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Randomized Controlled Trial
. 2025 Aug 1;11(8):874-882.
doi: 10.1001/jamaoncol.2025.1646.

Early ctDNA and Survival in Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors: A Secondary Analysis of the SAMCO-PRODIGE 54 Randomized Clinical Trial

Julien Taïeb  1   2 , Francesco Giulio Sullo  1   2   3 , Aurélie Lecanu  1   2 , Camille Bourreau  2 , Emilie Barbier  4 , Annalice Gandini  1   2 , Jérémie Bez  4 , Claire Mulot  2 , Frederic Di Fiore  5 , Farid Elhajbi  6 , Christophe Borg  7 , Olivier Bouché  8 , Thomas Aparicio  9 , Aziz Zaanan  1   2 , Thierry André  10 , David Tougeron  11 , Valerie Taly  2   12   13 , Pierre Laurent-Puig  2   14
Affiliations
Randomized Controlled Trial

Early ctDNA and Survival in Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors: A Secondary Analysis of the SAMCO-PRODIGE 54 Randomized Clinical Trial

Julien Taïeb et al. JAMA Oncol. .

Abstract

Importance: Immune checkpoint inhibitors (ICIs) have dramatically transformed the therapeutic landscape of deficient mismatch repair/microsatellite unstable-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC); however, ICI use is challenged by primary resistance and timing of discontinuation. Whether circulating tumor DNA (ctDNA) may be predictive of progression-free survival (PFS) and overall survival (OS) in this treatment context remains unknown.

Objective: To assess the prognostic and predictive role of ctDNA, detected by tumor-specific methylation markers, in patients with dMMR/MSI-H mCRC treated with ICIs.

Design, setting, and participants: This prespecified secondary analysis of the SAMCO-PRODIGE 54 randomized clinical trial evaluated ctDNA in patients with dMMR/MSI-H mCRC treated with avelumab or standard chemotherapy, with or without a targeted agent in the second-line setting, to assess its prognostic role. Plasma samples were obtained prospectively for ctDNA analysis, and digital droplet polymerase chain reaction amplification of bisulfite-converted cell-free DNA (cfDNA) for WIF1 and NPY genes was used to quantify ctDNA levels. These samples were collected from April 2018 to April 2021 at 49 sites in France at baseline (V1) and 1-month posttreatment initiation (V2) during. Data analyses were performed from October 1 to November 1, 2024.

Intervention: Avelumab or standard chemotherapy with or without targeted agents.

Main outcomes and measures: PFS and OS according to baseline ctDNA positivity or concentration, and early ctDNA variation (ΔctDNA = [V1-V2] ÷ V1).

Results: The predictive analysis included 99 patients (mean [SD] age, 66 [13] years; 51 female [51.5%]) with plasma samples available for ctDNA assessment at V1, of which 74 had samples available also at V2 for Change in ctDNA assessment. In the 99 patients with available V1 plasma samples, baseline ctDNA positivity or concentration were not associated with clinical outcomes. Change in ctDNA (cutoff at median value) was significantly associated with both PFS (hazard ratio [HR], 2.98; 95% CI, 1.77-5.01; P < .001) and OS (HR, 3.61; 95% CI, 1.81-7.17; P < .001). This association was evident in patients treated with avelumab (PFS HR, 4.22; 95% CI, 1.77-10.1; P = .001; OS HR, 17.40; 95% CI, 3.82-79.70; P < .001) than in those receiving chemotherapy (PFS HR, 2.09; 95% CI, 1.03-4.21; P = .04; OS HR, 1.51; 95% CI, 0.61-3.72; P = .38). Avelumab (vs chemotherapy) improved PFS in favorable ctDNA responders (HR, 0.33; 95% CI, 0.14-0.77; log-rank P = .008) but not in poor responders (HR, 1.32; 95% CI, 0.67-2.62; log-rank P = .42) Combined ctDNA response and RECIST, version 1.1, assessment accurately predicted long-term OS. In the multivariable analysis, lack of ctDNA response was associated with an increased risk of disease progression and death in the avelumab group (HR, 7.27; 95% CI, 2.23-23.7; P = .001) but not in the chemotherapy group (HR, 1.61; 95% CI, 0.66-3.93; P = .30).

Conclusions: The findings of this secondary analysis of an RCT found that change in ctDNA at 1-month posttreatment can predict long-term outcomes in patients with dMMR/MSI-H mCRC treated with ICIs.

Trial registration: ClinicalTrials.gov Identifier: NCT03186326.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Taïeb reported advisory or speaker roles for Amgen, Astellas, AstraZeneca, Boehringer, Bristol Myers Squibb (BMS), Brenus Pharma, BIcara Therapeutic, Oxford biotherapeutics, PROSKOPE, Merck, MSD, Novartis, ONO Pharma, Pierre Fabre, Natera, Sanofi, Servier, and Takeda; advisory or speaker role outside the submitted work. Dr Di Fiore reported Amgen, BMS, MSD, Merck, Servier, Pierre Fabre, AstraZeneca, Bayer, Incyte, Takeda, Viatris, and Sandoz outside the submitted work. Dr Borg reported grants from Bayer, Boehringer, Merck, and Molecular Partner; and Servier, outside the submitted work. Dr Bouché reported Amgen, Deciphera, Astellas, Takeda, Servier, Pierre Fabre, MSD, BMS, and Merck Sereno outside the submitted work. Dr Aparicio reported personal fees from Pierre Fabre, Servier, BMS, MSD, Amgen, and Bayer outside the submitted work. Dr Zaanan reported consulting and/or advisory fees from Amgen, Astellas, Merck, Roche, Servier, MSD, BMS, Pierre Fabre, Daiichi Sankyo, AstraZeneca, Bayer, BeiGene, Gilead, AbbVie during the conduct of the study. Dr André reported personal fees from BMS, MSD Oncology, GlaxoSmithKline, Merck Serono, Takeda, Servier, and Pfizer outside the submitted work. Dr Tougeron reported personal fees from MSD, BMS, Merck Serono, Takeda, Amgen, Servier, Pierre Fabre, Roche, Gilead, BeiGene, and AstraZeneca outside the submitted work. Dr Taly reported being co-founder and CSO of METHYS Dx during the conduct of the study; and a patent licensed to METHYS Dx covering methylation markers for ctDNA (not the signature of this article). Dr Laurent-Puig reported equity in METHYS Dx, Biocartis, MSD, BMS, and Pierre Fabre outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram of Included Patients
Figure 2.
Figure 2.. Progression-Free Survival (PFS) and Overall Survival (OS) per Circulating Tumor DNA (ctDNA) Response in Patients Treated With Chemotherapy vs Abelumab
In patients with deficient mismatch repair/microsatellite instability-high metastatic colorectal cancer, favorable responders were those with a ctDNA reduction greater than 86%, and poor responders, reduction of 86% or less. HR indicates hazard ratio; NR, not reached.
Figure 3.
Figure 3.. Progression-Free Survival (PFS) in Patients With Deficient Mismatch Repair/Microsatellite Instability-High Metastatic Colorectal Cancer Treated With Chemotherapy vs Avelumab
A and B, Favorable responders had a ctDNA reduction greater than 86%, and poor responders, reduction of 86% or less. C and D, Early change in ctDNA variations between baseline and on-treatment assessable ctDNA levels, RECIST response, and PFS in patients treated with chemotherapy (n = 35) vs avelumab (n = 38). Patients with both V1 and V2 measures are shown in the swimmer plots according to PFS, with total length of bar indicating PFS duration. CR indicates complete response; ctDNA, circulating tumor DNA; HR, hazard ratio; NR, not reached; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors, version 1.1; SD, stable disease.
See this image and copyright information in PMC

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