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. 2025 Apr 24;5(1):136.
doi: 10.1038/s43856-025-00867-x.

Circulating tumor DNA strongly predicts efficacy of chemotherapy plus immune checkpoint inhibitors in patients with advanced gastro-esophageal adenocarcinoma

David Tougeron  1 , Christophe Louvet  2 , Jérôme Desramé  3 , Ludovic Evesque  4 , Antoine Angelergues  5 , Aurélien Carnot  6 , Gilles Breysacher  7 , Aziz Zaanan  8 , Nicolas Etchepare  9 , May Mabro  10 , Laure Kaluzinski  11 , Caroline Petorin  12 , Benoist Chibaudel  13 , Thomas Aparicio  14 , Anaïs Bodere  15 , Yves Rinaldi  16 , Karine Le Malicot  17 , Jean-François Emile  18 , Côme Lepage  17 , Aurélia Baures  19 , Hanane Djamai  19 , Valérie Taly  19   20 , Pierre Laurent-Puig  19   21
Affiliations

Circulating tumor DNA strongly predicts efficacy of chemotherapy plus immune checkpoint inhibitors in patients with advanced gastro-esophageal adenocarcinoma

David Tougeron et al. Commun Med (Lond). .

Abstract

Background: Efficacy of 2nd line treatment in advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma remains limited with no identified strong predictor of treatment efficacy. We evaluated the prognostic value of circulating tumor DNA (ctDNA) in predicting the efficacy of immune checkpoint inhibitors (ICI) plus chemotherapy in the randomized PRODIGE 59-FFCD 1707-DURIGAST trial.

Methods: ctDNA was evaluated before treatment (baseline) and at 4 weeks (before the third cycle of treatment, C3) using droplet-digital PCR assays based on the detection of CpG methylation.

Results: Progression-free survival (PFS) and overall survival (OS) were shorter in patients with a high (>1.1 ng/mL) versus low (<1.1 ng/mL) ctDNA concentration at baseline (2.3 vs. 5.8 months; HR = 2.19; 95% CI, 1.09-4.41; p = 0.03 and 4.5 vs. 12.9 months; HR = 2.73; 95% CI, 1.29-5.75; p < 0.01), respectively, after adjustment for identified prognostic variables. Patients with a ctDNA decrease ≤75% between baseline and C3 versus a ctDNA decrease >75% had a worse objective response rate (p = 0.007), shorter PFS (2.2 vs. 7.4 months, HR = 1.90; 95% CI, 1.03-3.51; p = 0.04) and OS (6.6 vs 16.0 months; HR = 2.18; 95% CI, 1.09-4.37; p = 0.03).

Conclusions: An early decrease in ctDNA concentration is a strong predictor of the therapeutic efficacy of ICI plus chemotherapy in advanced gastric/GEJ adenocarcinoma. Clinical Trial Information NCT03959293 (DURIGAST).

Plain language summary

Some patients with advanced gastric cancer receive immunotherapy (treatments that help one’s own immune system recognize and attack cancer cells) in addition to other treatments. We measured circulating tumor DNA (ctDNA) in patient’s blood samples and looked at associations with treatment outcome. We found that survival was shorter in patients receiving immunotherapy plus chemotherapy, when the levels of ctDNA in the blood were high at the start of treatment and when they did not decrease over time. Our results suggest that ctDNA could be used as a predictor of how well this specific treatment will work in advanced gastric cancer patients.

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Conflict of interest statement

Competing interests: D.T. reports consultancy, advisory fees, honoraria from Servier, Pierre Fabre, Merck Serono, MSD, BMS, A.Z., Roche, Sanofi; research funding from Sandoz, AstraZenenca, Servier, MSD; travel grants from Pierre Fabre, MSD, Servier, Roche. P.L.P. reports consultancy, advisory fees, and honoraria from Servier, Pierre Fabre, and Biocartis. T.A. reports advisory fees, and honoraria from Pierre Fabre, Servier, MSD, BMS, Bayer. B.C. reports advisory fees from Bayer, MSD, BMS, Sanofi, and Roche, and honoraria from Amgen, Roche, Sanofi, Merck, BMS, SeqOne Genomics, and Pierre Fabre. A.Z. reported personal fees from Amgen, AbbVie, Astellas, Gilead, Merck, Sanofi, Roche, Servier, MSD, BMS, Pierre Fabre, Daiichi Sankyo, AstraZeneca, Zymeworks; grants from Amgen outside the submitted work. P.L.P. and V.T. are one of the founders of MethysDX. The other authors declare that there are no competing interests.

Figures

Fig. 1
Fig. 1. Flow chart.
mITT modified intention-to-treat population.
Fig. 2
Fig. 2. Association between ctDNA levels and clinical benefit (progression-free survival at 4 months).
Clinical benefit is defined as alive patients with no disease progression at 4 months.
Fig. 3
Fig. 3. Association between progression-free survival, overall survival and ctDNA level at baseline.
a Association between progression-free survival and ctDNA level at baseline. b Association between overall survival and ctDNA level at baseline High versus low ctDNA level at inclusion was defined using a cut-off of 1.1 ng/mL HR hazard ratio.
Fig. 4
Fig. 4. Association between progression-free survival, overall survival and ctDNA kinetic.
a Association between progression-free survival and ctDNA kinetic. b Association between overall survival and ctDNA kinetic ctDNA increase versus decrease is defined using a cut-off at 75% of decrease or more HR hazard ratio.
See this image and copyright information in PMC

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