Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial
机构：[a]Brustzentrum der Universität München and Comprehensive Cancer Center of the Ludwig-Maximilians-Universität München, Munich, Germany[b]National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan[c]Taiwan Breast Cancer Consortium, Taipei, Taiwan[d]University of California, Los Angeles, Los Angeles, CA, United States[e]Translational Research in Oncology, Los Angeles, CA, United States[f]Taichung Veterans General Hospital, Taichung, Taiwan[g]Fudan University Shanghai Cancer Center, Shanghai, China[h]Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea[i]Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea[j]Comprehensive Breast Health Center, Rui Jin Hospital, Shanghai, China[k]National Cancer Center, Goyang, South Korea[l]Medical University, Gdansk, Poland[m]Cancer Hospital of Harbin Medical University, Harbin, China[n]Samsung Medical Center, Seoul, South Korea[o]Comprehensive Cancer Centre, Medical University, Bialystok, Poland[p]Peking Union Medical College Hospital, Beijing, China[q]Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan[r]Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany[s]Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China[t]Peking Union Medical College, Beijing, China[u]Institut Jules Bordet, Brussels, Belgium[v]Cancer Hospital Chinese Academy of Medical Science, 86001, China[w]Taichung Veterans General Hospital, 88602, Taiwan[x]Fudan University Shanghai Cancer Center, 86010, China[y]Seoul National University Hospital, 82003, South Korea[z]Asan Medical Center, 82002, South Korea[aa]Shanghai Ruikin Hospital, 86009, China[ab]National Cancer Center, 82001, South Korea[ac]University Clinical Center, 48003, Poland[ad]National Taiwan University Hospital, 88601, Taiwan[ae]The Third Affiliated Hospital of Harbin Medical University, 86022, China[af]Samsung Medical Center, 82004, South Korea[ag]Bialystock's Oncology Center, 48002, Poland[ah]Peking Union Medical College Hospital, 86005, China[ai]Chang Gung Memorial Hospital, Linkou, 88605, Taiwan[aj]Regional Clinical Oncology Dispensary, 07001, Russian Federation[ak]Tianjin Medical University Cancer Institute and Hospital, 86006, China[al]Sujan Surgical Cancer Hospital, 91010, India[am]Kidwai Memorial Institute of Oncology, Bangalore, 91001, India[an]Ziema Lubelska Oncological Center, Lublin, 48007, Poland[ao]Zheijang Cancer Hospital, 86013, China[ap]Bibi General Hospital and Cancer Centre, 91011, India[aq]Central India Cancer Research Institute, 91013, India[ar]Severance Hospital, 82005, South Korea[as]Taipei Veterans General Hospital, 88603, Taiwan[at]National Cancer Institute, 94001, Sri Lanka[au]University of California at Los Angeles, 10004, United States[av]Edegem - University of Antwerp, 32005, Belgium[aw]Teaching Hospital Olomouc, 42003, Czech Republic[ax]National Cancer Institute, Vilnius, 37002, Lithuania[ay]Johns Hopkins Singapore International Medical Center, 65001, Singapore[az]Hospital Vall d'Hebron, 34011, Spain[ba]Hospital Insular de Gran Canaria, 34004, Spain[bb]Maroondah Hospital, 61004, Australia[bc]Public Health Institute, Minsk City, 37502, Belarus[bd]N N Alexandrov National Cancer Center of Belarus, 37501, Belarus[be]First Hospital of Jilin University, 86008, China[bf]Sun Yat-Sen University Cancer Center, 86016, China中山大学肿瘤防治中心[bg]The 81st Hospital of PLA, 86011, China[bh]1st Affiliated Hospital of College of Medicine, Zhejiang University, 86012, China浙江大学医学院附属第一医院[bi]The Chinese PLA General Hospital, 86002, China[bj]CLI Bordeaux Nord, 33009, France[bk]CTR Eugene Marquis, Rennes, 33016, France[bl]Gynak-onkol Gem praxis, Hildesheim, 49008, Germany[bm]Queen Elizabeth Hospital, 44005, United Kingdom[bn]Curie Manavata Cancer Center, 91006, India[bo]St Vincent's University Hospital, 35301, Ireland[bp]Mater Misericodiae University Hospital, 35303, Ireland[bq]Sheba Medical Center, Tel Hashomer, 97201, Israel[br]Pol Univ di Cagliari, 39007, Italy[bs]Korea University Anam Hospital, 82006, South Korea[bt]Hammoud Hospital University Medical Centre, 96101, Lebanon[bu]National University Hospital, 65002, Singapore[bv]National Institute of Oncology, Bratislava, 42102, Slovakia[bw]Hospital Clinico San Carlos, 34007, Spain[bx]Port Mazquarie Base Hospital, 61002, Australia[by]Kaiser Franz Josef Hospital, 43001, Austria[bz]Vitebsk Regional Clinical Oncology Dispensary, 37503, Belarus[ca]Hospital Jules Bordet, Brussels, 32001, Belgium[cb]Instituto Nacional do Cancer - INCA, 55004, Brazil[cc]Hospital Santa Cruz, 55010, Brazil[cd]Grand River Regional Cancer Centre, 11004, Canada[ce]Princess Margaret Hospital, 11003, Canada[cf]BC Cancer Agency, Vancouver, 11005, Canada[cg]307 Hospital of PLA, 86004, China[ch]Qilu Hospital, Shangdong University, 86015, China[ci]Wuhan Union Hospital, 86020, China[cj]Peking University People's Hospital, 86003, China[ck]West China Hospital Sichuan University, 86021, China[cl]CTR P Papin, Angers, 33011, France[cm]Hospital Jean Minjoz, Besançon, 33007, France[cn]Universität Erlangen, 49009, Germany[co]Universitätsklinikum Magdeburg, 49014, Germany[cp]Universitätsfrauenklinik am Klinikum Südstadt, 49012, Germany[cq]Universitätsklinik Aachen, 49004, Germany[cr]Uniklinik Köln, 49001, Germany[cs]St Elisabeth-Krankenhaus, 49006, Germany[ct]KEM Hospital, 91004, India[cu]Az Osp Univ di Ferrar-Arcispedale S Anna-UO Oncologia, 39008, Italy[cv]P Stradins Clinical University Hospital, 37101, Latvia[cw]Hospital of Lithuanian University of Health Sciences Kauno Klinikos, 37001, Lithuania[cx]Zuyderland Medisch Centrum, 31001, Netherlands[cy]Instituto Oncológico Miraflores SA, 51002, Peru[cz]Onocology Centre of Olsztyn, 48001, Poland[da]IOP Porto Francisco Gentil, EPE, 35110, Portugal[db]GUZ Kazansky Oncology Dispensary, 07006, Russian Federation[dc]GUZ Regional Clinical Oncology Dispensary, 07011, Russian Federation[dd]National Cancer Centre, 65003, Singapore[de]POKO Poloclinic Dept of Clinical Oncology, 42104, Slovakia[df]Institute of Oncology Ljubljana, 38601, Slovenia[dg]Wits Donal Gordon Clinical Trial Site, 27001, South Africa[dh]Langenhoven Drive Oncology Centre, 27005, South Africa[di]GVI Oncology Medical Clinic, 27004, South Africa[dj]Medical Oncology Centre of Rosebank, 27006, South Africa[dk]Hospital Virgen de la Salud, 34005, Spain[dl]USP Institut Universitari Dexeus, 34002, Spain[dm]Chang-Hua Christian Hospital, 88607, Taiwan[dn]Kaohsiung Veterans General Hospital, 88608, Taiwan[do]North shore Cancer Research Associates, Skokie, 10031, United States[dp]St Jude Heritage Healthcare, Fullerton, 10112, United States[dq]Instituto Medico de Asistencia e Investigaciones SA, 54005, Argentina[dr]Sanatorio de la Provodencia, 54010, Argentina[ds]Mount Medical Centre, 61006, Australia[dt]St Vincents Hospital, 61001, Australia[du]Grodno Regional Clinical Hospital, 37504, Belarus[dv]Leige Hospital St Joseph, 32003, Belgium[dw]Centro de Pesquisas Clinicas em Oncologia, 55003, Brazil[dx]Associacäo Hospitalar Moinhos de Vento, 55005, Brazil[dy]Associcao Hospital de Caridade de Ijiu, 55012, Brazil[dz]Centro de Referécia da Saude da Mulher-Hosp Perola Byington, 55016, Brazil[ea]Faculdade de Medicina do ABC, 55011, Brazil[eb]Centro de Novos Tratamentos Clinionco, 55008, Brazil[ec]Irmandade da Santa Casa de Misericordia de Porto Alegre, 55002, Brazil[ed]Dr Leon Richard Oncology Centre, 11002, Canada[ee]Hospital du St Sacrement, 11007, Canada[ef]Hopital Notre-Dame du CHUM, 11001, Canada[eg]Instituto Clínico Oncológico del Sur - ICOS, 56001, Chile[eh]Fujian Provincial Tumor Hospital, 86019, China[ei]NanFang Hospital, 86017, China[ej]MEDICON a s Praha 4, 42002, Czech Republic[ek]General Faculty Hospital, Prague, 42001, Czech Republic[el]El Maial Specialized Hospital, 20003, Egypt[em]Oncology Centre, Mansoura University, 20001, Egypt[en]CTR René Huguenin, St Cloud, 33021, France[eo]Hopital Amiens Sud, Amiens, 33020, France[ep]Hopital Saint-Louis, Paris, 33012, France[eq]CTR Cehterine de Sienne, Nantes, 33013, France[er]Centre Paul Strauss, Strasbourg, 33008, France[es]Klinikum Deggendorf, 49002, Germany[et]Kliniken-Essen-Mitte, Innere Medizin, Essen, 49021, Germany[eu]Facharzt für Innere Medizin, 49024, Germany[ev]Onkologische Gemeinschaftspraxis, 49026, Germany[ew]LMU Innenstadt, 49025, Germany[ex]Medizinisches Zentrum Bonn, 49013, Germany[ey]Onkologische Praxis Oldenburg, 49011, Germany[ez]Klinikum rechts der Isar TU, München, 49007, Germany[fa]Ninewells Hospital, Dundee, 44002, United Kingdom[fb]Guy's Hospital Cancer Centre, 44001, United Kingdom[fc]Royal Marsden Hospital, Sutton, 44006, United Kingdom[fd]Orchid Nursing Home, 91009, India[fe]Dr Rai Memorial Cancer Centre, 91017, India[ff]King George Hospital, 91005, India[fg]Jehangir Hospital, 91022, India[fh]Mater Private Hospital, 35306, Ireland[fi]Rambam Med Center, Tel Aviv Medical Haifa, 97203, Israel[fj]Shaare Zedek Medical Center, Jerusalem, 97205, Israel[fk]Osaka Med Centre for Cancer and CV DIAs, Osaka, 81013, Japan[fl]Riga East University Hospital, 37102, Latvia[fm]Hospital de Jesus, 52003, Mexico[fn]Máxima Medisch Centrum, Eindhoven, 31004, Netherlands[fo]Isala Klinieken, Sophia, 31009, Netherlands[fp]Academisch Ziekenhuis Maastricht, 31005, Netherlands[fq]Albert Schweitzer ziekenhuis, Dorwijk, 31003, Netherlands[fr]Hospital Nacional Adolfo Guevara Velasco, 51004, Peru[fs]Kopernik's Specialised Hospital, 48004, Poland[ft]Military Medical Institute, 48010, Poland[fu]Wielkopolskie Oncology Centre n.a. Maria Sklodowska-Courie, 48013, Poland[fv]Centro Hospitalar Säo Joäo, EPE, 35103, Portugal[fw]IPO Coimbra Francisco Gentil, EPE, 35104, Portugal[fx]N A Semashko Central Clinical Hospital, Moscow, 07008, Russian Federation[fy]St Jacob's Hospital, Bardejov, 42103, Slovakia[fz]Rondebosch Oncology Centre, 27008, South Africa[ga]Hospital Arnau de Vilanova, 34008, Spain[gb]Hospital Clinico Universitario de Santiago de Compostela, 34009, Spain[gc]Hospital de Mar, 34001, Spain[gd]National Cheng Kung University Hospital, 88609, Taiwan[ge]Koo Foundation Sun Yet-Sen Cancer Center, 88610, Taiwan[gf]Hacettepe Universitesi Tip Fakultesi, Ic Hastalikari ABD, 90002, Turkey[gg]Ege Universitesi Tip Fakultesi Tibbi Onkoloji Bilim Dali, 90001, Turkey[gh]Thomas Jefferson University, Philadelphia, 10048, United States[gi]Cancer Care Associates Medical Group, Redondo Beach, 10109, United States[gj]Utah Cancer Specialists, Salt Lake City, 10043, United States[gk]Hope Women's Cancer Center, Asheville, 10110, United States[gl]Santa Barbara Hematology Oncology Medical Group, 10103, United States[gm]Cedar Valley Cancer Center, Waterloo, 10020, United States
We showed that afatinib plus vinorelbine did not improve progression-free survival or objective response and was also associated with shorter overall survival compared with trastuzumab plus vinorelbine. Afatinib was also less well tolerated than was trastuzumab. Cross-signalling by other members of the ErbB family is thought to be an important mechanism through which HER2 can remain activated, despite HER2-targeted therapy. We therefore expected that broader inhibition of the ErbB family with afatinib might improve efficacy compared with trastuzumab in patients who were anticipated to have trastuzumab resistance (based on progression during or shortly after trastuzumab treatment). However, the results show that continuation of trastuzumab beyond progression conferred better outcomes than did switching to an ErbB family blocker. Our findings also suggest that the definition of trastuzumab resistance remains challenging. Despite progressing on or shortly after trastuzumab treatment, a proportion of patients may retain some sensitivity to this drug, which could have implications for future studies in this area. Our findings accord with those from studies of tyrosine kinase inhibitors for HER2-overexpressing metastatic breast cancer. In the MA.31 trial, 23 a taxane (paclitaxel or docetaxel) plus lapatinib was associated with shorter median progression-free survival than was a taxane plus trastuzumab for first-line treatment of metastatic breast cancer (9·0 months vs 11·3 months; HR 1·37 [95% CI 1·13–1·65]; p=0·001), resulting in early closure of the trial. Overall survival did not significantly differ between lapatinib plus taxane and trastuzumab plus taxane in the intention-to-treat group (HR 1·28 [95% CI 0·95–1·72]; p=0·11); however, overall survival was worse with lapatinib than with trastuzumab in patients with centrally confirmed HER2-positive disease (HR 1·47 [95% CI 1·03–2·09]; p=0·03). 23 In the CEREBEL trial, 24 median progression-free survival and overall survival were shorter with lapatinib plus capecitabine than with trastuzumab plus capecitabine in patients with HER2-positive metastatic breast cancer, although the difference was not significant for overall survival (progression-free survival was 6·6 months vs 8·1 months; HR 1·30 [95% CI 1·04–1·64]; p=0·021; overall survival was 22·7 months vs 27·3 months; HR 1·34 [95% CI 0·95–1·90]; p=0·095). In MA.31, roughly 40% of patients had a primary diagnosis of metastatic breast cancer and thus had not received any previous anti-HER2 treatment. By contrast, to our knowledge, our study is the first to compare trastuzumab-based treatment in multiple lines versus switching to an alternative treatment on progression. Furthermore, although MA.31 and CEREBEL assessed lapatinib (an EGFR and HER2 inhibitor), we used a second-generation irreversible ErbB family inhibitor to provide broader inhibition. By contrast with the CEREBEL trial, which included patients without brain metastases at baseline, our study enrolled those with inactive, asymptomatic brain metastases. In this small subgroup of patients, there was no evidence that switching to irreversible ErbB family inhibition was beneficial compared with remaining on trastuzumab-based therapy. Similarly, a retrospective subgroup analysis of EMILIA 25 showed that the rate of CNS progression was similar for patients receiving trastuzumab emtansine and those receiving lapatinib plus capecitabine. In the present study, the incidence of drug-related adverse events was consistent with the safety profiles of each drug; however afatinib plus vinorelbine was less well tolerated than was trastuzumab plus vinorelbine. More patients in the afatinib group than in the trastuzumab group had adverse events leading to treatment discontinuation, serious adverse events, and fatal adverse events. The incidence and severity of haematological adverse events (including neutropenia) were generally similar between treatment groups; however, more patients in the afatinib group had fatal infections than did those in the trastuzumab group. One potential explanation for poorer tolerability could be a negative pharmacological interaction between afatinib and vinorelbine. However, extensive investigation of the combination in phase 1 studies, 26,27 based on plasma exposure, did not suggest any pharmacokinetic interaction between these two compounds. LUX-Breast 1 was a large randomised multicentre trial; nevertheless, there were some limitations. First, recruitment was terminated early and patients receiving afatinib were required to switch to alternative treatments, which only enables an adequate comparison of efficacy and safety results between the randomised treatment groups up to the point of the treatment switch. The findings for overall survival could be affected by subsequent treatments, the data for which are still being collected, and many patients have still not had an overall survival event, which could render the findings immature. Additionally, second-generation antibodies, such as pertuzumab and trastuzumab emtansine (not available at the time of study design), are now standard treatments in many countries. As such, use of trastuzumab across multiple lines or trastuzumab plus vinorelbine as first-line treatment is limited in clinical practice. However, trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer failing on trastuzumab. Contributors NH, C-SH, ZS, R-GG, MU-F, BX, and MP-G designed the study. NH, C-SH, SH, D-CY, KHJ, KS, JR, Y-HI, MW, QS, and BX recruited patients. NH, C-SH, SH, D-CY, ZS, S-AI, KHJ, KS, JR, JJ, QZ, Y-HI, MW, QS, S-CC, MU-F, BX, and MP-G collected data. NH, C-SH, SH, S-AI, KHJ, JR, JJ, QZ, Y-HI, S-CC, R-GG, MU-F, and BX analysed and interpreted data. MU-F provided administrative and technical support. All authors drafted and reviewed the report, and approved the final version for submission. Declaration of interests NH has received research fees to her institution for conducting studies from Boehringer Ingelheim; and personal fees from Roche and Novartis. C-SH has received grants from Boehringer Ingelheim and Roche. SH has received research funds to her institution from Boehringer Ingelheim, Genentech/Roche, Novartis, Lilly, OBI Pharmaceuticals, Merrimack, PUMA, Biomarin, GlaxoSmithKline, and Amgen; personal fees for reimbursement for travel to meetings from Boehringer Ingelheim, Genentech/Roche, Novartis, Lilly, OBI Pharmaceuticals, and Merrimack; honoraria for leading an advisory board from Boehringer Ingelheim; and honoraria for speaking at a conference from Genentech/Roche. S-AI has received research funding from AstraZeneca and has participated in advisory boards for AstraZeneca, Novartis, and Roche. KHJ has received a grant from Eisai Korea. JJ has held an advisory role with Boehringer Ingelheim. R-GG and MU-F are employees of Boehringer Ingelheim. The other authors declare no competing interests. Acknowledgments This study was supported by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. We thank the patients, their families, and all of the investigators who participated in this study. Additionally, we thank the Boehringer Ingelheim trial manager Annick Lahogue for her excellent support throughout the trial. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Caroline Allinson of GeoMed, an Ashfield company, part of UDG Healthcare, during the preparation of this Article.
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出版当年[2016]版：
大类|1 区医学
小类|1 区肿瘤学
最新[2023]版：
大类|1 区医学
小类|1 区肿瘤学
第一作者：
第一作者机构：[a]Brustzentrum der Universität München and Comprehensive Cancer Center of the Ludwig-Maximilians-Universität München, Munich, Germany
推荐引用方式(GB/T 7714)：
Harbeck N,Huang C.-S,Hurvitz S,et al.Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial[J].LANCET ONCOLOGY.2016,17(3):357-366.doi:10.1016/S1470-2045(15)00540-9.
APA：
Harbeck, N,Huang, C.-S,Hurvitz, S,Yeh, D.-C,Shao, Z...&The LUX-Breast 1 study group.(2016).Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial.LANCET ONCOLOGY,17,(3)
MLA：
Harbeck, N,et al."Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial".LANCET ONCOLOGY 17..3(2016):357-366
医学