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Advances in Next Generation Sequencing (NGS) technologies have enabled the accurate detection and quantification of circulating tumor-derived (ct)DNA in most gastrointestinal (GI) cancers. The prognostic and predictive utility of ctDNA in patiets with different stages of colorectal (CRC), gastro-esophageal (GEC) and pancreaticobiliary cancers (PBC) are currently under active investigation. The most mature clinical data to date are derived from studies in the prognostic utility of personalized ctDNA-based NGS assays in the detection of minimal residual disease (MRD) and early recurrence after surgery in CRC and other GI cancers. These findings are being validated in several prospective studies which are designed to test if ctDNA could outperform conventional approaches in guiding adjuvant chemotherapy, and in post-operative surveillance in some GI cancers. Several adaptive studies using ctDNA as a screening platform are also being used to identify patients with actionable genomic alterations for clinical trials of targeted therapies. In the palliative setting, ctDNA monitoring during treatment has shown promise in the detection and tracking of clonal variants associated with acquired resistance to targeted therapies and immune-checkpoint inhibitors (ICI). Moreover, ctDNA may help to guide the therapeutic re-challenge of targeted therapies in patients who have prior exposure to such treatment. This review will examine the most updated research findings on ctDNA as a biomarker in CRC, GEC and PBCs. It aims to provide insights into how the unique strengths of this biomarker could be optimally leveraged in improving the management of these GI cancers.

BI836880 is a humanized bispecific nanobody directed against angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF)-derived peptides, with selective and potent antiangiogenic and antineoplastic activities. It comprises of blocking domains that bind to Ang2 and VEGF and prevents Ang2- and VEGF-mediated signalling; thus, inhibits both angiogenesis and tumour cell proliferation. Tumor angiogenesis contributes to progression of nasopharyngeal cancer (NPC) and VEGF/receptor inhibitors agents have activity in NPC patients. In this study, the preclinical activity of a novel VEGF/Ang-2 bi-specific nanobody, BI836880, was evaluated in two NPC-PDX models - Xeno-2117 and Xeno-666. The effect of BI836880 on tumor growth was compared with the control, bevacizumab - an anti-VEGF antibody which has been evaluated in NPC patients. Tumor-bearing mice were randomized into three groups: vehicle control, 15mg/kg bevacizumab (b.i.w) and 15mg/kg BI836880 (b.i.w.). Drug was administered by intraperitoneal injection and the treatment duration was four weeks. Tumor sizes and body weights were monitored by caliper and balance, respectively. The results showed that BI836880 was very well tolerated in mice, with no signs of stress and loss of weight observed during the treatment. At day 14, the mean tumor volumes of BI836880, bevacizumab vs vehicle control was 264.5±36.0, 290.0±32.4 vs 697.38±88.4 mm3 in Xeno-666 (p<0.001, BI836880 vs control), and 293.5±39.3, 319.6±37.6 vs 1016.8±107.6 mm3 in Xeno-2117 (p<0.0001, BI836880 vs control), respectively. Angiogenesis marker CD34 was analyzed by IHC staining and the microvessel densities were calculated by Image J. The results showed that BI836880 could significantly reduce the numbers of microvessels to a comparable extent as bevacizumab in NPC model. In addition, BI836880 had increased the tumor internal necrotic area by 118.7% compared to vehicle control in Xeno-2117 (p=0.0148), but the effect was insignificant in Xeno-666 (p=0.5467). In conclusion, BI836880 can inhibit NPC growth to an extent that is comparable to bevacizumab, further investigation in combination with cytotoxic or immunotherapeutic agents are warranted. Citation Format: Eric Chi Wong, Gigi Lam, Connie Wong, Rachel C. Lam, Kwok Wai Lo, Edwin Pun Hui, Anthony Tak Chan, Brigette B. Ma. Preclinical evaluation of VEGF Ang2 bispecific nanobody BI836880 in patient-derived xenograft models of nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 948.