EORTC 1707 VESTIGE: Adjuvant immunotherapy in patients (pts) with resected gastroesophageal adenocarcinoma (GEA) following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1)—an open-label randomized controlled phase II study

GEA pts with tumor-positive lymph nodes (ypN+) or incomplete surgical resection (R1) following neoadjuvant chemotherapy (chemo) are high risk for relapse. Adjuvant nivolumab is effective in non-pathCR esophageal/GEJ pts following chemoradiotherapy and surgery, and nivolumab and ipilimumab (nivo/ipi) have demonstrated activity in advanced GEA. We hypothesized that high risk (ypN+ and/or R1) post resection GEA pts treated with nivo/ipi would have better disease-free survival (DFS) than pts who continue with standard post-operative chemo.

VESTIGE was an European, open label randomized phase II study to evaluate the efficacy of adjuvant nivo/ipi versus standard post-operative chemo in GEA patients with high risk for relapse post resection. Eligible pts were randomized 1:1 to receive post-operative adjuvant chemo (identical regimen as pre-operatively) or nivolumab 3mg/kg IV q2w plus ipilimumab 1mg/kg IV q6w x 1 year. Key inclusion criteria included ypN+ and/or R1 status following neoadjuvant chemo plus surgery and an adequate pre-specified surgical resection. The primary endpoint of the study was DFS, with secondary endpoints of overall survival (OS), safety, toxicity, and quality of life. The study was designed to have 80% power to detect an increase in DFS rate at 1 year from 65% to 74% (HR=0.7) with nivo/ipi vs chemo with a one-sided alpha of 10%. The primary analysis was intent-to-treat. Cox regression was used to estimate treatment effect (hazard ratio, HR).

The EORTC IDMC in charge of independently monitoring the study reviewed the data from 191 of a planned 240 pts in June 2022 and recommended to stop further enrolment. At the time of this review, median follow up was 11.1 months (m) for 189 pts (94 chemo: 95 nivo/ipi). Median DFS for the chemo arm was 23.3m (95% CI 11.8- not reached (NR)) vs 11.9m (8.4–16.8m) for nivo/ipi HR 1.80 (95% CI 1.09– 2.98) p=0.02. 12m DFS were 62.2% and 49.3% respectively. Median OS for the chemo arm was not reached vs 25.1m (95% CI 18.6m – NR) HR 1.79 (95% CI 0.89 –3.59) p=0.1. No new toxicity concerns or excess early discontinuations were identified.

Nivo/ipi did not improve DFS over chemo in pts with ypN+ and/or R1 GEA following neoadjuvant chemotherapy and surgery. Subgroup and biomarker analysis may be critical to understand whether any subgroup may benefit from adjuvant immunotherapy. The IDMC recommended to perform an analysis after longer follow-up to confirm these preliminary results. Analysis of PD-L1 and MMR status will be presented.

NCT03443856.

EORTC.

BMS.

E. Smyth: Advisory / Consultancy: Amgen, Astellas Pharma, AstraZeneca, BeiGene, BMS, Daiichi Sankyo, Elsevier, Merck, Novartis, Pfizer, Servier, Turning Point Therapeutics and Zymeworks; Research grant / Funding (institution): BMS, Astra Zeneca ; Officer / Board of Directors: EORTC; Spouse / Financial dependant: HCA International. M. Mauer: Research grant / Funding (institution): Roche , Bristol Myers Squibb . C. Cella: Honoraria (self): Leo Pharma ; Advisory / Consultancy: BMS; Research grant / Funding (institution): IPSEN. G. Piessen: Advisory / Consultancy: BMS, Astellas, Nestlé; Travel / Accommodation / Expenses: medtronic. M. Stahl: Honoraria (self): Lilly Germany; Advisory / Consultancy: Lilly Germany. P. Thuss-Patience: Advisory / Consultancy: Roche, BMS, MSD, Novartis, Lilly, Astellas, Servier, Daiichi, AstraZeneca, Merck; Research grant / Funding (institution): Merck. K. Shiu: Honoraria (self): Merck, Merck KGaA, Daiichi-Sankyo; Advisory / Consultancy: Merck, Roche, Mirati Therapeutics; Research grant / Funding (institution): Merck, Roche, Astra Zeneca. F. Lordick: Honoraria (self): Roche; Advisory / Consultancy: Roche. All other authors have declared no conflicts of interest.