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Page 208 Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16

Cantuzumab CanAg Gastrointestinal Cantuzumab mertansine, a maytansinoid Phase I Completed
mertansine malignancies immunoconjugate directed to the CanAg
antigen: a phase I , pharmacokinetic, and
biologic correlative study
PF-06263507 5T4 Gastrointestinal A study of PF-06263507 in patients with Phase I Terminated
malignancies advanced solid tumors
HER2: growth factor receptor 2; GCC: guanylyl cyclase C

consequence, T-DM1 performed poorly as a second-line option for HER2 positive advanced gastric cancer.

Several mechanisms may explain the absence of OS benefit in patients with advanced gastric cancer treated
with T-DM1 compared to patients treated with taxanes. First, emtansine may have limited antitumor efficacy
in gastric cancer; there is evidence showing that the microtubule polymerization inhibitor vinorelbine was
less active in gastric cancer than in other cancers . Additionally, patients in the GATSBY trial were selected
[16]
based on archival HER2 status, which might be altered by previous anti-HER2 treatment. In addition, there
is evidence of HER2 discordance between primary and metastatic tumours and between tumours before
and after first line chemotherapy for metastatic disease (with or without trastuzumab) [17-21] . Meanwhile, high
incidence of heterogeneous HER2 overexpression in gastric cancer might affect activity of T-DM1 because
the non-cleavable linker does not allow for bystander activity [22,23] . Future clinical trials are warranted to
clarify the role of T-DM1 either combining with chemotherapy or with immunotherapy in advanced gastric
cancer. The phase I/II TRAX-HER2 trial (NCT01702558) of capecitabine +/- T-DM1 has recently completed,
which demonstrated that the combination of T-DM1 and capecitabine is tolerable in HER2-positive
[24]
advanced breast and gastric cancer patients . However, there was no statistically significant difference in
ORR between patients with metastatic breast cancer who received T-DM1 + capecitabine vs. T-DM1 alone
[25]
(44.4% vs. 36.3%; P = 0.336) . Two phase II clinical trials (NCT03418558 and NCT03225937) are currently
recruiting patients with metastatic colorectal cancer to evaluate the anti-tumour benefits of T-DM1 alone or
in combination with programmed cell death receptor 1 (PD-1) inhibitor pembrolizumab.

DS-8201A
DS-8201a is a new HER2-targeted ADC, which conjugates a humanized anti-HER2 antibody to a
[26]
topoisomerase I inhibitor, deruxtecan, by a cleavable peptide-linker . Unlike T-DM1, DS-8201a has a
potent bystander killing effect due to its cleavable linker, which is beneficial in treating heterogeneous HER2
overexpressing tumours, such as gastric cancer. Also DS-8201a has a higher drug to antibody ratio (7 or
8) compared to that of T-DM1 (3 or 4). DS-8201a demonstrated promising antitumor activity in T-DM1
resistant HER2 expressing gastric cancer in pre-clinical trials because of these unique characteristics [27,28] .
A phase I multi-centre, dose escalation study (NCT02564900) reported in 2016 that DS-8201a was well
tolerated with satisfactory safety profiles. Only 14% of patients (n = 3/22) experienced more than grade 3 AE.
The most common AE were GI and haematological toxicities. A dose of 6.4 mg/kg every three weeks was
selected as the recommend phase II dose (RPIID). However there were no dose limiting toxicities identified
in this study and the MTD was not established. An ORR of 35% and a disease control rate (DCR) of 90%
were reported across several tumour types including breast and gastric cancer [29,30] . An updated report of this
study (NCT02564900) in February 2018 further confirmed that ORR and DCR were 44% (16/36) and 78%
(28/36) respectively in HER2 expressing gastric cancer patients. It also reported that 83% of subjects were
[31]
experiencing tumour shrinkage . In addition, DS-8201a showed efficacy in patients with HER2 expressing
non-breast and non-gastric malignancies. ORR (including outcomes awaiting confirmation) and DCR
were 33% and 91% respectively in 12 evaluable patients. Common side effects from DS-8201a were nausea,
[32]
reduced appetite, vomiting and reduced platelet count . The study of DS-8201a progressed to a phase II
trial (NCT03329690) to evaluate superiority of DS-8201a vs. either irinotecan or paclitaxel monotherapy in
gastric cancer. Another phase II trial (NCT03384940) has also commenced to investigate benefit of DS-8201a
in advanced colorectal cancer.