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Page 212 Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16

angiogenesis, and metastasis. CEACAM5 has been recognized as a tumour marker of colorectal cancers for
the last 50 years and is highly expressed at the surface of tumour cells, including more than 80% of colorectal
cancer cells. CEACAM5 has been recently exploited as a target for immunotherapy and vaccine-based
therapeutics. In the animal models of colorectal and pancreatic cancers, antibodies against CEACAM5 have
[64]
shown their potential effectiveness in cancer treatment . Therefore, CEACAM5 is another potential target
in ADCs development.

SAR408701 (SAR) is an ADC comprising an anti-CEACAM5 antibody, a cleavable N-succinimidyl
4-(2-pyridyldithio) pentanoate linker and the microtubule-targeting mitosis inhibitor, DM4. Pre-clinical
studies have shown promising anti-tumour efficacy with SAR in colorectal cancer, lung and gastric
[65]
xenografts . A phase I study (NCT02187848) investigated the safety and pharmacokinetics of SAR in
patients with GI tumours expressing CEACAM5. In this study, SAR showed an acceptable safety profile
2
with the MTD established as 100 mg/m . The most commons AE were fatigue, visual/eye changes and GI
disturbances. Twelve colorectal cancer patients were tested as CEACAM5 positive, three of which sustained
[66]
PR (lasting > 4 months) . A dose expansion trial in CEACAM5-expressing solid tumours (including
colorectal and gastric cancers) is ongoing with further results on the way (NCT02187848).

Labetuzumab govitecan (IMMU-130) is a CEACAM5 targeted ADC which conjugates the CEACAM5
antibody labetuzumab to the active metabolite of irinotecan, SN-38, through a proprietary linker.
Labetuzumab govitecan showed improved efficacy and reduced toxicity compared to irinotecan in pre-
clinical colorectal cancer xenografts [67-69] . Two phase I studies investigating the activity of labetuzumab
govitecan in patients with metastatic colorectal cancer were reported in a conference abstract in 2014. In
both trials, eligible patients had been pre-treated with standard chemotherapy (such as irinotecan) and had
an elevated CEA (> 5 ng/dL). In the first study, labetuzumab govitecan was given every two weeks; the MTD
was 16 mg/kg. One patient (out of 8) received 18 cycles of treatment and achieved PR with a 40.6% reduction
in liver and lung lesions, lasting for 4.7 months. In the second study, MTD was the same when labetuzumab
govitecan was given 4 mg/kg twice weekly. Three/six patients experienced PR with 40% tumour shrinkage.
In these two phase I trials, labetuzumab govitecan was well tolerated with the most common AE including
[70]
neutropaenia and diarrhea .
A phase I/II, multicentre dose-finding trial (NCT01605318) investigated the therapeutic index of
labetuzumab govitecan in patients with relapsed or refractory metastatic colorectal cancer. Eighty-six
patients were recruited with an elevated serum CEA (> 5 ng/mL) and had progressed after a median of
five prior treatments (including irinotecan). Weekly doses (8 or 10 mg/kg) or twice weekly doses (4 or 6
mg/kg) with 1 week breaks were demonstrated to be tolerable. The most common AE were neutropaenia,
leukopenia, anaemia and diarrhea. In this trial, thirty-eight percent patients (27/72) achieved a reduction
in tumour size with one patient achieving a sustained PR lasting for 2.7 years. Fifty-eight percent (42/72)
patients achieved SD with 33% (24/72) of these outcomes lasting more than 4 months. Median PFS for all 86
patients was 3.6 months (95% CI 2-4 months) and median OS was 6.9 months (95% CI 5.7-7.8). Compared to
the PFS and median OS of regorafenib (1.9 and 6.4 months, respectively), which is currently recommended as
third line treatment for relapsed or refractory metastatic colorectal cancer, labetuzumab govitecan provides
another option in the third-line setting . Labetuzumab govitecan also showed less toxicity than irinotecan,
[71]
particularly with regard to diarrhea. Combination approaches of labetuzumab govitecan with other agents
should be investigated; a pre-clinical study has demonstrated an enhanced anti-tumour effect in colorectal
[72]
cancer cells of labetuzumab govitecan combined with bevacizumab .

OTHER ADCS IN GI CANCERS
Cantuzumab mertansine is an ADC combining huC242, a highly selective mAb targeting CanAg, with
DM1 via a disulphide linker. CanAg is a transmembrane glycoprotein that is highly expressed in pancreatic