This is a prospective, international, randomized, investigator-initiated phase II/III trial. Patients (pts) with resectable, Her2-negative EGA(≥ cT2 or cN+) were randomized to 4 pre-and post-operative cycles of FLOT (docetaxel 50 mg/m2; oxaliplatin 85 mg/m2; leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2w) alone (Arm A) or FLOT with RAM 8mg/kg q2w, followed by 16 cycles RAM (Arm B, FLOT-RAM). Here, we report the main results along with the subgroup analysis explaining the higher rate of R0-resection in the FLOT-RAM arm...In total, 180 pts (FLOT, 91; FLOT-RAM, 89) were randomized. Baseline characteristics were similar between arms (male, 73%; median age, 60y; cT3/T4, 83%; cN+, 78%; GEJ, 54%). The rate of signet-ring cell cancer was high (40%). As reported at ASCO, no difference in path response rates was seen (FLOT, 30%; FLOT-RAM, 27%). However, FLOT-RAM significantly improved R0-resection rate (FLOT, 82%; FLOT-RAM, 96%, p=0.0078). This difference was due to less pts in the FLOT-RAM arm with disease progression prior to operation (FLOT, 6%; FLOT-RAM, 1%), more pts proceeding to operation (FLOT, 93%; FLOT-RAM, 97%), more pts receiving resectional surgery (FLOT, 88%; FLOT-RAM, 97%), and less pts having residual tumor out of the resected pts (FLOT, 4; FLOT-RAM, 1).

Pts with resectable, Her2-negative, adenocarcinoma of the stomach and GEJ (≥ cT2 or cN+) were enrolled...91% of pts with FLOT and 92% with FLOT-RAM completed the 4 pre- cycles. R0-resection (in the full set) could be achieved in 83% of pts with FLOT and 97% of pts with FLOT-RAM (p = 0.0049). The rate of major path response was similar in both arms and was 30% for FLOT and 27% for FLOT-RAM. Surgical morbidity was observed in 37% of pts with FLOT and 44% of pts with FLOT-RAM. Mortality was 2.5% with FLOT and 5.9% with FLOT-RAM including GEJ type I tumors and dropped to 2.9% in both arms after excluding type I tumors per amendment.

...Negative HER-2 detection (score IHC HER-2 0 or IHC HER-2 1+ ); IHC HER-2 2+ and negative by FISH, SISH or CISH1 2....

The rate of major path response was similar in both arms and was 29% for FLOT and 26% for FLOT-RAM. Median DFS was slightly improved in pts with FLOT-RAM (32 months vs. 21 months), while median OS was similar in both treatment arms (FLOT 45 months, FLOT-RAM 46 months). Surgical morbidity was observed in 32% of pts with FLOT and 41% of pts with FLOT-RAM. Mortality at 60 days after surgery was 4.1% with FLOT and 2.8% with FLOT-RAM. There were bit more G≥3 adverse events with FLOT-RAM (76% vs. 92%). In this phase II trial, the addition of ramucirumab to perioperative FLOT significantly improved R0-resection rates and slightly prolonged DFS without an impact on path response or overall survival.