# First-line modified FOLFOX plus/minus nivolumab and Ipilimumab or FLOT plus nivolumab in advanced gastroesophageal adenocarcinoma: a phase II multi-cohort IKF-AIO-MOONLIGHT trial

## TL;DR

This study tests different chemotherapy and immunotherapy combinations for advanced stomach/esophageal cancer, finding that some combinations increase toxicity without benefit.

## Contribution

The study compares novel combinations of chemotherapy and dual immune checkpoint inhibition in gastroesophageal cancer.

## Key findings

- Combining mFOLFOX with dual checkpoint inhibition increased toxicity without improving outcomes.
- FLOT plus nivolumab showed promising efficacy and manageable toxicity.
- Delayed immunotherapy after chemotherapy was less effective.

## Abstract

This multi-cohort study evaluates whether dual immune checkpoint inhibition with nivolumab and ipilimumab in parallel or sequentially, or triplet chemotherapy with nivolumab can enhance efficacy as first-line therapy for advanced or metastatic gastroesophageal adenocarcinoma. Patients are randomized 1:1 to Arm A (mFOLFOX + nivolumab 240 mg every two weeks + ipilimumab 1 mg/kg every six weeks in parallel or Arm B (mFOLFOX). Subsequently, patients are randomized 1:2 to Arm A1 (identical to Arm A) or Arm A2 (three cycles of mFOLFOX followed by nivolumab + ipilimumab). In Arm C all patients receive FLOT + nivolumab. Primary endpoint is progression-free survival. Secondary endpoints include overall survival and objective response rate. Median progression-free survival (months) is: Arm A/A1, 5.8; Arm A2, 4.0; Arm B, 6.6 and Arm C, 7.0.Toxicity is manageable across all arms, with higher rates in arms receiving dual checkpoint inhibition. Here we show that chemotherapy with dual checkpoint inhibition in parallel increases toxicity without improving efficacy, while FOLFOX followed by immunotherapy is insufficient. FLOT with nivolumab appears feasible and shows promising efficacy. ClinicalTrials.gov number NCT03647969

Current research focuses on enhancing the efficacy of immune checkpoint blockade combined with chemotherapy in HER2-negative gastrointestinal adenocarcinoma. This trial evaluates different first-line chemotherapy regimens in combination with immunotherapy.