Early ctDNA Signal Offers a Path for Precision Care in Advanced Melanoma

Circulating tumor DNA (ctDNA) has been employed in many areas of cancer care as a method of monitoring disease rapidly and noninvasively. Beyond using ctDNA to identify relapsed disease, it has other applications including early in the course of treatment. A retrospective analysis of ctDNA testing in patients treated with immune checkpoint inhibitors (ICIs) for advanced melanoma has been published in JCO Precision Oncology. The findings show that a ctDNA decrease or increase at 3 to 4 weeks after initiation of therapy has the potential to prognosticate treatment outcomes.¹

If these results are validated by prospective trials, it could become a valuable tool for oncologists to assess results faster than imaging and help to resolve ambiguous findings on the first scan, said Vincent Ma, MD, in an interview with Targeted Oncology.

“What we anticipate in the future is that early ctDNA increase could lead to things like prompt treatment escalation, trigger clinical trial enrollment, and even encourage closer radiographic monitoring,” said Ma, assistant professor at the University of Wisconsin School of Medicine and Public Health and first author of the publication. “Whereas [for] patients who have an early ctDNA decrease or clearance, that might reinforce the continuation of therapy, provide reassurance in cases of equivocal imaging, and help provide the rationale for informing even treatment de-escalation strategies.”

Ma discussed the findings and how they are particularly applicable in advanced melanoma, where patients have limited options should frontline ICI therapy fail and early knowledge could shape further treatment decisions.

Targeted Oncology: Could you describe the background for using ctDNA to evaluate melanoma?

Vincent Ma, MD: ICIs have transformed the treatment landscape for advanced melanoma. But what we know about this particular treatment is that a good proportion of patients don't respond to treatment, or they ultimately progress. Currently, the treatment response that we typically use is imaging, and we typically tend to do this around 2 to 4 months after starting ICI therapy. Unfortunately, this delay can limit timely treatment adjustments, and we know that imaging itself has its limitations as it can be complicated by the effects of pseudo-progression or inflammatory changes.

ctDNA represents more of a minimally invasive tumor specific biomarker that can reflect real-time tumor burden. ctDNA studies have been assessed across multiple different solid tumors, including melanoma, and we've seen that ctDNA detectability and clearance may correlate with prognosis. Most prior melanoma studies, though, have evaluated ctDNA at later time points during treatments, around 6 to 9 weeks or beyond. But for our particular study, we sought to determine whether very early ctDNA changes within 3 to 4 weeks of starting immunotherapy can provide clinically meaningful prognostic information.

How did your study analyze early ctDNA changes?

In our study, we conducted a multi-institutional retrospective analysis of 117 patients with unresectable stage III or stage IV melanoma [who] were treated with anti–PD-1–based ICI therapy. All patients underwent tumor informed ctDNA testing with Signatera at baseline and again at 3 to 4 weeks, but before their second treatment dose of checkpoint inhibition. We categorized these patients based on whether their ctDNA levels decreased—either they had a zero change or a decrease from their baseline—or [had] an increase from above their baseline during that early interval. Then what we did was we correlated that early ctDNA dynamic with objective response based on RECIST [criteria], disease control, progression-free survival [PFS], overall survival, and then we examined the impact of early ctDNA clearance as well as longer-term ctDNA kinetics.

What were the key findings from your analysis?

The findings were pretty compelling. What we found was that ctDNA decrease at just as early as 3 to 4 weeks was associated with a 30-fold higher odds of disease control, a 23-fold higher odds of objective response, an 82% reduction in risk of progression, and a 72% reduction in risk of death. In contrast, what we saw is that patients who [had] ctDNA increase early on had a median PFS of just 2.3 months. Importantly, early ctDNA clearance, which was another end point that we also assessed, was found to be strongly associated with favorable outcomes. What we saw was that among patients with early decreases, those who ultimately achieved a complete ctDNA clearance has…a 1-year overall survival exceeding 90%. Notably, baseline ctDNA levels, which we also analyzed, if we just look at the ctDNA levels alone, it was not necessarily predictive or prognostic of response. So, our study demonstrated the importance of dynamic changes to help prognosticate clinical outcomes of patients.

What insights would you say this ctDNA level can tell clinicians about the outcomes of frontline treatment?

The key insight is that the trajectory is what matters most [rather than] just a single timepoint measurement. In contrast to what we used to believe, which is that it's really difficult to gauge treatment benefit from ICIs before the 2- to 3-month assessment with imaging, our study found that early decrease in ctDNA at 3 to 4 weeks can suggest that the immune system can effectively engage in antitumor benefit earlier than what we had previously expected, and we can tell if a patient is likely to derive clinical benefit. Conversely, an early increase in ctDNA can help identify a high-risk group that is likely to have a poor short-term outcome.

ctDNA dynamics can help interpret ambiguous findings…. What we found was that in a subset of patients with what may look like radiographic progression, but ctDNA decrease, we subsequently found that imaging could suggest pseudo-progression. This raises the possibility that ctDNA may help differentiate between immune-related inflammatory changes from true disease progression, and so for clinicians and patients, we think that early ctDNA dynamics may provide a window into treatment efficacy weeks before the traditional imaging.

How might early ctDNA level potentially inform your treatment decisions?

At this present time, I think ctDNA remains more of as a prognostic biomarker, and imaging continues to remain the current standard of care. However, we know that ctDNA may have potential application applications that may be quite significant. What we anticipate in the future is that early ctDNA increase could lead to things like prompt treatment escalation, trigger clinical trial enrollment, and even encourage closer radiographic monitoring, whereas [for] patients who have an early ctDNA decrease or clearance, that might reinforce the continuation of therapy, provide reassurance in cases of equivocal imaging, and help provide the rationale for informing even treatment de-escalation strategies, particularly in select contexts. But ultimately, prospective trials are going to be essential to determine whether ctDNA guided treatment adaptation may improve outcomes.

How could these findings be applied considering the limited number of treatment options following failure of ICI therapy?

Advanced melanoma includes multiple approved immunotherapy options, including anti–PD-1 monotherapy, dual checkpoint inhibition, targeted therapy for BRAF V600–mutant disease, and TIL [tumor-infiltrating lymphocyte] therapy.² As outcomes have dramatically improved with the availability of all these treatment options, we know that treatment-related toxicities can be quite significant. In that context, a biomarker can help identify nonresponders early on.

This could be incredibly valuable, because…for patients who are dealing with ineffective therapy that might be, for example, too toxic, this can allow for transitions to alternative therapies that might be more effective and may potentially have less debilitating adverse events. Even though we have very few treatment options in our arsenal compared to other tumor types, using ctDNA dynamics can help inform our ability to make transitions and care for patients where we know, for example, that they may be doomed to failure early on in their therapy.

Could knowing that certain patients are likely to have disease progression be especially helpful in planning TIL therapy?

TIL therapy has become the new therapy option for patients who have developed ICI therapy [and] BRAF/MEK targeted therapy resistance, and by allowing or incorporating the use of ctDNA early on in the treatment course, that might segue into this idea that for patients who we know are unlikely to do well by that 2- to 3-month scan report, we could think about having these patients potentially evaluated earlier on for TIL therapy, because there's such a long window period to have TIL therapy available to patients once they're identified as a potential candidate. As of right now, our study still requires ongoing, prospective validation before we think about using this type of information, the early ctDNA dynamics, to inform treatment decisions. But that is certainly the direction that…our study could potentially inform as a future clinical trial option.

What are the next steps for this research?

Although our work has been primarily retrospective in nature, the next step is prospective validation. We need clinical trials designed specifically to incorporate early ctDNA monitoring, predefined response, adapted interventions to evaluate whether ctDNA-guided decisions improve survival. But there are still some additional areas of investigations, which include standardizing ctDNA threshold, as well as the optimal timing, evaluating cost-effectiveness, integrating ctDNA with imaging and potentially other peripheral blood biomarkers, as well as assessing its role especially as an early surrogate end point, particularly in immunotherapy-based clinical trials.

But ultimately, I think the goal is to move towards a more dynamic model of a precision immuno-oncology, where treatment decisions are informed not only by baseline characteristics, but by real-time molecular responses.

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. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: Cutaneous, version 2.2025. Accessed March 2, 2026. https://tinyurl.com/5b39f96p