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
Journal
The Lancet Oncology
Journal Volume
17
Journal Issue
3
Pages
357-366
Date Issued
2016
Author(s)
Harbeck N.
Hurvitz S.
Yeh D.-C.
Shao Z.
Im S.-A.
Jung K.H.
Shen K.
Ro J.
Jassem J.
Zhang Q.
Im Y.-H.
Wojtukiewicz M.
Sun Q.
Chen S.-C.
Goeldner R.-G.
Uttenreuther-Fischer M.
Xu B.
Piccart-Gebhart M.
Krasnozhon D.
Tong Z.
Arora R.S.
Jacob L.A.
Staroslawska E.
Wang X.
Satya Suresh Attili V.
Mehta A.O.
Lee S.H.
Tseng M.-L.
Perera N.A.M.
Huizing M.
Melichar B.
Grigiene R.
Bharwani L.
Cortes J.
Garcia M.
Chirgwin J.
Baranau Y.
Ermakov N.
Li W.
Lin T.
Qin S.
Shen P.
Yang J.
Dohollou N.
Kerbrat P.
Uleer C.
Kristeleit H.
Nagarkar R.V.
Crown J.
Kelly C.
Kaufman B.
Ionta M.T.
Park K.H.
Farhat F.
Chin L.S.
Sufliarsky J.
Saenz J.A.G.
Begbie S.
Dittrich C.
Karchmit Y.
Awada A.
Bines J.
Rigo R.
Califaretti N.
Sridhar S.
Villa D.
Jiang Z.
Wang X.
Wu G.
Shu W.
Zheng H.
Delva R.
Pivot X.
Beckmann M.
Bischoff J.
Gerber B.
Maass N.
Richters L.
Schumacher C.
Jain M.M.
Indelli M.
Purkalne G.
Juozaityte E.
Erdkamp F.L.G.
Sanchez F.S.
Susko-Kazamowicz M.
Sousa S.
Mukhametshina G.
Shomova M.
Yap Y.S.
Beniak J.
Grasic C.
Demetriou G.
Maart K.
Pienaar R.
Rapoport B.
Chacon J.I.
Cao M.G.
Chen S.-T.
Chang H.-T.
Kaplan E.
Lawler W.
Carraro S.
Lerzo G.
Chan A.
Snyder R.
Noryk D.
Graas M.-P.
Aleixo S.
Caleffi M.
Franke F.
Hegg R.
Santi P.X.
Vinholes J.
Zereu M.
Ghedira S.
Poirier E.
Yelle L.
Yanez E.
Liu J.
Luo R.
Pecha V.
Petruzelka L.
Azim H.A.
Shamaa S.S.
Brain E.
Chauffert B.
Espie M.
Lortholary A.
Petit T.
Augustin D.
Barinoff J.
Fett W.
Hannig C.V.
Kurbacher C.M.
Otremba B.
Paepke S.
Adamson D.
Kristeleit H.
O'brien M.
Bhattacharyya G.S.
Krishnan S.
Mohan R.
Nag S.
Fried G.
Isacson R.
Nakayama T.
Kudaba I.
Luna G.A.
Dercksen M.W.
Honkoop A.
Tjan-Heijnen V.C.G.
van den Bosch J.
Palominos O.M.
Blasinska-Morawiec M.
Szczylik C.
Wysocki P.
Damasceno M.
Pais A.
Biakhov M.
Chovanec J.
Harris J.
Caranana V.
Lopez R.
Tusquets I.
Chang T.-W.
Liu M.-C.
Altundag K.
Gokmen E.
Avery T.
Chan D.
Kendall S.
Hetzel D.
Kass F.
Singh J.
The LUX-Breast 1 study group
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. ? 2016 Elsevier Ltd.
SDGs
Other Subjects
afatinib; alanine aminotransferase; estrogen receptor; hemoglobin; navelbine; progesterone receptor; trastuzumab; afatinib; antineoplastic agent; epidermal growth factor receptor 2; navelbine; quinazoline derivative; trastuzumab; vinblastine; acne; adult; alanine aminotransferase blood level; anemia; Article; asthenia; bone marrow depression; bone marrow toxicity; breast cancer; cancer adjuvant therapy; constipation; controlled study; decreased appetite; dehydration; diarrhea; drug dose reduction; drug withdrawal; epistaxis; fatigue; febrile neutropenia; female; fever; hand foot syndrome; hemoglobin blood level; HER2 positive metastatic breast cancer; HER2 positive metastatic breast cancer; human; hypertension; hypokalemia; infection; leukocyte count; leukopenia; loading drug dose; major clinical study; middle aged; monotherapy; mouth ulcer; mucosa inflammation; multicenter study; nausea; neutropenia; neutrophil count; open study; paronychia; patient compliance; peripheral neuropathy; phase 3 clinical trial; priority journal; progression free survival; randomized controlled trial; rash; side effect; stomatitis; vomiting; weight reduction; adjuvant chemotherapy; aged; analogs and derivatives; Breast Neoplasms; clinical trial; comparative study; disease free survival; dose response; drug administration; Kaplan Meier method; mastectomy; metabolism; metastasis; mortality; pathology; procedures; prognosis; proportional hazards model; risk assessment; survival analysis; treatment outcome; tumor invasion; tumor recurrence; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Mastectomy; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Proportional Hazards Models; Quinazolines; Receptor, ErbB-2; Risk Assessment; Survival Analysis; Trastuzumab; Treatment Outcome; Vinblastine
Publisher
Lancet Publishing Group
Type
journal article