Perioperative FLOT plus ramucirumab for resectable esophagogastric adenocarcinoma: A randomized phase II/III trial of the German AIO and Italian GOIM

TY - JOUR

T1 - Perioperative FLOT plus ramucirumab for resectable esophagogastric adenocarcinoma: A randomized phase II/III trial of the German AIO and Italian GOIM

AU - Goetze, Thorsten O

AU - Hofheinz, Ralf-Dieter

AU - Gaiser, Timo

AU - Schmalenberg, Harald

AU - Strumberg, Dirk

AU - Goekkurt, Eray

AU - Angermeier, Stefan

AU - Zander, Thomas

AU - Kopp, Hans G

AU - Pink, Daniel

AU - Siegler, Gabriele

AU - Schenk, Michael

AU - de Vita, Ferdinando

AU - Galizia, Gennaro

AU - Maiello, Evaristo

AU - Bechstein, Wolf O

AU - Elshafei, Moustafa

AU - Loose, Maria

AU - Sookthai, Disorn

AU - Brulin, Tanita

AU - Pauligk, Claudia

AU - Homann, Nils

AU - Al-Batran, Salah-Eddin

N1 - © 2023 UICC.

PY - 2023/7/1

Y1 - 2023/7/1

N2 - This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared with FLOT alone (A:82% B:96%; P = .009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, P = 0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, P = 0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade ≥ 3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted.

AB - This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared with FLOT alone (A:82% B:96%; P = .009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, P = 0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, P = 0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade ≥ 3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted.

KW - Humans

KW - Adenocarcinoma/drug therapy

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - Esophageal Neoplasms/drug therapy

KW - Esophagogastric Junction/pathology

KW - Fluorouracil

KW - Leucovorin

KW - Stomach Neoplasms/drug therapy

KW - Vascular Endothelial Growth Factor A

KW - Ramucirumab

U2 - 10.1002/ijc.34495

DO - 10.1002/ijc.34495

M3 - SCORING: Journal article

C2 - 36883420

VL - 153

SP - 153

EP - 163

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 1

ER -