ctDNA Predicts Outcome for Frontline Immunotherapy in Metastatic Melanoma, But Not Second Line

November 20, 2020
Hayley Virgil
Hayley Virgil

Senior Editor, OncLive®
Hayley Virgil heads OncLive's feature article efforts and specializes in social issues and equality in oncology. Prior to joining the company in early 2020, she worked as an editor in numerous industries, including media, marketing, hospitality, and computer science, and freelanced in subjects such as history, culture, and the natural sciences.

November 20, 2020 - Circulating tumor DNAhas been found to be a reliable indicator of outcomes to treatment with frontline immune checkpoint inhibitors in patients with metastatic melanoma, but not in the second-line setting.

Circulating tumor DNA (ctDNA) has been found to be a reliable indicator of outcomes to treatment with frontline immune checkpoint inhibitors in patients with metastatic melanoma, but not in the second-line setting, according to results from a study published in Clinical Cancer Research.1

Moreover, early evidence from the study suggests that treatment-naïve patients who have high ctDNA may derive greater benefit from immune checkpoint inhibitor combinations.

“Immunotherapy has become an increasingly common treatment for patients with melanoma, often as the second-line treatment after disease progression on BRAF inhibitors,” Elin Gray, PhD, an associate professor and postdoctoral research fellow in Melanoma at Edith Cowan University and senior author on the study, stated in a press release.2 “There is a lot of interest in identifying biomarkers that reliably indicate how patients will respond to this treatment.”

Results showed that patients who had low ctDNA levels (n = 18), defined as 20 copies/mL or less, prior to their first line of treatment with immune checkpoint inhibitors experienced a longer progression-free survival (PFS) versus those with a high level of ctDNA (HR, 0.20; 95% CI, 0.07-0.53; P <.0001). Low ctDNA at baseline was validated as an independent predictor of longer PFS via a multivariate Cox regression analysis that controlled for age, sex, tumor stage, brain metastases, and BRAF mutational status (HR, 5.18; 95% CI, 1.88-14.31; P =.001).

However, no association was seen between low ctDNA levels and a longer PFS in patients with melanoma who received immune checkpoint inhibitors as second-line treatment (n = 27; HR, 1.05; 95% CI, 0.41-2.72; P=.913). Moreover, in patients who progressed following treatment with a BRAF inhibitor, with or without a MEK inhibitor, and were then treated with a second-line immune checkpoint inhibitor, low baseline ctDNA was not found to be predictive of a longer median PFS (HR, 0.59; 95% CI, 0.16-2.24; P =.356).

“Our results indicate that it is necessary to carefully consider context when implementing biomarkers,” Gray added. “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.”

Multiple studies have indicated that elevated baseline ctDNA levels in patients with melanoma are indicative of both a short PFS and a low overall response rate. Based on these previous data, investigators analyzed a prospective group of patients with metastatic melanoma who were receiving systemic treatment; notably, this cohort included those with BRAF wild-type disease. The study objective was to compare the predictive value of ctDNA prior to treatment to inform survival outcomes in patients who received immune checkpoint inhibitors in both the first- and second-line settings.

Investigators evaluated 125 samples of baseline plasma that had been taken from 110 patients with unresectable stage IV cutaneous melanoma prior to starting systemic treatment; this was referred to as the discovery cohort. Of these patients, a subset of 15 patients were considered as the baseline for their first- and second-line therapy.

Among the samples collected from the discovery cohort, 66 came from patients who had BRAF-mutated disease who were starting treatment with a first-line targeted therapy. Ninety-two percent of patients received dabrafenib (Tafinlar)/trametinib (Mekinist). Thirty-two patients received a frontline immune checkpoint inhibitor, either as a monotherapy or in combination; 22 patients received anti–PD-1 monotherapy and 10 received a combination regimen comprised of an anti–CTLA-4 agent plus an anti–PD-1 agent.

Twenty-seven patients received treatment with immune checkpoint inhibitors in the second line. Nineteen of these patients had received a BRAF inhibitor with or without a MEK inhibitor as their frontline treatment, while 8 received treatment with a single-agent immune checkpoint inhibitor followed by an immunotherapy combination. Two patients with BRAF-mutated disease were in the discovery cohort and they received frontline immunotherapy, while 21 of these patients were in the second-line immunotherapy group.

Two independent cohorts of patients with melanoma who had received immune checkpoint inhibitors in the frontline or second-line treatment settings were combined to comprise a validation cohort (n = 128). Within this cohort, 77 patients were treated with frontline immunotherapy; 37 received an anti–PD-1 monotherapy and 40 received the combination of anti–CTLA-4 and anti–PD-1 agents. An additional 51 patients were administered an immune checkpoint inhibitor in the second-line setting. Of these patients, 36 patients received frontline treatment with a BRAF inhibitor with or without a MEK inhibitor, 14 received ipilimumab (Yervoy), and 1 received ipilimumab/nivolumab (Opdivo).

Similar to what was observed in the discovery cohort, patients within the validation cohort who had low baseline ctDNA prior to receiving a first-line immune checkpoint inhibitor were noted as having a significantly longer PFS compared with those who had higher ctDNA at baseline; the median PFS was undefined versus 42 weeks, respectively (HR, 0.42; 95% CI, 0.22-0.83; P = 0.006). The multivariate Cox regression analysis confirmed that low baseline ctDNA prior to a first-line immune checkpoint inhibitor was an independent predictor for longer PFS (HR, 2.423; 95% CI, 1.17- 5.02; P =.017). Moreover, low ctDNA was not found to be associated with longer PFS for patients who were undergoing a second-line treatment, much like the discovery cohort (HR 0.61, 95% CI, 0.30-1.25, P =.143).

Although it wasn't determined to be a significant finding, investigators additionally observed a trend showing a longer PFS in patients who had high baseline ctDNA and were treated with a combination of immune checkpoint inhibitors compared with patients who were given an anti–PD-1 monotherapy. Here, the median PFS was 42 weeks versus 7.5 weeks, respectively (HR, 1.79; 95% CI, 0.90-3.53; P =.081). Patients who were given a combination therapy also demonstrated a longer OS (HR, 1.91; 95% CI, 0.87-4.21; P =.104). Patients who had low levels of ctDNA didn't experience a difference in PFS or OS when treated with a combination of immune checkpoint inhibitors compared with a monotherapy (HR, 1.97; 95% CI, 0.87-4.47; P=.124; HR, 1.74; 95% CI, 0.63-4.79; P =.306).

“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,” Goodman concluded.


  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. Clin Cancer Res. 2020;26(22):5926-5933. 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. American Association for Cancer Research. October 16, 2020. Accessed November 20, 2020. https://bit.ly/2HkSUp2.