unfavorable by the DMC and recruitment was stopped. Pts ongoing on AV therapy were switched to TV, received A or V monotherapy, or stopped treatment. Primary endpoint analysis was performed with 307 of the originally 484 planned PFS events (211 [62.2%] AV arm; 96 [56.8%] TV arm). Median PFS was 5.5 months with AV vs 5.6 months with TV (HR 1.10; 95% CI 0.86, 1.41; P=0.4272). ORR was 46.1% with AV and 47.0% with TV (OR 1.04; 95% CI 0.71, 1.51; P=0.8510). OS analysis was based on 144 (28.4%) OS events (108 [31.9%] in AV arm; 36 [21.3%] in TV arm). Median OS was 19.6 months with AV and 28.6 months with TV (HR 1.76; 95% CI 1.20, 2.59; P=0.0036).
The most common drug-related AEs were diarrhea (80.1%), neutropenia (75.1%) and rash (45.1%) with AV, and neutropenia (78.7%), leukopenia (37.3%) and anemia (27.8%) with TV. Rate of infections (53.0% vs 40.5%) was higher with AV vs TV. More AV than TV pts discontinued due to AEs (15.4% vs 7.1%). Fatal AEs were reported for 18 (5.3%) in the AV vs 5 (3.0%) pts in the TV arm, and were mainly associated with PD (9 pts in AV and 1 in TV arm). Three AV pts died due to treatment-related causes (sepsis/multi-organ failure; septic shock; pulmonary fibrosis).
Conclusions: AV and TV demonstrated similar PFS and ORR, but OS diverged and was shorter for AV compared to TV in pts with HER2-positive MBC. The safety profile of AV was consistent with the individual monotherapies, but its tolerability compared unfavorably to TV. Analyses are ongoing to elucidate potential factors (e.g. impact of follow up treatments) contributing to the diverging PFS and OS outcomes.
1. Lin NU et al. Breast Cancer Res Treat 2012;133:1057-65
2. Bahleda R et al. J Clin Oncol 2011;29; abs 2585
3. Masuda N et al. SABCS 2013 abs P4-16-11.
Citation Format: Nadia Harbeck, Chiun-Sheng Huang, Sara Hurvitz, Dah-Cherng Yeh, Zhimin Shao, Seock-Ah Im, Kyung Hae Jung, Kunwei Shen, Jungsil Ro, Jacek Jassem, Qingyuan Zhang, Young-Hyuck Im, Marek Wojtukiewicz, Qiang Sun, Shin-Cheh Chen, Rainer-Georg Goeldner, Annick Lahogue, Martina Uttenreuther-Fischer, Binghe Xu, Martine Piccart-Gebhart, on Behalf of the LUX-Breast 1 Study Group. Randomized Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-01.