Perioperative FLOT plus anti-PD-L1 avelumab (FLOT-A) in resectable oesophagogastric adenocarcinoma (OGA): Interim safety analysis results from the ICONIC trial.

Abstract

201 Background: ICONIC is a single-arm phase II trial investigating the safety and efficacy of perioperative FLOT-A in resectable OGA. Following a 3+3 design safety run-in phase, standard dose FLOT with 10mg/kg IV avelumab (dose level 0) q2weeks was taken forward into the main study. The aims of this pre-planned interim analysis were to assess perioperative safety and R0 resection rates. Methods: The interim analysis occurred once the 15th patient treated at dose level 0 reached 30 days post-surgery. Results: At data cut-off, 15 patients had received at least one cycle of FLOT-A and had undergone resection. The median age of patients was 63y (range: 25 – 73). 71% had an ECOG PS of 0. 60% of tumours were staged as T3 at baseline and 40% T2; 67% were N0, 7% N1 and 27% N2. Due to 5-FU related cardiac toxicity, two patients switched to alternative chemotherapy without 5-FU and avelumab. 13/15 patients (87%) completed 4 cycles of pre-operative FLOT-A; of these, five patients had avelumab omitted for one cycle for toxicity evaluation and management. 9/15 patients (60%) experienced a G3/4 adverse event (AE). These were FLOT-A-related in 8/15 patients (53.3%). The commonest G3/4 AEs were febrile neutropenia, neutropenia and diarrhoea. Median time from last chemotherapy to surgery was 6.4 weeks. No delays or failure to proceed to surgery occurred due to avelumab-related complications. 7% of patients had an American Society of Anaesthesiologists (ASA) preoperative risk score of I, 47% a score of II and 47% a score of III. 73% of patients had operations involving a thoracic approach (10 minimally invasive Ivor-Lewis oesophagogastrectomy with two field radical lymphadenectomy, 1 left thoracoabdominal oesophagogastrectomy and 4 gastrectomy with D2 lymphadenectomy). Median time to extubation was 6h (IQR: 4-24). The median Acute Physiology and Chronic Health Evaluation (APACHE) score at day 1 post-op was 12 (IQR: 10-15) with a median of 3 days (IQR: 2-4) of CCU care. No unexpected complications were reported intra-operatively or during post-operative recovery in FLOT-A treated patients. 5/14 evaluable patients at data cut-off (35.7%) had Clavien-Dindo grade II post-operative complications and 3/14 (21.4%) grade IIIa complications; of these 1 patient had an anastomotic leak that was treated endoscopically. There were no emergency re-operations. All 15 patients achieved R0 resections and were discharged home after a median of 13d (IQR: 11-16) in hospital. Conclusions: To date, FLOT-A has not led to unexpected or unusually severe perioperative complications in the context of major complex upper GI surgery for resectable OGA. Clinical trial information: NCT03399071.

Evaluation of Clinical and Safety Outcomes of Neoadjuvant Immunotherapy Combined With Chemotherapy for Patients With Resectable Esophageal Cancer

“…The geographic distribution of included studies is shown in eFigure 1 in the Supplement. non-RCTs, and 25 of them were single-group 21,22,[24][25][26][27]30,31,[33][34][35][36][37][39][40][41][42][43][44][45][46][47] and 2 were dual-group trials. 28,29 Twenty-three trials 21,23,24,[27][28][29][31][32][33][34][35][36][37][38][39][42][43][44]46,47 enrolled patients with ESCC and applied anti-PD-1 antibody.…”

“…Meanwhile, based on 17 trials, 23,25,27,30,[33][34][35][36][37][38][39][40][41][42][43]46,47 the pooled MPR rate was 48.9% (95% CI, 42.0%-55.9%), with mild heterogeneity (I 2 = 50.3%; 95% CI, 13.1%-71.5%; P = .10) (Figure 3). In terms of safety, 14 trials, 23,26,27,29,32,34,36,38,40,42,[44][45][46]48 23,[27][28][29]31,[33][34][35][37][38][39][40][41][42]44,[46][47][48] was 98.6% (95% CI, 97.1%-99.6%), with no evidence of significant heterogeneity (eFigure 9 in the Supplement).…”

Immunotherapy-Based Neoadjuvant Treatment of Advanced Microsatellite Instability–High Gastric Cancer: A Case Series

“…Our observations appear consistent with other small prospective trials reported to date in which ICIs have been incorporated into perioperative chemotherapy for molecularly unselected patients with GC. [32][33][34] Ongoing phase III trials randomizing patients with GC receiving perioperative chemotherapy to the addition of an ICI or placebo may validate acceptable toxicities. 35,36 Despite the dramatic responses to ICIs demonstrated in MSI-H tumors, the adoption of MSI/dMMR testing in the clinical setting remains a challenge.…”

A narrative review of the evolving role of immunotherapy in the management of esophageal and gastric cancer

“…In a phase 2 study in (20). Atezolizumab and avelumab are also being studied in combination with FLOT in the DANTE (NCT03421288) and ICONIC (NCT03399071) trials (21,22). Finally, KEYNOTE-585 is an active phase 3 trial that will establish the OS, event-free survival (EFS) and pCR rate of neoadjuvant and adjuvant pembrolizumab plus chemotherapy (cisplatin + 5-FU before and after surgery) versus placebo plus chemotherapy in patients with advanced (T3/T4 or node positive) gastric or GEJ adenocarcinoma (23).…”