Early ctDNA Changes Predict Immunotherapy Outcomes in CRC

Medscape

18-07-2025

TOPLINE:
In patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (CRC) who received immune checkpoint inhibitors, changes in circulating tumor DNA (ctDNA) concentrations at 1-month post-treatment predicted progression-free survival (PFS) and overall survival. Favorable ctDNA responders experienced significantly improved survival with the immune checkpoint inhibitor avelumab than with chemotherapy.
METHODOLOGY:
Immune checkpoint inhibitors have improved outcomes among patients with dMMR/MSI-H metastatic CRC, but early resistance is common, and the optimal treatment duration remains unclear. Using liquid biopsy to monitor ctDNA changes may enable earlier prediction of long-term outcomes, but this approach requires further validation.
Researchers performed a secondary analysis using data from the SAMCO-PRODIGE 54 trial, in which 99 patients with dMMR/MSI-H metastatic CRC (mean age, 66 years; 51.5% women) were randomly assigned to receive either avelumab every 15 days or standard chemotherapy with or without targeted therapy.
Researchers collected plasma samples at baseline and 1 month after treatment initiation and analyzed ctDNA using digital droplet polymerase chain reaction assays.
Favorable ctDNA responders were defined as those who exhibited a decline in ctDNA concentrations greater than or equal to the median value (-86%), whereas poor responders were those with a decline less than the median value.
Researchers assessed PFS and overall survival according to baseline ctDNA positivity or concentration as well as early ctDNA variation.
TAKEAWAY:
Changes in ctDNA concentration were significantly associated with both PFS (hazard ratio [HR], 2.98; P < .001) and overall survival (HR, 3.61; P < .001). This association was stronger in the avelumab group (HR, 4.22 for PFS and HR, 17.44 for overall survival) vs the chemotherapy group (HR, 2.09 and HR, 1.51; P = .38, respectively).
In the avelumab group, the median PFS was 29.0 months for favorable ctDNA responders vs 2.3 months for poor responders; median overall survival was not reached among favorable responders compared with 15.0 months among poor responders (HR, 17.40; P < .001). Compared with chemotherapy, avelumab was associated with significantly improved PFS for favorable ctDNA responders (HR, 0.33) but not for poor responders (HR, 1.32).
In multivariable analysis, a change in ctDNA concentration was confirmed to be independently associated with PFS in patients treated with avelumab (HR, 7.27; P = .001) but not in those treated with chemotherapy.
Several patients with a poor ctDNA response did have long-lasting stable disease — indicating that cDNA change is 'informative,' the authors noted, but not in itself enough to drive decisions on early treatment discontinuation.
IN PRACTICE:
'Our findings suggest that change in ctDNA may theoretically be useful for early prediction of immune checkpoint inhibitor efficacy,' the author concluded. 'Therefore, the added value of change in ctDNA is having an earlier assessment and providing additional information on the long-term outcome of the disease compared with a classic RECIST assessment.'
SOURCE:
The study, led by Julien Taïeb, MD, PhD, Service de gastroenterologie et d'oncologie digestive, Paris CARPEM institute, Hopital Européen Georges Pompidou, Assistance Publique Hopitaux de Paris, Université Paris Cité in Paris, France, was published online in JAMA Oncology.
LIMITATIONS:
The study was limited by a moderate sample size, particularly affecting the interpretation of subgroup analyses. A potential risk for immortal-time bias could have been introduced as the study endpoints were defined from randomization to the event, but patients were not at risk until at least 4 weeks post-treatment. Additionally, having only a single ctDNA monitoring timepoint may have affected outcome predictions.
DISCLOSURES:
The SAMCO-PRODIGE 54 phase 2 randomized clinical trial received partial funding from Merck KGAa and was sponsored by the Fédération Francophone de Cancérologie digestive. Several authors reported receiving grants or personal fees and having other ties with various sources. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.