Clinical trial results from a study 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, and others, and published in Clinical Cancer Research, a journal of the American Association for Cancer Research, demonstrate that baseline levels of circulating tumor DNA (ctDNA) predicted responses to first-line, but not second-line, immune checkpoint inhibition in patients with melanoma.[1]

ctDNA is shed from tumors and can be detected in the bloodstream and levels of ctDNA have been shown to correlate with responses to targeted therapies in patients with melanoma. However, the potential of ctDNA to predict responses to immunotherapy remained, so far, unclear.

“Immunotherapy has become an increasingly common treatment for patients with melanoma, often as the second-line treatment after disease progression on BRAF inhibitors,” explained Elin Gray, Ph.D., an associate professor at Edith Cowan University in Australia and senior author on the study.

“There is a lot of interest in identifying biomarkers that reliably indicate how patients will respond to this treatment,” Grauy added.

Study
Prior to treartment, Gray and colleagues prospectively examined the association between baseline plasma circulating tumor DNA (ctDNA) levels and clinical outcomes in a discovery cohort of 125 adult patients with metastatic melanoma. They quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors, as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing immune checkpoint inhibitors therapies in the first- (N = 77) or second-line (N = 51) settings.[1]

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Consistent with previous studies, patients with low baseline ctDNA levels, which is considere 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 of greater than 20 copies per milliliter.

In patients treated with first-line immune checkpoint inhibition, those with low baseline ctDNA levels had an 80% longer progression-free survival than those with high ctDNA levels. Baseline ctDNA levels were associated with progression-free survival (PFS) 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.

Separate validation cohort
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.

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

“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, she added.

“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 concluded.

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.

Gray noted that these results, if validated, highlight a potential for ctDNA to identify patients who are more likely to benefit from combination immunotherapy.

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.

Reference
[1] Marsavela G, Lee J, Calapre L, Wong SQ, Pereira MR, McEvoy AC, Reid AL, Robinson C, 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 October 16 2020 DOI: 10.1158/1078-0432.CCR-20-2251

Featured image: Melanoma diagnosis. Photo courtesy: © 2016 – 2020 Fotolia/Adobe. Used woth permiussion.

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