ctDNA levels promising for tracking melanoma treatment progress, predicting outcomes

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By Marilynn Larkin

NEW YORK (Reuters Health) - Circulating tumor DNA (ctDNA) levels can be used to track treatment progress and predict outcomes in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, analyses of two pivotal studies shows.

"Our findings suggest that pre-treatment and early, on-treatment ctDNA measurements may help predict which patients with unresectable and metastatic melanoma will benefit from targeted therapies," Dr. David Polsky of NYU Langone Health in New York City told Reuters Health by email.

"The test is not yet ready for clinical use," he noted. "We need to conduct additional studies to determine how best to use the blood test results to inform medical decision-making, which in metastatic melanoma relies primarily on radiographic scans."

As reported in The Lancet Oncology, Dr. Polsky and colleagues measured BRAF V600-mutant ctDNA in pretreatment and on-treatment plasma samples from BRAF V600 mutation-positive unresectable or metastatic melanoma patients enrolled in two clinical trials.

One -- COMBI-d -- is a double-blind, randomized phase 3 study of dabrafenib plus trametinib versus dabrafenib plus placebo. Patients had Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Plasma samples were available from 345 of 423 (82%) and 224 of 423 (53%) patients, respectively.

The other -- COMBI-MB -- is an open-label, phase 2 study evaluating dabrafenib plus trametinib. Patients in cohort A of the trial had asymptomatic brain metastases, no previous local brain-directed therapy, and an ECOG PS 0 or 1. Pretreatment and on-treatment samples were available from up to 38 of 76 patients (50%) with intracranial and extracranial metastatic melanoma.

ctDNA was detected in pretreatment samples from 93% of COMBI-d participants and 89% of those in COMBI-MB.

"Overall, the higher the pretreatment levels of ctDNA, the shorter the survival," Dr. Polsky said. "This relationship was independent of blood levels of lactate dehydrogenase, which is a biomarker that is part of the current staging system."

A ctDNA cut point of 64 copies/mL of plasma stratified patients enrolled in COMBI-d with respect to survival outcomes; this was validated in the COMBI-MB cohort.

"Patients with levels below the cut point lived on average, nearly three times as long as patients with levels above the cut point," Dr. Polsky noted.

In COMBI-d, undetectable ctDNA at week four was significantly associated with extended progression-free and overall survival, particularly in patients with elevated lactate dehydrogenase levels.

However, longitudinal ctDNA results beyond four weeks were difficult to assess. Further, because a relatively low number of patients in the validation cohort, confirmational analyses are needed.

Summing up, the authors state, "pretreatment and on-treatment BRAF V600-mutant ctDNA measurements may serve as independent, predictive biomarkers of clinical outcome with targeted therapy."

Dr. Geoffrey Young, Chief of Head and Neck Surgery for Baptist Health's Miami Cancer Institute in Florida commented in an email to Reuters Health, "This is the largest study to date showing the ability to detect circulating tumor markers in certain patients with melanoma. This has the potential to be used as a surveillance tool or to monitor disease response to therapy, (and) would particularly be helpful in clinical scenarios where following disease radiologically is not optimal."

Although the method is promising, the findings apply only to patients with BRAF V600, he noted. Further, he added, "a head-to-head comparison of the sensitivity and cost-effectiveness of circulating tumor marker detection versus more commonly used methods of monitoring disease, such as imaging, is needed."

The study was funded by Novartis. Five coauthors are employees and Dr. Polsky and other coauthors have received fees from the company.

SOURCE: https://bit.ly/3kdNFXD The Lancet Oncology, online February 12, 2021.

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