Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade

Abstract

The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n=978) and on-treatment (n=171) ctDNA samples across 16 advanced stage tumor types from three phase I/II trials of durvalumab (± anti-CTLA-4 therapy tremelimumab).Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer PFS and OS, and increased ORR, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of "molecular response" using ctDNA, incorporating both pretreatment and on-treatment VAF that predicted long-term survival similarly to initial radiological response, while also permitting early differentiation of responders among patients with initially radiologically stable disease. SignificanceIn a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A "molecular response" metric identified long-term responders and adjudicated benefit among patients with initial radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints.

Plasma Circulating Tumor DNA Sequencing Predicts Minimal Residual Disease in Resectable Esophageal Squamous Cell Carcinoma

“…Raja et al demonstrated that early reduction in ctDNA MAF may be a useful predictor of long-term benefit from immunotherapy in patients with lung and bladder cancer, and the decrease in mean MAF may precede radiographic change in tumor volume by one year (44). Pretreatment ctDNA levels also appear to be prognostic and help predict the dynamics of durvalumab treatment in 16 advanced tumor types as reported in a previous study (45). In patients with urothelial bladder carcinoma, the ctDNA-NGS approach could predict metastatic relapse and monitor therapeutic efficacy (46).…”

Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib

“…Zhang et al suggested that on-treatment ctDNA kinetics are predictive of benefit with immune checkpoint blockade, which is a larger data set. They also had weighted the somatic SNVs and indels from the Guardant360 report equally when determining mean of VAF [ 51 ]. On the other hand, the analysis of the VAF mean -change within a particular mutation type revealed that there were minor populations that had a different direction of VAF change from the other major clones.…”

Prognostic and Predictive Value of Circulating Tumor DNA in Patients with Advanced Colorectal Cancer and Chemotherapy

“…Based on the study by Zhang et al, the dynamics of blood ctDNA is a predictor of immunotherapy bene ts in a variety of advanced cancers [17]. We then sought to explore the predictive value of ctDNA ngerprints in CRC patients who received chemotherapy.…”

“…National Comprehensive Cancer Network (NCCN) guidelines currently recommended ctDNA can be used to evaluated the presence of minimal residual disease (MRD) and predicted recurrence risk in earlystage CRC patients after surgery [13][14]. Moreover, some studies also have illustrated that ctDNA could provide an indication of e cacy of other newer therapies, such as molecular targeted therapies [15] and immunotherapies [16][17] in advanced CRC patients. However, in the above studies, the utility of ctDNA was focused on a limited number of tumor hotspots in population, which lack speci city to individual patient and may be ineffective to patients carrying no or low mutations at the hotspots probed.…”