Nadia Harbeck1, Chiun-Sheng Huang2, Sara Hurvitz3, Dah-Cherng Yeh4, Zhimin Shao5, Seock-Ah Im6, Kyung Hae Jung7, Kunwei Shen8, Jungsil Ro9, Jacek Jassem10, Qingyuan Zhang11, Young-Hyuck Im12, Marek Wojtukiewicz13, Qiang Sun14, Shin-Cheh Chen15, Rainer-Georg Goeldner16, Martina Uttenreuther-Fischer16, Binghe Xu17, Martine Piccart-Gebhart18. 1. Brustzentrum der Universität München and Comprehensive Cancer Center of the Ludwig-Maximilians-Universität München, Munich, Germany. 2. National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Taiwan Breast Cancer Consortium, Taipei, Taiwan. 3. University of California, Los Angeles, Los Angeles, CA, USA; Translational Research in Oncology, Los Angeles, CA, USA. 4. Taiwan Breast Cancer Consortium, Taipei, Taiwan; Taichung Veterans General Hospital, Taichung, Taiwan. 5. Fudan University Shanghai Cancer Center, Shanghai, China. 6. Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. 7. Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 8. Comprehensive Breast Health Center, Rui Jin Hospital, Shanghai, China. 9. National Cancer Center, Goyang, South Korea. 10. Medical University, Gdansk, Poland. 11. Cancer Hospital of Harbin Medical University, Harbin, China. 12. Samsung Medical Center, Seoul, South Korea. 13. Comprehensive Cancer Centre, Medical University, Bialystok, Poland. 14. Peking Union Medical College Hospital, Beijing, China. 15. Taiwan Breast Cancer Consortium, Taipei, Taiwan; Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan. 16. Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany. 17. Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Peking Union Medical College, Beijing, China. Electronic address: bhxu@hotmail.com. 18. Institut Jules Bordet, Brussels, Belgium.
Abstract
BACKGROUND:Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. METHODS: We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m(2) per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. FINDINGS:Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). INTERPRETATION:Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. FUNDING: Boehringer Ingelheim.
RCT Entities:
BACKGROUND:Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. METHODS: We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m(2) per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. FINDINGS: Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). INTERPRETATION:Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. FUNDING: Boehringer Ingelheim.
Authors: George Iancu; Dragos Serban; Cristinel Dumitru Badiu; Ciprian Tanasescu; Mihai Silviu Tudosie; Corneliu Tudor; Daniel Ovidiu Costea; Anca Zgura; Raluca Iancu; Danut Vasile Journal: Exp Ther Med Date: 2021-12-03 Impact factor: 2.447
Authors: G Nader-Marta; D Martins-Branco; E Agostinetto; M Bruzzone; M Ceppi; L Danielli; M Lambertini; N Kotecki; A Awada; E de Azambuja Journal: ESMO Open Date: 2022-05-30
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