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

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 gastrooesophageal 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/m(2) every 3 weeks or intravenous paclitaxel 80 mg/m(2) 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.