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Background Current approved immunotherapies exhibit limited efficacy in MSS mCRC due to its ‘immunologically cold’ phenotype, highlighting the need for novel treatments. Vilastobart, a tumor-activated, Fc-enhanced, high-affinity anti-CTLA-4, is being evaluated in phase 2 in combination with atezolizumab (Tecentriq®). A patient with locally advanced MSS rectal cancer treated during dose escalation achieved a complete endoscopic response with negative biopsies, accompanied by clearance of circulating tumor DNA (ctDNA), while radiographic response remained consistent with ‘stable disease’ (RECIST) with complete resolution of diffusion abnormalities (suggestive of fibrosis). Based on promising efficacy observed to date in phase 2, 1 we explored the utility of ctDNA kinetics as a potential surrogate biomarker for response. Highly sensitive ctDNA monitoring and its correlation with radiographic response in patients with MSS mCRC treated with vilastobart has not been reported before.Methods This phase 2 study evaluated vilastobart (100mg Q6W) in combination with atezolizumab (1200mg Q3W) in heavily pretreated patients (n=44) with MSS mCRC, including 27 with non liver metastases (NLM). In an exploratory biomarker analysis, plasma ctDNA was serially analyzed using the Guardant Infinity NGS assay, measuring methylation-based Tumor Fraction (TF). Among 27 NLM patients, 25 had evaluable ctDNA kinetics and response data for association analysis, 23 had target lesion and ctDNA data for correlation analysis. Statistical analyses (Spearman’s rank correlation, Wilcoxon rank sum, Fisher’s Exact) explored the relationship between ctDNA changes and RECIST responses.Results The combination of vilastobart and atezolizumab showed promising anti-tumor activity, with a preliminary overall response rate of 26% in patients with MSS mCRC, NLM, including 7 partial responses (PR) (6 confirmed) per RECIST as of May 12, 2025. A strong positive correlation was observed between best percentage changes in ctDNA TF scores and the sum of target lesion diameters (Spearman’s Rho=0.62; p=0.0016, n=23). ctDNA TF best percentage changes were significantly associated with clinical response status (PR vs. stable disease: p=4.5x10 -3; PR vs. progressive disease: p=3.1x10-4). All PR patients had significant reductions in ctDNA TF scores of ≥75% from baseline (Fisher’s Exact p=1.7x10-5; positive predictive value=87.5%; specificity=94%; sensitivity=100%). These reductions in ctDNA TF scores were measured 3.3 weeks (average) in advance of PRs.Conclusions The combination of vilastobart and atezolizumab showed promising activity in patients with MSS mCRC, NLM. This exploratory analysis supports the potential utility of ctDNA as a surrogate biomarker for assessing immunotherapy response. Larger, prospective studies are warranted to fully establish ctDNA as a surrogate endpoint.Trial Registration NCT04896697Reference Davar D, Fakih M, Bekaii-Saab TS, DeVito NC, Knecht JG, Vandross AL, Perez CA, Bessudo A, Gupta A, Patel E, Fantini D, Paramasivan S, Crowe D, Duncan M, McConnell S, Luptakova K, Parikh AR. Phase 1/2 study of XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, in combination with atezolizumab in patients with advanced solid tumors and in MSS CRC. Journal of Clinical Oncology 2025;43(4_suppl):206–206. https://ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.206Ethics Approval This study was approved by Advarra Institutional Review Board, approval number Pro00054400. All study participants gave informed consent before taking part in the study.