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ctDNA may predict outcomes with first-line, but not second-line immunotherapy for melanoma

October 16, 2020

Bottom Line:

Baseline levels of circulating tumor DNA (ctDNA) predicted responses to first-line, but not second-line, immune checkpoint inhibition in patients with melanoma.

Journal in Which the Study was Published:

Clinical Cancer Research, a journal of the American Association for Cancer Research

Author: Elin Gray, PhD, an associate professor at Edith Cowan University in Australia and senior author on the study


"Immunotherapy has become an increasingly common treatment for patients with melanoma, often as the second-line treatment after disease progression on BRAF inhibitors," explained Gray. "There is a lot of interest in identifying biomarkers that reliably indicate how patients will respond to this treatment."

Circulating tumor DNA (ctDNA) is shed from tumors and can be detected in the bloodstream. ctDNA levels have been shown to correlate with responses to targeted therapies in patients with melanoma, but the potential of ctDNA to predict responses to immunotherapy remained unclear.

How the Study was Conducted:

In this study, Gray and colleagues prospectively examined the association between baseline (pre-treatment) ctDNA levels and clinical outcomes in a discovery cohort of 125 adult patients with metastatic melanoma. Thirty-two patients were treated with immune checkpoint inhibition in the first-line setting, while 27 patients received immune checkpoint inhibition in the second-line setting. The remaining 66 patients were not treated with immune checkpoint inhibition and instead received first-line treatment with targeted therapy.


Consistent with previous studies, patients with low baseline ctDNA levels (fewer than or equal to 20 copies per milliliter) who were treated with targeted therapy had longer progression-free survival than those with high baseline ctDNA levels (greater than 20 copies per milliliter). In patients treated with first-line immune checkpoint inhibition, those with low baseline ctDNA levels had an 80 percent longer progression-free survival than those with high ctDNA levels. Baseline ctDNA levels were associated with progression-free survival after first-line immune checkpoint inhibition even after controlling for other factors, such as sex, age, tumor stage, BRAF mutation status, and brain metastases. In contrast, there was no significant association between baseline ctDNA levels and progression-free survival in patients who received immune checkpoint inhibitors in the second-line setting.

Gray and colleagues then verified these results in a separate validation cohort of 128 patients with melanoma recruited at other institutions across Australia (the Melanoma Institute Australia and the Peter MacCallum Cancer Centre). Patients in the validation cohort were treated with immune checkpoint inhibition in either the first- or second-line setting (77 and 51 patients, respectively). Similar to results seen in the discovery cohort, baseline ctDNA levels were associated with progression-free survival in patients who received first-line immune checkpoint inhibition, but not in those who received second-line immune checkpoint inhibition. In patients treated with first-line immune checkpoint inhibition, low baseline ctDNA levels were associated with a 58 percent longer progression-free survival than those with high baseline ctDNA levels. The association was independent of sex, age, tumor stage, BRAF mutation status, and brain metastases.

In addition, the authors observed that patients with high ctDNA levels who were treated with combination immune checkpoint inhibition (anti-CTLA4 and anti-PD1) had longer progression-free survival and overall survival than those treated with a single agent (anti-PD1); however, these results were not statistically significant. Gray cautioned that these results were obtained by combining the discovery and validation cohorts and therefore require independent validation. She added that these results, if validated, highlight a potential for ctDNA to identify patients who are more likely to benefit from combination immunotherapy.

Author's Comments:

"Our results indicate that it is necessary to carefully consider context when implementing biomarkers," said Gray. "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," she added.

Future work from Gray and colleagues will aim to understand how tumor biology and the tumor site affect the release of ctDNA. In addition, they are interested in evaluating ctDNA as a biomarker of disease progression.

Study Limitations:

Limitations of the study included small sample sizes within some subgroups and potential variability in how progressive disease was measured among different patients.
Funding & Disclosures:

The study was supported by the National Health and Medical Research Council, the Cancer Council, the Department of Health Western Australia, the Spinnaker Foundation, the Perpetual Foundation, the Merck Sharpe & Dohme Investigator Studies Program Grant, the ECU Early Career Research Grant, the Cancer Research Trust, the Western Australia Health Translational Network, the Victorian Cancer Agency, the Cancer Institute NSW, the Melanoma Institute Australia, the University of Sydney Medical Foundation, and the School of Medical and Health Sciences at Edith Cowan University. Gray has received funds for travel from Merck Sharpe & Dohme.

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes 47,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 127 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops--the largest of which is the AACR Annual Meeting, with more than 100,000 attendees for the 2020 virtual meetings and more than 22,500 attendees for past in-person meetings. In addition, the AACR publishes nine prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit

To interview Elin Gray, please contact Richard Lobb at or 215-906-3322.

American Association for Cancer Research

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