A study by Marsavela et al published in Clinical Cancer Research evaluating the predictive value of pretreatment circulating tumor DNA (ctDNA) to inform therapeutic outcomes in patients with advanced-stage melanoma relative to type and line of treatment has found that baseline levels of ctDNA predicted responses to first-line, but not second-line, immunotherapy, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence from the study indicates that treatment-naive patients with high ctDNA may preferentially benefit from combined anti–CTLA-4/anti–PD-1 therapy rather than anti–PD-1 therapy alone.

Although melanoma accounts for only about 1% of skin cancers, it causes a large majority of skin cancer deaths. This year, over 100,000 people will be diagnosed with melanoma and about 6,850 people will die from the cancer. While the emergence of targeted therapy and immune checkpoint inhibitors over the last decade have significantly changed the clinical management and outcome of patients with metastatic melanoma, durable response is only achieved in a minority of patients.

Study Methodology

The researchers analyzed data from 125 adult patients with metastatic melanoma. Thirty-two patients were treated with immune checkpoint inhibitors in the first-line setting, and 27 patients received immune checkpoint inhibitors in the second-line setting. The remaining 66 patients were not treated with immune checkpoint inhibitors and instead received first-line treatment with targeted therapy.

Results

In the discovery cohort, the researchers found that low ctDNA (≤ 20 copies/mL) prior to commencing therapy predicted longer progression-free survival in patients treated with first-line immune checkpoint inhibitors (hazard ratio [HR] = 0.20, 95% confidence interval [CI] = 0.07–0.53, P < .0001) but not in the second-line setting. An independent cohort validated that ctDNA is predictive of progression-free survival in the first-line setting (HR = 0.42, 95% CI = 0.22–0.83, P = .006), but not in the second-line setting. Moreover, ctDNA prior to commencing immune checkpoint inhibitor treatment was not predictive of progression-free survival for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced progression-free and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy relative to those treated with combination anti–CTLA-4/anti–PD-1 therapy.

“Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line immune checkpoint inhibitor treatment setting, but not in the second-line immune checkpoint inhibitor setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naive patients with high ctDNA may preferentially benefit from combined immune checkpoint inhibitors,” concluded the study authors.

“Our results indicate that it is necessary to carefully consider context when implementing biomarkers,” said Elin S. Gray, PhD, Associate Professor at Edith Cowan University in Perth, Australia, and senior author of this study, in a statement. “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.”

Disclosure: For full disclosures of the study authors, visit clincancerres.aacrjournals.org.