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Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16 Page 213
[73]
cancer, cholangiocarcinoma and colorectal cancer . Cantuzumab mertansine was highly effective
against CanAg positive tumours in pre-clinical studies that showed complete responses in CanAg positive
[74]
gastric, colon, pancreatic and non-small cell lung cancer xenografts . Three phase I studies have assessed
cantuzumab mertansine in solid tumours, including GI cancer patients. AE included fatigue, deranged liver
function tests and GI disturbances. Best response was SD, lasting 4-5 months on average [73,75,76] . Cantuzumab
mertansine did not progress to phase II study for unknown reasons.

PF-06263507 is an ADC comprising humanized anti-5T4 antibodies (huA1), a non-cleavable linker and
[77]
a monomethylauristatin F payload (a microtubule polymerization inhibitor) . 5T4 is a surface antigen
expressed in many tumour types including pancreatic, oesophageal, colorectal and gastric cancers. High
levels of 5T4 expression have been associated with poorer clinical outcomes in colorectal, ovarian and gastric
cancers [78-81] . In a phase 1 study, twenty-six patients with solid tumours (including GI cancers) were treated
with PF-06263507 with the MTD determined to be 4.34 mg/kg. 5T4 expression was not assessed. No ORRs
were observed; two patients achieved SD. The most common AE were fatigue, photophobia, dry eyes and
[77]
GI disturbances . Pre-clinical studies have since demonstrated how 5T4 positive cells can down-regulate
expression of 5T4 in response to 5T4 targeting ADCs, leading to resistance over time [82-84] . Pre-clinical studies
have also revealed enhanced anti-tumour activity of combination treatments involving PF-06263507 [85,86] .

CONCLUSION AND FUTURE PROSPECTS
GI malignancies represent the most common cancers and are a leading cause of cancer-related death
worldwide. ADCs are a rapidly growing cancer treatment that are expected to selectively deliver cytotoxic
drugs to cancer cells for increased efficacy, while minimizing toxicity to normal healthy cells. In this review,
we have outlined pre-clinical and clinical evidence of current popular ADCs trials in GI malignancies,
including HER2, mesothelin, GCC and CEACAM5 targeted ADCs. However, none of these ADCs have
advanced into clinical practice for treating GI cancers.

Future strategies to investigate the efficacy of ADCs should assess combinations with other oncology
modalities including chemotherapy, radiotherapy, immune checkpoint inhibitors or targeted therapy.
Most clinical trials of ADCs in GI malignancies to date have attempted to demonstrate superiority as
monotherapy. However, their higher tolerability and safer toxicity profiles, when compared to cytotoxic
chemotherapy, indicate that they may be suitable to combine with other agents. Although the TRAX-
HER2 study did not show superiority of the T-DM1/capecitabine combination compared to T-DM1 alone in
patients with metastatic breast or gastric cancer, many other chemotherapy/ADC combinations are under
consideration to enhance anti-tumour effects of ADCs. Furthermore, ADCs with DNA damaging agents
(especially microtubule inhibitors) as the payload have the potential to enhance and sustain anti-tumour
effects when combined with immune checkpoint inhibitors such as anti-PD1 antibodies (Pembrolizumab,
Nivolumab) or anti-programmed death ligand 1 antibodies (atezolizumab). There is accumulating pre-
clinical evidence to suggest that DNA damaging agents can promote anti-tumour immune responses by
[87]
increasing antigen presentation, activating dendritic cells and promoting immunogenic cells death . Pre-
clinical trials proved that T-DM1 renders HER2 positive breast cancer cells highly susceptible to PD-1
[88]
blockade . An active phase I/II clinical trial (NCT02318901) is evaluating the potential of T-DM1 in
combination with pembrolizumab in advanced breast, gastric, oesophageal and colorectal cancers. Finally,
HER2 over expression was identified as a factor contributing to radio-resistance in breast cancers. Radiation
may result in a more potent anti-tumour effect when combined with anti-HER2 therapy. Further exploration
[89]
of concurrent administration of T-DM1 with radiotherapy is warranted in GI cancers . The challenges
of combining ADCs with other modalities includes choice of ADC with other cytotoxic agents, dose of
compounds, toxicity of combination and scheduling/sequencing of combinations.

Another major trend in ADC research is to design new generations of ADCs with increased homogeneity,
stability and potency through the large variety of ADC technologies developed over the past decade. The