Circulating tumour DNA predicts outcome form first-, but not second-line treatment and identifies melanoma patients who will benefit from combination immunotherapy

Gabriela Marsavela, Jenny H. J. Lee, Leslie Calapre, Stephen Q. Wong, Michelle R. Pereira, Ashleigh C. McEvoy, Anna L Reid, Cleo Robinson, Lydia Warburton, Afaf Abed, Adnan Khattak, Tarek Meniawy, Sarah Jane Dawson, Shahneen Kaur Sandhu, Matteo S. Carlino, Alexander M. Menzies, Richard A Scolyer, Georgina V. Long, Benhur Amanuel, Michael MillwardMelanie Ziman, Helen Rizos, Elin Gray

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

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 ¼ 32) or second-line (n ¼ 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n ¼ 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N ¼ 77) or second-line (N ¼ 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 ¼ 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-na€ve patients with high ctDNA may preferentially benefit from combined ICIs.
Original languageEnglish
Pages (from-to)5926-5933
Number of pages8
JournalClinical Cancer Reserach
Volume26
Issue number22
DOIs
Publication statusPublished - 15 Nov 2020

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