Extended follow-up from the phase 2 IKF-AIO-moonlight trial suggests that first-line FLOT plus nivolumab may provide durable benefit for a selected subgroup of patients with previously untreated, HER2-negative, unresectable and/or metastatic gastric or gastroesophageal junction adenocarcinoma, particularly those with positive PD-L1 combined positive score (CPS) and low baseline monocyte-to-lymphocyte ratio (MLR).
The results were reported in the original research article, “Biomarker-defined benefit from FLOT plus nivolumab in metastatic gastroesophageal cancer: Extended follow-up and immune-inflammatory markers of the phase II IKF-AIO-moonlight trial,” published in the European Journal of Cancer.
Authors: Michael Masetti, Alexander Nieto, Sylvie Lorenzen, Thorsten Oliver Goetze, Peter C. Thuss-Patience, Jorge Riera-Knorrenschild, Eray Goekkurt, Tobias Nicolaas Dechow, Thomas Jens Ettrich, Ralf Dieter Hofheinz, Kim Barbara Luley, Daniel Pink, Udo Lindig, Gunnar Folprecht, Gunter Schuch, Michael Bitzer, Volker Heinemann, Stefan Angermeier, Claus Bolling, Maria Looser, Sabine Junger, Claudia Pauligk, Salah-Eddin Al-Batran, Alexander Stein, and Joseph Tintelnot.
Why the Study Was Conducted
For patients with advanced gastroesophageal adenocarcinoma (GEA), first-line treatment has increasingly moved toward biomarker-guided therapy. In PD-L1-positive disease, fluoropyrimidine-platinum doublet chemotherapy combined with anti-PD-1 therapy is an established first-line approach. At the same time, docetaxel-containing triplet chemotherapy such as modified FLOT or TFOX has shown activity in selected patients who are fit enough for more intensive therapy.
However, combining triplet chemotherapy with immunotherapy in the metastatic setting raises an important clinical question: can intensified treatment improve outcomes enough to justify the additional treatment burden?
This is especially relevant in advanced GEA, where treatment is usually palliative and quality of life remains central to treatment selection. The IKF-AIO-moonlight trial evaluated different first-line chemotherapy-immunotherapy strategies in patients with previously untreated, HER2-negative, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. The current analysis focused on extended follow-up for Arm C, which evaluated FLOT plus nivolumab, and explored whether immune-inflammatory markers could help identify patients most likely to benefit.
Trial Design
The AIO-STO-0417 trial enrolled 261 patients across 27 sites in Germany between November 2018 and February 2022. Eligible patients had treatment-naïve, unresectable and/or metastatic, HER2-negative adenocarcinoma of the stomach or gastroesophageal junction.
Patients were assigned to one of several treatment arms: mFOLFOX plus nivolumab and ipilimumab given concurrently, mFOLFOX followed by nivolumab and ipilimumab, FOLFOX alone, or FLOT plus nivolumab. Arm C included 52 patients who received FLOT plus nivolumab.
The current analysis presented extended follow-up data for Arm C, with a data cutoff of March 15, 2025. The investigators also analyzed PD-L1 CPS, neutrophil-to-lymphocyte ratio (NLR), and MLR as potential markers of outcome. Baseline NLR was categorized as low if <5 and high if ≥5. Baseline MLR was categorized as low if <0.5 and high if ≥0.5. Quality of life was assessed using the EORTC QLQ-C30 questionnaire at baseline and during treatment.
Survival Outcomes With FLOT Plus Nivolumab
At the extended follow-up cutoff, median follow-up for Arm C was 12.7 months, with a range of 0.5 to 40.9 months.
Among patients treated with FLOT plus nivolumab, median progression-free survival (PFS) was 7.0 months, with a 95% confidence interval (CI) of 5.5 to 12.7 months. Median overall survival (OS) was 14.6 months, with a 95% CI of 8.3 to 28.4 months.
PFS rates at 6, 12, and 24 months were 56%, 35%, and 20%, respectively. OS rates at 6, 12, and 24 months were 77%, 51%, and 39%, respectively. In addition, 22% of patients achieved long-term survival of more than 3 years.
The investigators also evaluated outcomes according to PD-L1 CPS. Patients with CPS ≥1 had numerically longer survival than those with CPS <1. Median PFS was 7.6 months in the CPS ≥1 subgroup compared with 3.9 months in the CPS <1 subgroup. Median OS was 17.4 months versus 10.0 months, respectively. These differences were numerical and did not reach statistical significance.
Immune-Inflammatory Markers and Survival
The study further examined whether baseline immune-inflammatory markers were associated with survival outcomes. In Arm C, univariable analysis showed that signet-ring cell histology was associated with worse OS. There was also a trend toward improved survival for G2 tumors compared with G3 tumors, and a trend toward improved OS in patients with positive CPS.
Among routine blood-based markers, NLR and MLR showed notable associations with survival. These markers reflect the balance between circulating inflammatory cells and lymphocytes and can be derived from standard blood counts.
In Arm C, patients with low NLR had longer median OS than those with high NLR. Median OS was 25.5 months for NLR <5 compared with 6.8 months for NLR ≥5. Median PFS was also longer in the low-NLR group, at 13.1 months compared with 6.2 months.
A similar pattern was observed with MLR. Patients with MLR <0.5 had a median OS of 28.4 months, compared with 8.3 months among those with MLR ≥0.5. Median PFS was 9.9 months versus 5.7 months, respectively.
The same general direction was observed across other treatment arms, supporting the prognostic relevance of these markers. However, the authors noted that the survival difference appeared particularly pronounced in the FLOT plus nivolumab arm, raising the possibility that NLR and MLR may have predictive value for benefit from this intensified immunochemotherapy approach. Because of the study size and exploratory design, this remains a hypothesis that requires prospective validation.
CPS and MLR Defined a Subgroup With Enhanced Survival
The combined analysis of PD-L1 CPS and MLR further identified a subgroup with enhanced survival. Among patients with PD-L1 CPS ≥1, those with low MLR had substantially longer survival than those with high MLR. Median PFS was 16.6 months for MLR <0.5 compared with 6.2 months for MLR ≥0.5. Median OS was 32.3 months versus 7.4 months, respectively. Both comparisons reached statistical significance in this exploratory subgroup analysis.
Stratification by NLR in the CPS ≥1 subgroup also showed numerically longer outcomes in patients with low NLR. Median PFS was 14.1 months for NLR <5 compared with 6.4 months for NLR ≥5. Median OS was 29.7 months compared with 7.0 months.
In contrast, among patients with CPS <1, stratification by NLR or MLR did not show the same degree of separation. This supports the authors’ conclusion that the combination of positive CPS and low MLR may identify a subgroup with enhanced benefit from FLOT plus nivolumab.
Quality-of-Life Findings
Because FLOT plus nivolumab is an intensive regimen, the study also examined patient-reported outcomes. Global health status and overall quality of life remained largely stable across treatment arms. However, physical functioning worsened over time, with the most pronounced numerical decline at week 16 observed in Arm C. Physical functioning later improved after the week 16 nadir in the FLOT plus nivolumab arm.
Pain improved by week 8 in the FLOT plus nivolumab arm, as well as in the FOLFOX-alone arm and the sequential immunotherapy arm. Fatigue worsened by week 16 in the FLOT plus nivolumab arm and in the sequential mFOLFOX followed by nivolumab and ipilimumab arm.
These findings are important because the potential survival benefit of intensified therapy must be weighed against treatment burden, especially in the palliative setting. The authors concluded that FLOT plus nivolumab reduced pain but was also associated with decreased physical functioning and increased fatigue.
Limitations
The biomarker findings should be interpreted cautiously. The analysis of NLR and MLR was retrospective, and some subgroups were small. The cutoffs for NLR and MLR were determined through a data-driven approach and remain exploratory. The authors emphasized that these thresholds require external and prospective validation before they can be used in routine clinical decision-making.
Another important limitation is that the study cannot definitively determine whether NLR and MLR are purely prognostic markers or whether they also predict benefit from FLOT plus nivolumab. The marked survival differences observed in the FLOT plus nivolumab arm support further investigation and require prospective validation.
Conclusion
Extended follow-up from Arm C of the IKF-AIO-moonlight trial showed that FLOT plus nivolumab produced clinically meaningful survival outcomes in patients with previously untreated, HER2-negative, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.
The analysis suggests that patients with PD-L1 CPS ≥1 and low baseline MLR may derive particular benefit from this intensified first-line approach. Low NLR and low MLR were also associated with longer survival, but their role as predictive biomarkers remains exploratory.
At the same time, FLOT plus nivolumab was associated with increased fatigue and reduced physical functioning, highlighting the need for careful patient selection. The findings support further prospective evaluation of NLR and MLR as accessible blood-based biomarkers that may help guide treatment intensification in advanced gastroesophageal cancer.
The full article is available in European Journal of Cancer.
