Disclosures: Novartis supported the study. Polsky reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
February 15, 2021
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Circulating tumor DNA could help guide treatment of BRAF V600-mutant metastatic melanoma

Disclosures: Novartis supported the study. Polsky reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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Circulating tumor DNA measurements before and during treatment could help guide selection of therapy for patients with BRAF V600-mutant unresectable or metastatic melanoma, according to study results published in The Lancet Oncology.

“Treatment of metastatic melanoma has made enormous strides within the past 10 years; however, we still lack validated, sensitive and specific blood-based biomarkers to predict and monitor treatment efficacy,” David Polsky, MD, PhD, Alfred W. Kopf professor of dermatologic oncology at NYU Langone Health, told Healio. “Cell-free circulating tumor DNA [ctDNA] has emerged as a promising blood-based biomarker in several cancer types. Studies to date in melanoma have been generally small, mostly retrospective and have used various methodologies.”

photo of melanoma/skin cancer
Source: Adobe Stock.

For this reason, Polsky and colleagues sought to validate the use of droplet digital polymerase chain reaction assays for the measurement of ctDNA among 383 adults included in two clinical trials — COMBI-d and COMBI-MB — who received the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK1/2 inhibitor trametinib (Mekinist, Novartis) for treatment of BRAF V600-mutant unresectable metastatic melanoma.

David Polsky, MD, PhD
David Polsky

“More specifically, we wanted to assess how well ctDNA levels prior to treatment, and at 4 weeks into treatment, predicted patient survival in a clinical trial setting, which is the gold standard for clinical validation of a biomarker,” Polsky said.

The double-blind, randomized, phase 3 COMBI-d trial evaluated dabrafenib plus trametinib vs. dabrafenib plus placebo for previously untreated BRAF V600-mutant unresectable or metastatic melanoma. PFS served as the primary outcome.

The open-label, phase 2 COMBI-MB trial evaluated the dabrafenib-trametinib combination among patients with BRAF V600-mutant metastatic melanoma and brain metastases. Intracranial response in cohort A, which included patients with asymptomatic brain metastases, no prior brain-directed local therapy, and an ECOG performance score of 0 or 1, served as the primary outcome.

For the current study, researchers obtained pretreatment plasma samples of 345 patients and on-treatment samples of 224 patients in the COMBI-d trial, and pretreatment and on-treatment samples of 38 patients in cohort A of the COMBI-MB trial who had intracranial and extracranial metastatic melanoma.

Results showed ctDNA in pretreatment samples of 93% of patients in the COMBI-d group and 89% of patients in the COMBI-MB group. Elevated baseline BRAF V600 mutation-positive ctDNA levels, when evaluated as a continuous variable, predicted worse OS outcomes among patients in the COMBI-d trial, regardless of baseline lactate dehydrogenase levels.

Researchers also found that a ctDNA cut point of 64 copies/mL of plasma appeared to predict survival outcomes in the COMBI-d trial. They further validated this among patients in the COMBI-MB trial.

Patients with pretreatment ctDNA of less than 64 copies/mL had longer median PFS (12.7 months vs. 6.5 months; HR = 1.74; 95% CI, 1.37-2.21) and longer median OS (35.1 months vs. 13.4 months; HR = 2.23; 95% CI, 1.73-2.87) than patients with ctDNA of 64 copies/mL or greater.

Undetectable ctDNA at week 4 among those in the COMBI-d trial was significantly associated with improvements in PFS and OS, especially among those with high lactate dehydrogenase levels, according to the researchers.

“With respect to the management of patients with unresectable and metastatic disease, future research should explore whether clinical decision-making, informed by ctDNA measurements, can improve patient survival compared to standard approaches, which rely primarily on radiographic scans,” Polsky said.

For more information:

David Polsky, MD, PhD, can be reached at NYU Langone Health, 522 First Ave., SML-404, New York, NY 10016; email: david.polsky@nyulangone.org.