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ADCT-502 is currently in a phase I dose escalation trial (NCT03125200) involving patients with HER2
expressing advanced solid tumours, including gastroesophageal cancer.

These new generation HER2 targeted ADCs showed superior anti-tumour activity compared to T-DM1 in
various pre-clinical trials, even in HER2 low-expressing or HER2 negative cancer models. Consequently
these new generation of HER2 targeted ADCs provide a potential treatment option not only in patients who
become resistant/refractory to T-DM1, but also in patients whose tumours express low-level or no HER2,
and are not eligible for treatment with T-DM1.

MESOTHELIN TARGETED ADCS
Mesothelin is a tumour differentiation antigen that is highly expressed in certain human malignancies which
[45]
includes 86%-100% of pancreatic ductal adenocarcinomas , 97% of ovarian adenocarcinomas and 89%-
100% of mesotheliomas. The limited expression of mesothelin in essential human tissue and high expression
[46]
in certain cancers make mesothelin a good target for cancer therapy, such as in pancreatic cancer . Several
anti-mesothelin antibody based treatments are under clinical investigation, which include vaccines, T-cell
therapy and ADC therapy . Amatuximab is the first monoclonal mesothelin targeted antibody. In a phase
[47]
II clinical trial (NCT00570713), Amatuximab combined with gemcitabine showed no clinical benefit in
patients with pancreatic cancer when compared to placebo groups . Further investigation of mesothelin
[48]
targeted therapy, such as new generation anti-mesothelin antibodies and ADCs, are in progress.

DMOT4039A is the first generation of mesothelin targeted ADCs. DMOT4039A consists of humanized
anti-mesothelin mAb conjugated to an antimitotic agent, monomethyl auristatin (MMAE) via a protease
cleavable linker. DMOT4039A has a drug to antibody ratio of approximately 3.5:1. A pre-clinical trial showed
tumour growth inhibition in pancreatic cancer xenografts treated with DMOT4039A . A phase I study of
[49]
DMOT4039A (NCT01469793) in patients with unresectable pancreatic cancer or platinum resistant ovarian
cancer demonstrated that DMOT4039A has antitumor activity with an acceptable safety profile. In this study,
the RPIID level was determined to be either 2.4 mg/kg three weekly or 1.0 mg/kg weekly. Dose limiting
toxicities included grade 3 hyperglycaemia and hypophosphatemia. eight percent (2/26) of patients with
pancreatic cancer on the three weekly regime achieved PR and 35% (9/26) of patients had SD as best response
with a median duration of 5.7 months. The low response rate might be explained by inherent variability
[50]
in assessing small cohorts or heterogeneous expression of mesothelin in pancreatic cancer . Therefore,
DMOT4039A warrants further clinical trials in combination with either chemotherapy or immunotherapy
in patients with pancreatic cancer.

Anetumab ravtansine, also called BAY 94-9394 is another potent mesothelin targeted ADC. Anetumab
ravtansine is composed of human anti-mesothelin antibodies conjugated to the microtubule polymerase
inhibitor, DM4, through a disulphide bond. Pre-clinical trials showed that anetumab ravtansine exhibited
antiproliferative activity with bystander effect in mesothelin positive cancer cell lines, which included
[51]
pancreatic cancer and patient-derived pancreatic cancer xenograft models . In a phase I trial (NCT01439152),
MTD of anetumab ravtansine was established at 6.5 mg/kg given every three weeks. The AE included
[52]
reversible keratitis, asymptomatic liver impairment and GI disorders . A parallel trial (NCT02485119)
enrolling Japanese patients showed similar results. Several phase I/II clinical trials are actively recruiting
patients presenting with different malignancies. A phase Ib study (NCT03102320) is recruiting patients
with mesothelin expressing advanced cholangiocarcinoma or advanced pancreatic adenocarcinoma. This
study aims to test the MTD of anetumab ravtansine in combination with either cisplatin or gemcitabine for
cholangiocarcinoma or adenocarcinoma of the pancreas . A phase II, multicentre, non-randomized trial
[53]
(NCT03023722) is evaluating the efficacy of anetumab ravtansine in patients with pre-treated mesothelin-
expressing advanced pancreatic cancer .
[54]