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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 205

5 years survival of GI cancers remains poor. A new class of treatments under development is antibody drug
conjugates (ADCs).

ADCs combine a tumour-antigen specific mAb with a cytotoxic drug (or “payload”) using a linker. ADCs
exert their cytotoxic effects after the mAb directly binds to a tumour specific antigen and the ADC complex
is internalized into the tumour cell. The complex is then degraded, which frees the cytotoxic drug to exert its
cytotoxic effects on tumour cells. ADCs represent an attractive oncology treatment modality as they allow
[2-4]
targeted delivery of cytotoxic agents directly to cancer cells, causing minimal toxicity to normal tissue .
Only two ADCs are currently approved by US Food and Drug Administration and the European Medicines
Agency. Brentuximab vedotin, targeting cancer antigen CD30, was first approved in 2011 for the treatment
[5,6]
of patients with relapsed or refractory CD30-expressing Hodgkin’s and anaplastic large cell lymphomas .
T-DM1 (also known as trastuzumab emtansine or ado-trastuzumab emtansine) was approved in 2013 for use
in patients with human epidermal growth receptor 2 (HER2)-expressing metastatic breast cancers who have
disease progression following standard chemotherapy or HER2 targeted therapy . Since 2013, more than 60
[7]
ADCs have reached clinical trials under investigation for haematological and oncological indications.

There are no ADCs in use for GI malignancies and many clinical trials that assess ADCs in GI cancers
remain in the early stages. Due to the acting mechanism of ADCs, ideal target antigens are highly expressed
on tumour cells and minimally expressed on healthy cells. GI potential tumour antigens under evaluation
as ADC targets currently include HER2, mesothelin, guanylyl cyclase C (GCC), carcinogenic antigen-related
cell adhesion molecule 5 (CEACAM5) and other tumour antigens. This review will examine ADC trials in
GI cancers [Table 1], and discuss the possible challenges for their success and new strategies in the future to
facilitate improvement of GI cancer management.

HER2 TARGETED ADCS
HER2 is a tyrosine protein kinase receptor which has been demonstrated to be expressed in certain GI
[8,9]
malignancies, including gastro-oesophageal, gastric, pancreatic, gallbladder and colorectal cancers . The
HER2 mAb trastuzumab is the first biological therapy to have shown a median survival benefit of nearly 3
months in combination with chemotherapy for HER2 positive advanced gastric/gastro-oesophageal junction
[10]
cancer compared to chemotherapy alone . Thus, HER2 is a suitable target for ADCs in GI cancers.

T-DM1
Trastuzumab emtansine, or T-DM1, is made by conjugation of the microtubule polymerization inhibitor,
[11]
emtansine, to trastuzumab via a noncleavable linker . A phase I study of T-DM1 in breast cancer suggested
that T-DM1 was well tolerated at maximum tolerated dose (MTD) of 2.4 mg/kg with potential antitumor
[12]
activity . However, despite significant efficacy and minimal toxicity in HER2 positive advanced breast
cancer [13,14] , T-DM1 was not superior to taxanes (docetaxel or paclitaxel) in patients with previously treated
HER2 positive advanced gastric cancer . The phase II/III GATSBY study enrolled patients with HER2-
[15]
positive advanced gastric cancer who progressed during or after first-line therapy. Patients were randomly
assigned to treatment groups of T-DM1 3.6 mg/kg every 3 weeks (n = 70) or 2.4 mg/kg weekly (n = 228)
or a taxane (n = 117). The median overall survival (OS) was 7.9 months (95% CI 6.7-9.5) with T-DM1
2.4 mg/kg weekly and 8.6 months (95% CI 7.1-11.2) with taxane treatment (HR 1.15; 95% CI 0.87-1.51, one-
sided P = 0.86). The results of the secondary efficacy endpoints, including progression-free survival (PFS),
objective response rate (ORR) and duration of response were consistent with the primary endpoints. In the
GATSBY trial, the T-DM1 2.4 mg/kg group showed slightly lower incidence of ≥ grade 3 adverse events (AE)
compared to taxane group. The most common ≥ grade 3 AE in the T-DM1 group were anaemia (26%) and
[15]
thrombocytopenia (11%) compared with neutropaenia (39%) and anaemia (26%) in the taxane group . As a