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Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study

 Peter C Thuss-Patience  ;  Manish A Shah  ;  Atsushi Ohtsu  ;  Eric Van Cutsem  ;  Jaffer A Ajani  ;  Hugo Castro  ;  Wasat Mansoor  ;  Hyun Cheol Chung  ;  Gyorgy Bodoky  ;  Kohei Shitara  ;  Gail D Lewis Phillips  ;  Tina van der Horst  ;  Marie-Laurence Harle-Yge  ;  Betsy L Althaus  ;  Yoon-Koo Kang 
 Lancet Oncology, Vol.18(5) : 640-653, 2017 
Journal Title
 Lancet Oncology 
Issue Date
Adenocarcinoma/chemistry ; Adenocarcinoma/drug therapy* ; Adenocarcinoma/secondary ; Adult ; Aged ; Aged, 80 and over ; Anemia/chemically induced ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use* ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use* ; Bridged-Ring Compounds/adverse effects ; Bridged-Ring Compounds/therapeutic use* ; Esophagogastric Junction* ; Febrile Neutropenia/chemically induced ; Female ; Follow-Up Studies ; Gastrointestinal Hemorrhage/chemically induced* ; Humans ; Intention to Treat Analysis ; Male ; Maytansine/adverse effects ; Maytansine/analogs & derivatives* ; Maytansine/therapeutic use ; Middle Aged ; Pneumonia/chemically induced ; Receptor, ErbB-2/analysis ; Retreatment ; Stomach Neoplasms/chemistry ; Stomach Neoplasms/drug therapy* ; Stomach Neoplasms/pathology ; Survival Rate ; Taxoids/adverse effects ; Taxoids/therapeutic use* ; Thrombocytopenia/chemically induced ; Trastuzumab
BACKGROUND: Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). METHODS: This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939. FINDINGS: Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1-23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2-18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7-9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1-11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87-1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group. INTERPRETATION: Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. FUNDING: : F Hoffmann-La Roche.
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정현철(Chung, Hyun Cheol) ORCID logo https://orcid.org/0000-0002-0920-9471
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