A study was conducted to investigate the baseline levels of circulating tumour DNA (ctDNA) predicted responses to first-line, but not second-line, immune checkpoint inhibition in patients with melanoma.

The results of which were published in the journal of Clinical Cancer Research.

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 tumour DNA (ctDNA) is shed from tumours 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.

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, tumour 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, tumour 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 tumour biology and the tumour site affect the release of ctDNA.

In addition, they are interested in evaluating ctDNA as a biomarker of disease progression.

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

Source: AACR