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.
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).



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/m2every 3 weeks or intravenous paclitaxel 80 mg/m2weekly). 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.



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.



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.



F Hoffmann-La Roche.
Department of Hematology, Oncology, and Tumor Immunology, Charité-University Medicine Berlin, Berlin, Germany.
Peter C
PC
Thuss-Patience
Medical Oncology/Solid Tumor Program, Meyer Cancer Center of Weill Cornell Medical College, New York, NY, USA.
Manish A
MA
Shah
Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital, Kashiwa, Japan.
Atsushi
A
Ohtsu
University Hospitals Leuven and KU Leuven, Leuven, Belgium.
Eric
E
Van Cutsem
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jaffer A
JA
Ajani
Guatemala City, Guatemala.
Hugo
H
Castro
Christie Hospital NHS Trust, Manchester, UK.
Wasat
W
Mansoor
Yonsei Cancer Center, Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea.
Hyun Cheol
HC
Chung
Fovarosi Szent Laszlo Korhaz-Rendelointezet, Budapest, Hungary.
Gyorgy
G
Bodoky
National Cancer Center Hospital East, Chiba, Japan.
Kohei
K
Shitara
Department of Molecular Oncology, Genentech, South San Francisco, CA, USA.
Gail D Lewis
GDL
Phillips
Biostatistics, F Hoffmann-La Roche, Basel, Switzerland.
Tina
T
van der Horst
Pharmaceutical Development Clinical Oncology, F Hoffmann-La Roche, Basel, Switzerland.
Marie-Laurence
ML
Harle-Yge
Product Development Oncology, Genentech, South San Francisco, CA, USA.
Betsy L
BL
Althaus
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address: ykkang@amc.seoul.kr.
Yoon-Koo
YK
Kang
D000230:Adenocarcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000556:secondary; D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D004943:Esophagogastric Junction; D064147:Febrile Neutropenia / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced*; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008453:Maytansine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008875:Middle Aged; D011014:Pneumonia / Q000139:chemically induced; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D019233:Retreatment; D013274:Stomach Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D000068878:Trastuzumab
D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C080625:taxane; C508053:ERBB2 protein, human