Abstract 976: Detection of circulating tumor DNA predicts survival in advanced HCC patients treated with personalized therapeutic DNA cancer vaccine in combination with immune checkpoint blockade

Abstract Circulating tumor DNA (ctDNA) has enabled the non-invasive monitoring of molecular residual disease (MRD) which reflects therapeutic response/resistance prior to conventional imaging approaches. However, little is known about the applications of ctDNA in the neoantigen-targeted personalized cancer vaccine setting, potentially due to the limited sensitivity of current ctDNA assays. NeXT Personal®, an ultra-sensitive tumor-informed ctDNA assay was used to longitudinally track ctDNA in advanced hepatocellular carcinoma (HCC) patients treated with GNOS-PV02 (a personalized therapeutic DNA cancer vaccine) in combination with pembrolizumab. Advanced unresectable or metastatic HCC patients that progressed on, or were intolerant to, first-line TKI therapy were enrolled into the Phase 1b/2a GT-30 study [NCT04251117]. Whole exome/transcriptome tumor sequencing was used for the design of GNOS-PV02. Patients were treated with GNOS-PV02 (1mg; Q3W x 4, Q9W) and plasmid-encoded IL-12 (0.3mg; Q3W x 4, Q9W) in combination with pembrolizumab (200mg; Q3W). Clinical Response was evaluated by RECIST 1.1 at baseline and Q9W. The ctDNA analysis and tracking for progression was performed as an exploratory objective. Over 200 prospective baseline and on-treatment plasma samples from 31 patients were collected and analyzed using NeXT Personal. WGS was performed to identify up to ~1,800 selected tumor variants to create a personalized panel for MRD detection. NeXT Personal has been analytically validated to detection thresholds down to 1-3 parts per million (PPM) of ctDNA with >99.95% specificity. ctDNA was detected in 152 of 207 plasma samples with a dynamic range of 1.76 - 166,968 PPM. The limit of ctDNA detection ranged down to 1.05 PPM. 96% (24/25) of patients were baseline ctDNA+. The percentage change of ctDNA relative to baseline at week 9 (C4D1) significantly correlated with best overall response (CR/PR/SD vs. PD: p = 0.0076). The ctDNA change from baseline to week 9 was predictive of OS (P=0.008), with 31.2% 2-yr OS (95% CI: 13.2 - 73.7%) for molecular non-responders vs 100% 2-yr OS (95%CI: 100 - 100%) for molecular responders. In addition, the ctDNA levels at week 9 were predictive of best overall response (P = 0.017). ctDNA burden at week 9 was significantly correlated with overall survival (HR = 5.46, 95%CI: 1.79 - 16.65; P=0.003; C-index = 0.886). ctDNA clearance was observed in all 3 CR patients with a lead time of 483, 126 and 105 days compared with MRI. This ultra-sensitive ctDNA assay shows significant association between ctDNA change and clinical response and survival, and can be used to accurately predict clinical outcome. The convenience of non-invasive liquid biopsy and rapid availability of data could enable the use of ctDNA to allow real-time monitoring of personalized cancer immunotherapy. Citation Format: Jian Yan, Bailiang Li, Josette Northcott, Charles W. Abbott, Rachel M. Pyke, Renzo Perales-Linares, Neil Cooch, Sarah Rochestie, Joann Peters, Edward J. Gane, Mark Yarchoan, Thomas U. Marron, Sean M. Boyle, Ildiko Csiki, Richard Chen, Niranjan Y. Sardesai. Detection of circulating tumor DNA predicts survival in advanced HCC patients treated with personalized therapeutic DNA cancer vaccine in combination with immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 976.