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Claudin 18.2 – an emerging drug target for metastatic gastric cancer

Prof. Salah-Eddin Al-Batran

Al-Batran

Claudin 18.2 – an emerging drug target for metastatic gastric cancer

Professor Salah-Eddin Al-Batran

Director Gastrointestinal Center, Multidisciplinary Cancer Centre, Frankfurt, Germany

Video transcript

Q. Hello from Barcelona. We are here at the ESMO World Congress of GI Cancer. I have the honour to speak now with Dr Salah Al-Batran from Frankfurt. He presented interesting data on a new cancer druggable target which is called claudin18.2 and there is a study targeting this new protein. Salah, you just presented results of a randomise Phase 2 trial, do you want to tell us a bit about the design and about major findings of this trial?

A. Yes. As you mentioned, the FAST trial was a randomised Phase 2 trial in patients with gastric and gastroesophageal junction adenocarcinoma, receiving first-line chemotherapy and these patients were randomised to either first-line chemotherapy with an EOX regimen or first-line chemotherapy with EOX plus the IMAB antibody. This was, as mentioned, a randomised Phase 2 trial. The primary endpoint was progression free survival and the study had typical secondary endpoints. Approximately one year after the start of the study a third exploratory arm was included, exploring a higher dose of the IMAB antibody.

Q. What about this target? It is called claudin18.2, so it is part of the claudin family. Can you explain what the specific character of this target is? Why is it interesting for gastric cancer?

A. Claudin18.2 is a component of the tight junction protein and this target is especially interesting because it is specific for the gastric mucosa and it is not expressed on any other healthy tissues, but it is expressed on about 70 to 80% of gastric cancers, but also in some other diseases, especially bile duct cancer and pancreatic cancer.

Q. It is a very cancer-specific target it sounds like. Very interesting. What were the main findings of this randomised Phase 2 study? It was progression free survival as the primary endpoint and this was met. Do you want to tell us something about the effect sizes you have seen?

A. Yes. The primary endpoint PFS was improved with IMAB and also the overall survival as a main secondary endpoint was significantly improved. The hazard ratios were around 0.5 and these are good results.

Q. It is quite impressive as a ratio, but what are the side effects? Is there any drawback in what you have studied?

A. The treatment was well-tolerated in fact, but there were some side effects; particularly two side effects that were increased. The neutropenia or rate of neutropenia was slightly increased but without febrile neutropenia or without an increase in neutropenic infections. Interestingly also the rate of vomiting was increased. It was at grade 1/2, around 55% with EOX plus IMAB and at grade 3 it was around 10%.

Q. Do you think the vomiting side effect occurs because the target is also expressed in healthy stomach mucosa?

A. Yes. We believe that probably the vomiting is a pharmacodynamics effect of the antibody because also the target is expressed in the gastric mucosa and there was a dose-dependent increase in vomiting in the study among a group of three arms. Yes.

Q. In view of the fact that vomiting is increased, do you think that epirubicin, oxaliplatin, capecitabine that was used as a chemotherapy backbone is optimal, implementing one drug, epirubicin, which is also quite emetogenic?

A. Yes, for sure. Now the results have been delivered and knowing that vomiting is an issue we would say that it is better to use a less emetogenic combination like two drug combinations with oxaliplatin 5FU or oxaliplatin and capecitabine; yes, for the future it would be better to use a doublet than a triplet.

Q. We are talking already about the future. To your knowledge or what you are about to say and disclaim at this time point, what will be the future development of this drug? Will it be carried on?

A. Yes, we are not exposing too much if we say that there will be Phase 3 trials. It is in planning and there are also trials in other diseases, especially in pancreatic cancer are planned.

Q. Very interesting. Thank you for giving us some insights about this interesting new drug. We are looking forward to how the next trials will be designed if there will finally be progress on the treatment for metastatic gastric cancer. Thank you very much for listening.


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