Gastric cancer is a major health problem, and we know since many years that about 10-20% of gastric cancers are HER2 positive. Since 2010, when the so-called ToGA trial was published, we know that in patients with metastatic gastric cancer the prognosis can be significantly improved by adding trastuzumab to cisplatin 5FU chemotherapy. So adding trastuzumab in this setting improves survival significantly. We know that from breast cancer that adding a HER2 targeting agent to neoadjuvant therapy, for example trastuzumab to neoadjuvant chemotherapy with docetaxel, improves survival significantly in metastatic breast cancer by more than 10% at five years according to the NOAH study.

So in locally advanced gastric cancer, we need as well systemic treatment, but even with optimal systemic treatment with FLOT chemotherapy and standard-of-care surgery, survival is not better than 50% at five years. So we wanted to approve this for the subgroup of patients with HER2 positive gastric cancers; this was the reason for the design of the INNOVATION trial where we added trastuzumab.

We had three trial arms: one arm with standard-of-care chemotherapy, one arm with chemotherapy, the same chemotherapy plus trastuzumab, and the second experimental arm was chemotherapy plus trastuzumab and pertuzumab. In both experimental arms chemotherapy was given during adjuvant chemotherapy and continued until a total of one year, according to the HERA trial. 

So what is important for this trial is that when we started recruitment in 2015, the chemotherapy backbone, the only one which was possible to agree upon with our colleagues in Korea who participated in the trial, the chemotherapy backbone was cisplatin and 5FU. A few years later the FLOT4 trial was published by Doctor Al-Batran and colleagues who showed that the chemotherapy with FLOT2 is significantly better than the chemotherapy with cisplatin and 5FU. For this reason, we made an amendment and changed the chemotherapy backbone in our trial to FLOT so that in the end 50% of the patients included in our trial are treated with FLOT and 50% of the patients are treated with cisplatin 5FU, and about 10% of all patients which were included were included in Korea. 

The primary endpoint of this trial was major pathologic response rate, and the trial was designed to demonstrate an increase in major pathologic response rate from 25% to 45%, with 80% of power and 10% alpha. 

According to the results of this trial, the major pathologic response rate, which was really evaluated in blinded by two independent senior pathologists with a third review in case of disagreement, this major pathologic response rate was 23% in the patients treated with chemotherapy alone, 37% for patients treated with chemotherapy and trastuzumab, and 26% for the patients treated with trastuzumab and pertuzumab. 

The question is why did the arm with chemotherapy and trastuzumab and pertuzumab perform so poorly? We have the response to this, and this is probably due to reduced chemotherapy intensity due to toxicity in this arm. For example, the number of patients treated with four cycles of FLOT was 93% and 94% in the patients treated with chemotherapy alone and with chemotherapy and trastuzumab, and it was only 80% in the patients treated with both antibodies. So regarding the major pathologic response rates, what I already said is how they were in the overall patient population; I think it is really important to look at the major pathological response rates, as well, according to the chemotherapy backbone. For example, in the patients treated with chemotherapy alone major pathologic response rate was 8% in patients treated with chemotherapy alone, but it was 33% in patients treated with FLOT chemotherapy, so 8% that was with cisplatin 5FU. Among the patients treated with FLOT and trastuzumab, the major pathologic response rate is increased from 33% to 53%.

Certainly, this was an underpowered phase II trial but I think these results are really interesting. We had planned to include a total of 215 patients; unfortunately due to slower recruitment we had to close the trial after 172 patients, but I think that really these results are really interesting and I think that what we can conclude is that certainly the addition of trastuzumab to perioperative chemotherapy, and especially when perioperative chemotherapy is done with FLOT, increases the major pathologic response rate. In patients treated with FLOT this increase is 20%, especially in patients with borderline resectable disease where response is needed to obtain a curative surgery, The addition of trastuzumab to perioperative chemotherapy is something that merits consideration. What is important is that we don’t have survival results at the moment; I hope that we will be able to present them in two more years.

What are the next steps for this trial?

The next steps for this trial is really to wait for the analysis of all endpoints so that we really understand exactly what the clinical benefit will be in all subgroups of patients. Then we will do some translational research, look if eventually we can better characterise those patients who did respond. For example, it seems that in a subgroup analysis that the patients with the HER2 3+ status at immunohistochemistry responded better, so maybe we can improve the precision of the selection to define those patients who benefit most from the addition of trastuzumab to chemotherapy.

Anything else to add?

There is only one other trial which as well randomised patients for perioperative treatment who are HER2 positive to chemotherapy alone or chemotherapy plus trastuzumab; this is the Japanese TRIGGER trial. The difference to our trial were the inclusion criteria – in the TRIGGER trial patients with limited metastatic disease with positive lymph nodes were included. In this trial as well a significant improvement was observed by the addition of trastuzumab to chemotherapy for these HER2 positive patients, and we are now discussing a pooled analysis with this trial.