Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy

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.

The Prognostic Impact of Circulating Tumour DNA in Melanoma Patients Treated with Systemic Therapies—Beyond BRAF Mutant Detection

“…The prognostic value of ctDNA in melanoma patients has been previously shown by number of studies [17,18,20,24,25]. In this study, we found ctDNA detectability at baseline and during treatment course to be a strong predictor of clinical outcome.…”

“…In melanoma, ddP (ctDNA) is a potential non-invasive alternative to tumour tissue biopsy for molecular profiling and longitudinal disease monitoring in the metastatic setting [13][14][15][16][17][18][19][20][21][22][23]. In addition, baseline ctDNA levels and subsequent decline with treatment have been indicated as an early predictor of tumour response and clinical benefit [13,15,24,25]. To confirm the utility of ctDNA as a clinical biomarker, its ability to monitor and/or predict treatment response and clinical outcome requires further validation in a large cohort of melanoma patients, especially in those treated with immunotherapy.…”

Circulating Tumour DNA in Advanced Melanoma Patients Ceasing PD1 Inhibition in the Absence of Disease Progression

“…Droplets were generated and analysed using the QX200 system (Bio-Rad, Hercules, CA, USA). The threshold for each assay used for ctDNA detection was previously reported by Calapre et al [29] and Marsavela et al [31].…”

Current status of ctDNA in precision oncology for hepatocellular carcinoma

“…Moreover, ctDNA can differentiate the true progress from pseudo-progression caused by inflammation from ICB therapy [133] and alterations in some specific genes may be related to immune-related adverse events [134]. Relevant studies have mainly focused on melanoma, non-small cell lung cancer, and gastric cancer [134][135][136]. There is still a gap in clinical research of ctDNA in ICB therapy for HCC patients because mutational DNA molecules in the HCC population have not been pre-defined and those aberrations which exist in HCC can also be detected in benign hepatic diseases [137].…”