Perioperative ramucirumab in combination with FLOT versus FLOT alone for resectable esophagogastric adenocarcinoma (RAMSES/FLOT7): Results of the phase II-portion—A multicenter, randomized phase II/III trial of the German AIO and Italian GOIM.
Salah‐Eddin Al‐Batran, Ralf‐Dieter Hofheinz, Harald Schmalenberg, Dirk Strumberg, Eray Goekkurt, Stefan Angermeier, Thomas Zander, Jochem Potenberg, Hans‐Georg Kopp, Daniel Pink, Gabriele Margareta Siegler, Michael Schenk, Ferdinando De Vita, Evaristo Maiello, Timo Gaiser, Disorn Sookthai, Ulli Simone Bankstahl, Claudia Pauligk, Thorsten Oliver Goetze, Nils Homann
Abstract
4501 Background: Periop. FLOT has become SOC for resectable, esophagogastric adenocarcinoma. However, patient’s outcome is still poor. This trial evaluates the addition of the VEGF-R2 inhibitor ramucirumab (RAM) to FLOT for resectable patients (pts). Methods: This is a prospective, international, randomized, investigator-initiated phase II/III trial. Pts with resectable, Her2-negative, adenocarcinoma of the stomach and GEJ (≥ cT2 or cN+) were enrolled. Pts 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 the same regimen with RAM 8mg/kg q2w, followed by 16 cycles RAM (Arm B, FLOT-RAM). Important endpoints of phase II (exploratory) were major pathological (complete and nearly complete) response, centrally assessed acc. to Becker criteria, R0-resection rate, and safety. GEJ type I tumors and pts requiring trans-thoracic esophagectomy were excluded for safety reasons during the conduct of the study. Results: In total, 180 pts were randomized. Baseline characteristics were similar between arms (male, 73%; median age, 60y; cT3/T4, 83%; cN+, 78%; GEJ, 54%; signet-ring cells, 40%). However, the FLOT-RAM arm included more unfavorable pts with T4 (9% vs. 4%), Siewert type I tumors (18% vs. 13%), impaired ECOG PS of 1 (34% vs. 20%), and concomitant disease (87% vs. 79%). 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. There was bit more G≥3 adverse events with FLOT-RAM (78% vs. 89%). Conclusions: In this phase II trial, the addition of ramucirumab to perioperative FLOT significantly improved R0-resection rates without an impact on path response, mainly because more patients could proceed to operation. The FLOT-RAM is safe, when type I tumors are excluded. Clinical trial information: NCT02661971 .