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

Abstract

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.

Phase I trial of apatinib and paclitaxel+oxaliplatin+5‐FU/levoleucovorin for treatment‐naïve advanced gastric cancer

“…In both the phase III RAINFALL study, which combined ramucirumab with cisplatin and fluoropyrimidine, 28 and the phase II RAINSTORM trial, which paired it with S‐1 and oxaliplatin, the combinations of ramucirumab and chemotherapy failed as first‐line treatments for AGC 29 . For the perioperative treatment of AGC, the addition of ramucirumab to the fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) regimen did not lead to a statistically significant improvement in the pathological CR rate as compared with FLOT chemotherapy alone in the randomized phase II/III trial of the German AIO and Italian GOIM 30 . Another generally used anti‐angiogenic monoclonal antibody, bevacizumab, binds to VEGF‐A, thereby inhibiting VEGFR‐2.…”

“…Actually, the combination of ramucirumab and paclitaxel was found to amplify paclitaxel's inhibitory effect on cell cycle progression and the suppression of VEGFR2 expression 35 . However, the failure of ramucirumab combined with FLOT chemotherapy for perioperative treatment of AGC indicated that the synergistic effect between ramucirumab and docetaxel remains questionable 30 . Such synergistic effect was also evident when apatinib was combined with a taxane and 5‐FU, as apatinib can bind to ABC transporters 15,19 .…”

“… 29 For the perioperative treatment of AGC, the addition of ramucirumab to the fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) regimen did not lead to a statistically significant improvement in the pathological CR rate as compared with FLOT chemotherapy alone in the randomized phase II/III trial of the German AIO and Italian GOIM. 30 Another generally used anti‐angiogenic monoclonal antibody, bevacizumab, binds to VEGF‐A, thereby inhibiting VEGFR‐2. The phase III AVAGAST trial did not meet its primary endpoint of improving OS with bevacizumab added to fluoropyrimidine‐cisplatin as first‐line treatment of AGC, although increased PFS and ORR were observed compared with fluoropyrimidine‐cisplatin alone.…”

“…29 For the perioperative treatment of AGC, the addition of ramucirumab to the fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) regimen did not lead to a statistically significant improvement in the pathological CR rate as compared with FLOT chemotherapy alone in the randomized phase II/III trial of the German AIO and Italian GOIM. 30 Another generally used anti-angiogenic monoclonal antibody, bevacizumab, binds to VEGF-A, thereby inhibiting VEGFR-2.…”

Neoadjuvant Immunotherapy in Gastroesophageal Cancer: A Promising Early Signal?

“…On one hand, pCR is a known strong prognostic factor in GEA, 14 also exhibiting a potential association with overall survival (OS) in RCTs that compared two chemotherapy-containing treatments, as our informal illustration suggests (Fig 1). 9,13,[15][16][17][18][19][20][21][22] The magnitude of the difference in pCR (tumor regression grade 1a) rates in DANTE was comparable to that observed in the phase II portion of the FLOT4/AIO trial comparing FLOT versus ECF/X (D9% in DANTE v D10% in FLOT4/AIO), with the phase III portion of that study going on to demonstrate a significant benefit in both DFS (hazard ratio [HR], 0.75) and OS (HR, 0.77). 9,23 Moreover, the efficacy of immune checkpoint inhibition (ICI) is not limited to short-term responses, but can extend to the control or eradication of micrometastases in the longer term in GEA and other tumor types.…”