Circulating tumor DNA predicts outcome from first-, but not second-line treatment and identifies melanoma patients who may benefit from combination immunotherapy
Authors
Gabriela Marsavela, Edith Cowan UniversityFollow
Jenny Lee
Leslie Calapre, Edith Cowan UniversityFollow
Stephen Q. Wong
Michelle Pereira, Edith Cowan UniversityFollow
Ashleigh McEvoy, Edith Cowan UniversityFollow
Anna L. Reid, Edith Cowan UniversityFollow
Cleo Robinson
Lydia Warburton, Edith Cowan UniversityFollow
Afaf Abed, Edith Cowan UniversityFollow
Muhammad K. Khattak, Edith Cowan UniversityFollow
Tarek M. Meniawy, Edith Cowan UniversityFollow
Sarah-Jane Dawson
Shahneen Sandhu
Matteo S. Carlino
Alexander M. Menzies
Richard A. Scolyer
Georgina V. Long
Benhur Amanuel, Edith Cowan UniversityFollow
Michael Millward
Melanie R. Ziman, Edith Cowan UniversityFollow
Helen Rizos
Elin S. Gray, Edith Cowan UniversityFollow
Author Identifier
Gabriela Marsavela
https://orcid.org/0000-0002-0487-3963
Leslie Calapre
https://orcid.org/0000-0001-7595-6523
Ashleigh McEvoy
https://orcid.org/0000-0001-5692-1317
Anna Reid
https://orcid.org/0000-0002-4588-1679
Lydia Warburton
https://orcid.org/0000-0001-9417-1596
Afaf Abed
https://orcid.org/0000-0001-7506-3362
Muhammad Adnan Khattak
https://orcid.org/0000-0002-4633-3818
Tarek Meniawy
https://orcid.org/0000-0002-1457-6137
Melanie Ziman
https://orcid.org/0000-0001-7527-3538
Elin Gray
Document Type
Journal Article
Publication Title
Clinical Cancer Research
Publisher
American Association for Cancer Research
School
School of Medical and Health Sciences
RAS ID
32390
Funders
Edith Cowan University - Open Access Support Scheme 2020
NHMRC
Grant Number
NHMRC Number : 1117911
Abstract
Purpose: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment.
Experimental Design: Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), 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 ICI therapies in the first- (N = 77) or second-line (N = 51) settings.
Results: In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07–0.53; P < 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22–0.83; P = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors.
Conclusions: Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naive patients with high ctDNA may preferentially benefit from combined ICIs.
DOI
10.1158/1078-0432.CCR-20-2251
Related Publications
Marsavela, A. (2021). Assessment of the clinical validity of ctDNA Analysis for melanoma management. https://ro.ecu.edu.au/theses/2407
Access Rights
free_to_read
Comments
Marsavela, G., Lee, J., Calapre, L., Wong, S. Q., Pereira, M. R., McEvoy, A. C., ... & Gray, E. S. (2020). Circulating tumor DNA predicts outcome from first-, but not second-line treatment and identifies melanoma patients who may benefit from combination immunotherapy. Clinical Cancer Research, 26(22), 5926-5933. https://doi.org/10.1158/1078-0432.CCR-20-2251