Circulating tumor DNA predicts outcome from first-, but not second-line treatment and identifies melanoma patients who may benefit from combination immunotherapy
Gabriela Marsavela, Edith Cowan UniversityFollow
Leslie Calapre, Edith Cowan UniversityFollow
Stephen Q. Wong
Michelle Pereira, Edith Cowan UniversityFollow
Ashleigh McEvoy, Edith Cowan UniversityFollow
Anna L. Reid, Edith Cowan UniversityFollow
Lydia Warburton, Edith Cowan UniversityFollow
Afaf Abed, Edith Cowan UniversityFollow
Muhammad K. Khattak, Edith Cowan UniversityFollow
Tarek M. Meniawy, Edith Cowan UniversityFollow
Matteo S. Carlino
Alexander M. Menzies
Richard A. Scolyer
Georgina V. Long
Benhur Amanuel, Edith Cowan UniversityFollow
Melanie R. Ziman, Edith Cowan UniversityFollow
Elin S. Gray, Edith Cowan UniversityFollow
Muhammad Adnan Khattak
Clinical Cancer Research
American Association for Cancer Research
School of Medical and Health Sciences
Edith Cowan University - Open Access Support Scheme
NHMRC Number : 1117911
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.