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Emerging new drugs for gastric cancer

Prof. Florian Lordick

Lordick

Emerging new drugs for gastric cancer  

Professor Florian Lordick

Director of University Cancer Centre Leipzig, Germany

Video transcript

Hello. My name is Florian Lordick, I am one of the Editors of the Elsevier GI Cancer Resource Centre and I am here in Barcelona where the ESMO World GI Cancer meeting is taking place.

I just want to give you some insights in what is going on in the treatment of metastatic gastric cancer. I had the honour to give a lecture on emerging drugs in the field and it was quite nice that over the last months at the ASCO meeting, but also here we saw some nice data about new drug development directions in metastatic gastric cancer. One of the most interesting directions is immunotherapy. We have recently seen the first full publication in the Lancet Oncology of one of the studies where they tested an immune checkpoint inhibitor – I am talking about the PD-1 inhibitor, pembrolizumab, that was tested in Phase 1b in heavily pre-treated patients with metastatic gastric cancer. The major findings were that it is feasible. In terms of toxicity it is feasible. The response rate is somewhere between 20 and 25%. More than 50% of the patients who were treated with pembrolizumab achieved a decrease in tumour size and probably more importantly many of the responses are of long duration – we are talking here about many months, even more than a year. This is an interesting new direction.

The question is, is it the only trial that is showing this? The answer is “No”. At the ASCO meeting and also here we got confirmatory data on other inhibitors like, for instance, the PD-1 inhibitor nivolumab, or the PD-L1 inhibitor, avelumab, which are going in the same direction.

Interestingly we have seen also now the first data combining two checkpoint inhibitors. There was a nice study presented by Yelena Janjigian from Memorial Sloan Kettering. She presented at ASCO a combination trial of ipilimumab, which is a CTLA-4 inhibitor, in combination with nivolumab, the PD-1 inhibitor in pre-treated patients with metastatic gastric cancer. It looks like the combination is even a bit more active, and maybe also a bit more efficacious than the monotherapy. It may also be interesting for patients who present with tumours which are less immunogenic, which have a low expression of PD-L1, but this really needs to be confirmed in future trials. All these drugs and also combinations are now brought into randomised Phase 3 trials in the different settings – first-line metastatic, second-line metastatic and it will be very interesting to see if a new checkpoint blockade will increase the survival and symptom control and quality of life in patients with metastatic gastric cancer.

Here in Barcelona as well as at ASCO we have also seen a very new immunotherapy. It is a monoclonal antibody which is directed against a new drug target. The target is called claudin-18.2. It is a very cancer specific target. It is a protein belonging to the tight junction family of proteins and it has a very specific expression in the stomach. It is over-expressed in approximately 70% of stomach cancers. A team from Mainz University - a small company - developed a diagnostic antibody to detect claudin-18.2 and they also developed a therapeutic antibody which is called IMAB362, which has now been tested in a randomised Phase 2 setting. The study is called FAST and it had a control arm, in which patients with first-line metastatic gastric cancer received EOX, which is epirubicin, oxaliplatin and capecitabine and in the two experimental arms they received different dosages of the monoclonal antibody IMAB362.

The results are very promising. The primary endpoint was progression free survival and this primary endpoint was improved by the addition of IMAB362 to the chemotherapy backbone of EOX with a hazard ratio of around 0.5, which is quite impressive. Also the secondary endpoint, overall survival, was improved, so this is really one of the most promising emerging drugs that we have currently in the field of gastric cancer. We need to see how this is brought forward, probably it will now go to Phase 3, randomised Phase 3. We are advising the company that they should switch the chemotherapy backbone. Probably EOX is not optimal because one of the side effects of this new antibody is vomiting and so they probably should go to a chemotherapy backbone with less emetogenicity, something like FOLFOX or CAPOX.

What else is new? We have an ongoing Phase 3 study with a compound which is called BBI608. It is a stem cell inhibitor, if you want to call it like that. It targets STAT3 induced gene expression, so it is a STAT3 inhibitor. It is investigated in randomised Phase 3 and in the second line setting of metastatic gastric cancer the design is paclitaxel versus paclitaxel plus BBI608; randomisation and study enrolment is ongoing. The enrolment target is somewhere between 600 and 700 patients and it is planned to finish accrual by the end of this year.

Another in my view interesting approach has also been shown here and at ASCO, it is a treatment directed against matrix metalloproteinase-9, MMP-9. It is a monoclonal antibody that can be combined to chemotherapy. Manish Shah from New York presented interesting Phase 1b data where in first-line metastatic gastric cancer FOLFOX has been combined to this new MMP-9 antibody. He reported about an interesting overall response rate of 55%, three complete responses were seen in this limited number of patients. Again duration of response was quite interesting, around 10 months progression free survival was interesting with a median of 12 months.

With this MMP-9 inhibitor there is also some promise in the field and it will also be brought forward to a randomised Phase 3 study in the metastatic setting. That is probably the most promising new emerging drug for the setting of metastatic gastric cancer.

I thank you very much for your interest. Thank you for listening.


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