ctDNA May Be Reliable Predictor of Outcomes with First-Line Immunotherapy for Melanoma


Pretreatment circulating tumor DNA was found to be a reliable indicator of patient outcome for those with metastatic melanoma in the first-line immune checkpoint inhibitor (ICI) treatment setting, but not in the second-line setting.

Pretreatment circulating tumor DNA (ctDNA) is a reliable indicator of patient outcome for patients with metastatic melanoma in the first-line immune checkpoint inhibitor (ICI) treatment setting, but not in the second-line setting, especially in those pretreated with BRAF/MEK inhibitors, according to study findings published in Clinical Cancer Research.1

“Our results indicate that it is necessary to carefully consider context when implementing biomarkers,” senior author Elin Gray, PhD, an associate professor at Edith Cowan University in Australia, said in a press release.2 “ctDNA is often heralded as a good prognostic biomarker, but we found that this is not the case for patients receiving immune checkpoint inhibitors in the second-line setting.”

“We need more of these kinds of studies evaluating the accuracy of ctDNA in various disease contexts, particularly now that liquid biopsy and ctDNA are being increasingly incorporated into the clinic,” Gray added.

In this study, researchers quantified plasma ctDNA in 125 samples collected from 110 patients with metastatic melanoma prior to beginning treatment with ICIs, as first- (n = 32) or second-line (n = 27) regimens, or before commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external cohort consisting of 128 patients starting ICI therapies in the first- (n = 77) or second-line (n = 51) settings was used to validate the findings.

Consistent with previous studies, patients with low baseline ctDNA levels (≤20 copies per milliliter) prior to commencing therapy treated with first-line ICIs experienced longer progression-free survival (PFS; HR, 0.20; 95% CI, 0.07-0.53; P < .0001); however, this was not observed in patients treated with second-line ICIs. Moreover, the external cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22-0.83; P = .006), though not in the second-line setting.

“The predictive significance of ctDNA levels prior to commencing targeted therapies has been previously demonstrated, with the absence of detectable ctDNA correlating with longer survival in large cohorts of patients with melanoma,” the authors noted. “Similarly, we found that baseline ctDNA level was a strong predictor of clinical outcome in melanoma patients in the first-line targeted therapy setting, showing that high ctDNA level is associated with poorer clinical outcomes.”

In addition, ctDNA before starting ICI treatment was not found to be predictive of PFS for patients treated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Further, reduced PFS and overall survival (OS) were seen in patients with high ctDNA receiving anti-PD-1 monotherapy, compared to those treated with combination anti-CTLA-4/anti-PD-1 inhibitors.

“Overall, our results redefine the context of use of ctDNA as a predictive biomarker in patients with melanoma receiving immunotherapy, confining its utility to the first-line treatment setting,” the authors wrote.

Of note, the researchers indicated that the study was limited by the low number of patients with high ctDNA included in the survival analysis of single-agent anti-PD-1 and combination of

ICIs. Therefore, prospective clinical trials are still needed to confirm the current observations and validate the use of ctDNA as a predictive biomarker for the treatment of patients with melanoma.

Moving forward, the investigators will be working to understand how tumor biology and the tumor site affect the release of ctDNA. Additionally, they are interested in evaluating ctDNA as a biomarker of disease progression.


1. Marsavela G, Lee J, Calapre L, et al. Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy. Clinical Cancer Research. doi: 10.1158/1078-0432.CCR-20-2251

2. Circulating Tumor DNA May Predict Clinical Outcomes with First-line, but not Second-line, Immunotherapy for Melanoma [news release]. Published October 16, 2020. Accessed October 16, 2020.

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