ctDNA Response Predicts Outcomes in MSI-H mCRC Immunotherapy

In patients with deficient mismatch repair or microsatellite instability–high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), a 1-month change in circulating tumor DNA (ctDNA) may serve as a powerful predictor of long-term outcomes following immune checkpoint inhibitor (ICI) therapy, according to one study.¹

Early circulating tumor DNA (ctDNA) changes predict survival in mismatch repair or microsatellite instability–high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICIs). | Image credit: Thaweechai - stock.adobe.com

The trial showed that ctDNA response strongly correlated with progression-free survival (PFS) and overall survival (OS), particularly in those treated with avelumab, supporting ctDNA's emerging role as a tool for guiding personalized oncology care and value-based treatment strategies.

This prespecified secondary analysis of the SAMCO-PRODIGE 54 (NCT03186326) randomized clinical trial is published in JAMA Oncology.

“Biomarker-directed use of ICI is an important frontier in precision medicine, and there is an ongoing need to better understand the potential role of ctDNA in advanced dMMR/MSI-H mCRC, including its prognostic value and its role for monitoring patients and predict[ing] long-term outcomes,” wrote the researchers of the study.

ctDNA has emerged as a promising biomarker tool for predicting CRC, with a recent study showing that blood-based ctDNA tests can detect CRC with high sensitivity and specificity in average-risk populations.² Therefore, as a noninvasive, real-time tool, ctDNA could help guide personalized treatment strategies and improve long-term outcomes.

In the current study, researchers aimed to assess the prognostic and predictive value of circulating tumor ctDNA in patients with dMMR/MSI-H mCRC treated with either avelumab or standard chemotherapy, with or without a targeted agent.¹ To do so, plasma samples were prospectively collected from 99 patients at 49 sites across France between April 2018 and April 2021. ctDNA levels were quantified at baseline and 1 month after treatment initiation using digital droplet polymerase chain reaction (PCR) amplification of bisulfite-converted cell-free DNA targeting WIF1 and NPY methylation markers.

The primary outcome was PFS and OS according to baseline and ctDNA positivity or concentration, and early ctDNA variation.

Among the patients included in the analysis, baseline ctDNA positivity and concentration were not associated with PFS or OS. However, changes in ctDNA levels 1 month after treatment initiation were significantly associated with both 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). These associations were more pronounced in patients treated with avelumab compared with those receiving chemotherapy. Moreover, avelumab improved PFS in patients with favorable ctDNA responses (HR, 0.33; 95 CI, 0.14-0.77; P = .008) but not in poor responders.

Additionally, combining ctDNA response with radiographic response using Response Evaluation Criteria in Solid Tumors 1.1 enhanced the prediction of long-term OS. In multivariable analysis, lack of ctDNA response was strongly associated with 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.

However, the researchers noted several limitations. First, the moderate sample size may impact generalizability, particularly when interpreting trends within small biomarker-defined subgroups. Second, the analysis used only a single posttreatment ctDNA monitoring time point, which may not capture delayed ctDNA clearance observed in other studies. Third, although the study evaluated avelumab, an anti–PD-L1 agent, current approvals for dMMR/MSI-H mCRC support PD-1 inhibitors, which may limit the applicability of these results to standard clinical practice.

Despite these limitations, the researchers believe the study encourages the applicability of ctDNA as a noninvasive tool to help oncologists predict clinical benefit and survival in this patient population.

“This may drive the design of future clinical trials to assess, for example, whether long-term survivors achieving a favorable ctDNA response at 1 month, or even earlier, could benefit from early treatment discontinuation, or whether those achieving a poor ctDNA response may benefit from an early treatment switch,” wrote the researchers. “Putative biomarkers could implement the selection of patients who could benefit from ICI treatment. Future studies should validate ctDNA kinetics to guide ICI treatment decisions in this population.”

References

1. Taieb J, Sullo FG, Lecanu A, et al. Early ctDNA and survival in metastatic colorectal cancer treated with immune checkpoint inhibitors. JAMA Oncol. Published online June 18, 2025. doi:10.1001/jamaoncol.2025.1646

2. Steinzor P. Blood test detects 79% of colorectal cancers in screening study. AJMC^®. June 3, 2025. Accessed June 18, 2025. https://www.ajmc.com/view/blood-test-detects-79-of-colorectal-cancers-in-screening-study