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

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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. 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. 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). 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). 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. Tougeron et al. evaluate the prognostic value of circulating tumor DNA (ctDNA) in predicting the efficacy of immune checkpoint inhibitors (ICI) plus chemotherapy in advanced gastric adenocarcinoma. An early decrease in ctDNA concentration is associated with a worse objective response rate, shorter progression free survival and overall survival.

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