Early ctDNA Level Linked to Survival After ICI in Advanced Melanoma

Decreases in circulating tumor DNA (ctDNA) within the first month of immune checkpoint inhibitor (ICI) therapy were strongly associated with higher response rates and longer survival in patients with unresectable stage III/IV melanoma, according to a multi-institutional analysis published in the Journal of Clinical Oncology Precision Oncology.¹

In the retrospective cohort of 117 patients treated with anti–PD-1–based regimens, a reduction in ctDNA levels 3 to 4 weeks after treatment initiation was associated with markedly higher odds of objective response and disease control, as well as significantly improved progression-free survival (PFS) and overall survival (OS).¹ The findings suggest that ctDNA dynamics may offer an earlier indicator of benefit than standard imaging, which is typically performed at 8 to 12 weeks.

“Our team found that ctDNA dynamics after only 3-4 weeks of immune checkpoint inhibitor therapy in patients with advanced-stage melanoma can prognosticate treatment response, risk of progression, and long-term survival,” Vincent T. Ma, MD, associate professor in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health, told Targeted Oncology.

Trial Overview

The study evaluated real-world data from 3 US academic centers between August 2021 and August 2024.¹ Eligible patients had histologically confirmed unresectable stage III or IV melanoma and were receiving anti–PD-1–based therapy, either nivolumab (Opdivo) or pembrolizumab (Keytruda) monotherapy or nivolumab in combination with relatlimab (Opdualag) or with ipilimumab (Yervoy). The majority (57.3%) received nivolumab/ipilimumab with 23.1% receiving anti–PD-1 monotherapy and 19.7% receiving nivolumab/relatlimab.

All patients underwent tumor-informed ctDNA testing using the personalized Signatera assay at baseline and again at 3 to 4 weeks, before the second treatment dose. Radiographic response was assessed retrospectively using RECIST version 1.1 criteria.

At a median follow-up of 13.4 months, 65% of the 117 patients demonstrated a decrease in ctDNA at 3 to 4 weeks. Compared with patients whose ctDNA level increased, those with a decrease had significantly higher odds of disease control (OR, 30.56; 95% CI, 10.64-87.74; P < .001) and objective response (OR, 23.54; 95% CI, 8.58-64.57; P < .001).

Survival outcomes were similarly differentiated. A ctDNA decrease was associated with improved PFS (HR, 0.18; 95% CI, 0.11-0.31; P < .001) and OS (HR, 0.28; 95% CI, 0.13-0.56; P < .001).¹ The 12-month PFS was 67.6% in the ctDNA-decrease group vs 23.1% in the ctDNA-increase group. The 12-month OS rate was 77.5% vs 43.5%, respectively.

Patients with ctDNA increase of at least 20% at 3 to 4 weeks had an increased risk of progression or death (HR, 7.25; 95% CI, 2.79-18.82; P < .001) and of death (HR, 7.35; 95% CI, 1.71-31.47; P = .07).

Nine of the 41 patients with ctDNA increase later achieved ctDNA clearance; 6 of the 9 received interventions including radiotherapy and palliative resection. Of 16 patients with undetectable baseline ctDNA, 15 remained undetectable and 1 developed detectable ctDNA at 3-4 weeks.

Notably, baseline ctDNA levels alone were not predictive of OR , underscoring the importance of dynamic change rather than absolute value.

Clinical Context of ctDNA

Despite the widespread adoption of dual and monotherapy ICI in advanced melanoma, a substantial proportion of patients experience primary resistance. Radiographic response assessment using RECIST 1.1 typically occurs after 2 to 4 months, and immune-related response patterns such as pseudoprogression complicate interpretation.² Early identification of nonresponders remains an unmet need.

ctDNA has emerged as a prognostic biomarker across multiple solid tumors, particularly in the minimal residual disease setting. In melanoma, prior studies have suggested that ctDNA kinetics correlate with ICI response, but most assessments occurred later in the treatment course.^3,4 The current study extends those observations to a 3- to 4-week interval.

In the present analysis, ctDNA clearance during therapy further stratified outcomes. Among patients with an early ctDNA decrease, those who ultimately achieved undetectable ctDNA had significantly improved PFS (HR, 0.14; P < .001) and OS (HR, 0.07; P < .001) compared with those without clearance.¹ However, some patients with transient increases later cleared ctDNA, often after adjunctive local interventions, highlighting the complexity of interpreting early rises.

Interpretation and Limitations

Although the magnitude of association was substantial, the study was retrospective and included heterogeneous treatment regimens. The median follow-up of 13.4 months limits long-term survival interpretation. In addition, imaging remained the reference standard for response assessment, and ctDNA testing was not used to guide treatment changes.

The Signatera assay is commercially available but not currently incorporated into guideline-directed management for advanced melanoma. Neither the National Comprehensive Cancer Network nor regulatory agencies recommend routine ctDNA monitoring to guide ICI decisions in this setting.³

Prospective trials will be required to determine whether early ctDNA–guided treatment modification improves outcomes. This study’s findings support ctDNA dynamics as a promising prognostic and potentially predictive biomarker rather than a practice-changing tool.

REFERENCES

1. Ma VT, Zhou AY, Forati A, et al. Multi-institutional study evaluating the role of early circulating tumor DNA dynamics during treatment with immune checkpoint inhibitors in patients with advanced-stage melanoma. JCO Precis Oncol. 2026;10:e2500254.

2. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026

3. Lee JH, Long GV, Boyd S, et al. Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma. Ann Oncol. 2017;28(5):1130-1136. doi:10.1093/annonc/mdx026

4. Bratman SV, Yang SYC, Iafolla MAJ, et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer. 2020;1(9):873-881. doi:10.1038/s43018-020-0096-5

5. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: Cutaneous, version 2.2025. Accessed February 17, 2026. https://tinyurl.com/5b39f96p