Introduction
Immune checkpoint inhibitors (ICIs) have revolutionized treatment for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), improving survival outcomes considerably. Despite these advances, primary resistance to ICIs and challenges in determining optimal treatment duration remain significant obstacles. Circulating tumor DNA (ctDNA), a non-invasive biomarker detectable in plasma, offers promise for dynamic monitoring of tumor burden and therapeutic response. However, the predictive utility of ctDNA in the specific context of ICI-treated dMMR/MSI-H mCRC had not been established prior to the SAMCO-PRODIGE 54 randomized clinical trial’s secondary analysis presented by Taïeb et al. This article critically reviews their findings on ctDNA as a prognostic and predictive biomarker for progression-free survival (PFS) and overall survival (OS) in this patient population.
Study Background and Disease Burden
Colorectal cancer remains a leading cause of cancer morbidity and mortality worldwide. Approximately 15% of mCRC cases exhibit deficient mismatch repair or high microsatellite instability (dMMR/MSI-H), a molecular subtype associated with elevated tumor mutational burden and presumed sensitivity to ICIs. While ICIs like avelumab have improved outcomes, not all patients respond equally, and early identification of responders versus non-responders is critical for tailored therapy. Current imaging and clinical assessments have limitations in early response evaluation and prognosis prediction. ctDNA analysis, specifically via tumor-specific methylation markers in WIF1 and NPY genes, may allow sensitive, quantitative assessment of tumor dynamics, offering actionable clinical insights.
Study Design
This prespecified secondary analysis utilized samples from the phase 2 SAMCO-PRODIGE 54 randomized clinical trial (NCT03186326), conducted across 49 sites in France from 2018 to 2021. The parent trial evaluated avelumab, an anti-PD-L1 antibody, versus standard second-line chemotherapy with or without targeted agents in patients with dMMR/MSI-H mCRC. Plasma samples for ctDNA quantification were prospectively collected at baseline (V1) and at one month post-treatment initiation (V2).
ctDNA was measured by digital droplet polymerase chain reaction of bisulfite-converted cell-free DNA focusing on methylation-specific markers for two genes, WIF1 and NPY. Ninety-nine patients had evaluable baseline samples, and 74 had paired samples permitting assessment of early ctDNA change (ΔctDNA = [V1-V2]/V1). The primary endpoints of this analysis were progression-free survival (PFS) and overall survival (OS) relative to baseline ctDNA status and early ctDNA variation.
Key Findings
Baseline ctDNA positivity or absolute concentration at V1 was not significantly associated with PFS or OS, indicating that static baseline ctDNA burden lacks prognostic value in this setting.
However, the change in ctDNA levels at one month post-treatment initiation emerged as a robust prognostic biomarker. Patients demonstrating greater reductions in ctDNA (above median cutoff) had significantly improved PFS (HR 2.98; 95% CI 1.77-5.01; P<.001) and OS (HR 3.61; 95% CI 1.81-7.17; P<.001) compared to poor reducers.
This prognostic signal was pronounced in the avelumab-treated group: favorable ctDNA responders showed dramatically better outcomes (PFS HR 4.22; OS HR 17.40). Conversely, in the chemotherapy arm, the associations were weaker and non-significant for OS (PFS HR 2.09; OS HR 1.51).
Notably, among favorable ctDNA responders, avelumab conferred superior PFS versus chemotherapy (HR 0.33; P=.008), highlighting ctDNA change as a predictor of immunotherapy benefit. Poor responders did not benefit significantly from avelumab over chemotherapy.
Combining early ctDNA response with RECIST v1.1 radiologic assessment enhanced prediction accuracy for long-term survival, supporting integrated biomarker approaches. Multivariable analysis confirmed that lack of ctDNA response independently predicted higher progression and mortality risks specifically in the ICI-treated cohort (HR 7.27; P=.001).
Expert Commentary
This study represents an important advancement in precision oncology for dMMR/MSI-H mCRC, identifying early ctDNA kinetics as a sensitive surrogate for immunotherapy response and long-term survival. The use of methylation markers WIF1 and NPY provides a tumor-specific and quantitative method applicable in clinical settings.
Limitations include the relatively modest sample size and secondary nature of the analysis, warranting prospective validation. Additionally, baseline ctDNA’s lack of prognostic value contrasts with other tumor types where baseline ctDNA burden often correlates with outcomes, highlighting disease-specific nuances.
Furthermore, while the findings suggest potential to tailor ICI therapy durations and identify those unlikely to benefit early, the integration of ctDNA monitoring with clinical decision-making algorithms requires further standardization and regulatory endorsement.
Mechanistically, ctDNA clearance presumably reflects effective immune-mediated tumor cell kill, aligning with the concept that early molecular responses precede and may predict radiologic improvement. This also supports earlier discontinuation or switching strategies in poor ctDNA responders to mitigate unnecessary toxicity and cost.
Conclusion
The SAMCO-PRODIGE 54 secondary analysis underscores that early ctDNA changes at one month after treatment initiation predict long-term outcomes in patients with dMMR/MSI-H metastatic colorectal cancer receiving immune checkpoint inhibitors. This biomarker may refine response assessment, guide therapeutic choices, and optimize patient management in an era of personalized immunotherapy.
Future research should focus on prospective validation, exploration of ctDNA-guided adaptive therapeutic strategies, and integration into clinical practice workflows.
References
1. Taïeb J, Sullo FG, Lecanu A, et al. Early ctDNA and Survival in Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors: Secondary Analysis of the SAMCO-PRODIGE 54 Randomized Clinical Trial. JAMA Oncol. 2025;11(8):874-882. doi:10.1001/jamaoncol.2025.1646
2. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in Patients With DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2017;35(15):1577-1585.
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4. Reinert T, Henriksen TV, Christensen E, et al. Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. JAMA Oncol. 2019;5(8):1124–1131.
