Circulating DNA Can Indicate Melanoma Treatment Failure

MedicalResearch.com Interview with:

David Polsky, MD, PhDDermatologist and Director of the Digmented Lesion Service

Dr. Polsky

David Polsky, MD, PhD
Dermatologist and Director of the Digmented Lesion Service

Mahrukh M. Syeda, MS
Research Associate

Ronald O. Perelman Department of Dermatology
NYU Langone Health

MedicalResearch.com: What is the background for this study?

Response: Several studies of metastatic melanoma patients have demonstrated that measuring circulating tumor DNA (ctDNA) associates with their disease burden and survival.  Generally, patients with detectable pre-treatment ctDNA levels and/or detectable ctDNA at various time intervals after starting treatment have shorter survivals than patients with lower pre-treatment or on-treatment ctDNA levels.  Studies have varied in their methods to detect ctDNA, the thresholds chosen to call a sample positive or negative, and the follow up time point for measurement, if any.

In this study, we examined pre-treatment and week 4 on-treatment plasma samples from patients enrolled in Combi-D, the Phase III, randomized, double-blind trial of the BRAF and MEK inhibitors Dabrafenib and Trametinib, which led to FDA approval of the combination therapy for patients with unresectable stage III/IV melanoma.

Only patients with BRAF V600E or V600K mutations identified from tumor genotyping were enrolled in the clinical trial.

MedicalResearch.com: What are the main findings? 

Response: There are several main findings of this study.  We quantified BRAF V600E and V600K ctDNA using droplet digital PCR assays that we analytically validated prior to conducting this study.

We detected ctDNA in 93% of pre-treatment samples, which to our knowledge is the highest mutation-detection rate in melanoma for these types of studies.

We found that:

  • 1) the level of pre-treatment ctDNA was associated with survival;
  • 2) patients whose ctDNA was detectable prior to treatment and then became undetectable after 4 weeks on treatment had a generally longer survival than those who still had detectable ctDNA after 4 weeks of treatment; and
  • 3) achieving undetectable ctDNA at 4 weeks also stratified patients with an elevated baseline lactate dehydrogenase (LDH) into shorter or longer survivals.  Baseline LDH is a poor prognostic indicator and a component of the AJCC Melanoma Staging System.We think that detectable ctDNA after 4 weeks of treatment was evidence of less effective drug treatment, which was in agreement with the shorter survival of those patients compared to the undetectable group. 

MedicalResearch.com: What should readers take away from your report? 

Response: Three important features of our study are:

  • 1) to our knowledge, this is the largest study of the ctDNA blood test in metastatic melanoma;
  • 2) these quantitative assays achieved the highest mutation-detection rate in pre-treatment samples among published studies; and
  • 3) the study was conducted using patients enrolled in a prospective clinical trial – the gold standard for clinical validation of disease biomarkers.The study provides solid evidence to support more studies to evaluate additional on-treatment blood measurements to best determine how we may be able to use these tests moving forward.The hope is that monthly monitoring of ctDNA in patients undergoing treatment for metastatic melanoma can provide an early indication treatment failure, alerting doctors to consider modifying the patient’s treatment or ordering a radiographic scan ahead of the routine schedule. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work? 

Response: To move these tests out of a research setting and into the clinic requires additional studies including clinical utility trials in which the biomarker is integrated into treatment selection, to formally evaluate how the blood test can help doctors manage their patients. 

MedicalResearch.com: Is there anything else you would like to add?

Response: To move these tests out of a research setting and into the clinic requires additional studies including clinical utility trials in which the biomarker is integrated into treatment selection, to formally evaluate how the blood test can help doctors manage their patients.

Citation:

To move these tests out of a research setting and into the clinic requires additional studies including clinical utility trials in which the biomarker is integrated into treatment selection, to formally evaluate how the blood test can help doctors manage their patients. 

Jun 2, 2019 @ 11:28 am

ASCO Abstract June 1 2019

Circulating tumor DNA (ctDNA) kinetics to predict survival in patients (pts) with unresectable or metastatic melanoma treated with dabrafenib (D) or D + trametinib (T).

Author(s): Mahrukh M Syeda, JENNIFER M WIGGINS, Broderick Corless, Georgina V. Long, Keith Flaherty, Dirk Schadendorf, Paul D. Nathan, Caroline Robert, Antoni Ribas, Michael A. Davies, Jean Jacques Grob, Eduard Gasal, Matthew Squires, Mahtab Marker, Jan C. Brase, David Polsky; NYU Langone Medical Center, New York, NY; Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia; Dana-Farber Cancer Institute/Harvard Medical School and Massachusetts General Hospital, Boston, MA; Department of Dermatology, University Hospital Essen, Essen, Germany; Mount Vernon Cancer Centre, Northwood, United Kingdom; Paris-Sud University, Gustave Roussy, Villejuif Cedex, France; University of California, Los Angeles, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; AIX-Marseille University, Marseille, France; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Novartis Pharma AG, Basel, Switzerland

https://abstracts.asco.org/239/AbstView_239_259011.html

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