ESMO WCGIC 2023 | INNOVATION: chemotherapy with trastuzumab and pertuzumab in HER2+ gastric cancer

And the INNOVATION trial was designed giving the fact that since more than ten years we know that adding trastuzumab to chemotherapy improves survival in patients who undergo palliative chemotherapy for advanced gastric cancer. But we know that patients who have locally advanced disease need as well systemic therapy. Without systemic therapy, they have a very poor survival. So first we treated patients with locally advanced disease, all comers with chemotherapy. ECF was the formal standard according to MAGIC, and this standard was changed by publication of the flawed trial. But whether HER2-positive patients benefit from her two targeted therapy was unclear. And this is the scenario where we can really improve survival. So I found this unacceptable not to give a drug which we know that is effective in metastatic disease but not to give it to patients who have locally advanced disease who have a chance for cure. So this is why we designed the INNOVATION trial, a large effort.

Finally, it took us over ten years. It’s 1203. It’s called the 1203 trial because it was in 2012 that I presented the idea to the EORTC board and we finally could start in 2015. The design of this trial is a randomized Phase II trial. Primary endpoint is major pathologic response rate as assessed by an independent pathologic pathology review. And so patients were randomized into three trial arms. One was chemotherapy alone, one was chemotherapy plus trastuzumab and one was chemotherapy plus trastuzumab plus pertuzumab. So patients treated with the antibodies were treated during perioperative chemotherapy and then the antibody treatment was continued for a total of one year. The chemotherapy backbone corresponding to the standard of care, which when we started the trial was Cisplatin 5-Fu And after the publication of the plot for trial, we changed the chemotherapy backbone to FLOT. So about half of the patients included in this trial were treated with Cisplatin 5-Fu. The other half were patients were treated with FLOT.

And what we saw is that the major pathologic response rate in the patients treated with chemotherapy alone was 23% In the patients treated with chemotherapy plus trastuzumab it was 37%. And in patients treated with chemotherapy, trastuzumab and pertuzumab, it was 26%. And we finally found we could as well identify the reason for this relative lack of efficacy in the patients treated with a double antibody combination. This was most likely due to an insufficient dose intensity of chemotherapy. For example, the percentage of patients who were treated with who could be treated with four cycles of perioperative preoperative FLOT was 93% in patients with treated with FLOT alone as well as in patients treated with FLOT plus trastuzumab. But it was only 80% in patients treated with the double antibody combination and accordingly the number of patients, the dose intensity of the chemotherapy drugs dropped as well in the patients treated with a double antibody combination and this made a major difference. So what is interesting as well is to look at the results for according to the chemotherapy backbone, for example, for patients treated with Cisplatin 5-Fu, the pathologic major pathologic response rate was 7%. Then it increased to nearly 27% by changing just chemotherapy backbone to FLOT. But when adding trastuzumab to FLOT, the pathologic response rate increased further for the up to 53%. So really it seems that FLOT chemo.

Plus trastuzumab seems the winner according to the pathologic response rate. But we don’t have any results for survival yet. And I have to say that the adding trastuzumab that the arm with a single antibody trastuzumab is a this was an must be considered as an unplanned analysis because according to our statistical plan, we decided first to test the double antibody combination and only if the double antibody combination would be positive, then the single antibody combination would be tested. So this must be considered as an unplanned analysis. Nevertheless, I think this is these are important results and this is really the first trial randomized trial which randomized patients in the perioperative setting to chemotherapy alone and or chemotherapy plus trastuzumab. And now we need to wait for the results of progression free and overall survival patients are followed and we need some more two years about to get these results. I mean, regarding the subgroup analysis which are new at this meeting, I think the overall number of patients in this included in this trial was too small really. Patients treated with cisplatin 5-Fu and was and with FLOT was too small to really draw meaningful conclusions from the subgroup analysis. But one thing I can say is that it looks like if all patients treated with chemotherapy plus trastuzumab seemed to benefit from this combination.

Liquid biopsies are certainly very important and I we would love to have them integrated in this trial and we had even an opportunity to do it. But the recruitment for this trial was very difficult, as for all perioperative trials. And so because of these problems with recruitment after discussion with the IRGC headquarter, we we could not do this in this trial just for practical reasons because we didn’t want to make it even harder and even more complicated to treat these patients. But from a scientific point of view, I mean, it would be really great to have the more information about CD8 ctDNA and I’m very much convinced that this will this biomarker will would be able to help to select patients for this treatment in the future.