The study I had the pleasure to present at ASCO GI was the EORTC-1203, the INNOVATION trial. INNOVATION stands for the integration of trastuzumab with or without pertuzumab into perioperative chemotherapy of HER2 positive stomach cancer. The study was conducted by EORTC as the leading group, together with the Korean Cancer Study Group and the Dutch Upper GI Cancer Group.
It’s a study under perioperative treatment of HER2 positive gastric cancer. We’ve known since 2010 that patients when they have metastatic gastric cancer the addition of trastuzumab to chemotherapy improves overall survival. We know that since even longer that in patients with breast cancer, both metastatic disease and localised locally advanced disease, when patients with HER2 positive disease are treated with trastuzumab or a combination of trastuzumab and pertuzumab this leads to significant survival improvement. So the question was if these findings from breast cancer are applicable as well to the gastric cancer population and if patients who are candidates for curative surgery with HER2 positive localised gastric cancer benefit from the addition of either one or these two antibodies to chemotherapy with regard to major pathologic response rates or survival.
What was the study design?
The method of this trial was an open-label randomised phase II trial with a 1:2:2 randomisation. Patients were randomised to one arm, that was the control arm, chemotherapy alone; the first experimental arm was chemotherapy plus trastuzumab and the second experimental arm was chemotherapy plus trastuzumab and pertuzumab. In total 172 patients have been included in this trial. Major pathologic response rate was the primary outcome measure.
What is important as well to say is that we started this trial in 2015 when cisplatin and 5FU were considered as the standard chemotherapy backbone for these patients after discussion with colleagues from Korea. In 2019 this standard chemotherapy backbone changed by the publication of the FLOT4 trial, for this reason we made an amendment and patients before the amendment were treated with cisplatin 5FU as a chemotherapy backbone and after the amendment they were treated with FLOT as the chemotherapy backbone. Those patients who were considered as not eligible for chemotherapy with a triplet combination of FLOT could be treated with either CAPOX or FOLFOX as chemotherapy backbone.
What were the results of this study?
The primary endpoint of this trial, as I said, was major pathologic response rate. So this trial showed in general an improvement of major pathologic response rate by adding trastuzumab to chemotherapy. So there is one treatment arm which really stood out in terms of major pathologic response rate, these were the patients treated with both FLOT as chemotherapy backbone plus trastuzumab. So in these patients major pathologic response rate was 53% in contrast to 33% in patients who were treated with FLOT without the addition of trastuzumab. So the benefit from adding trastuzumab to FLOT chemotherapy was 20%.
However, patients treated with both antibodies did not have any relevant benefit in terms of major pathologic response rate. So the overall major pathologic response rate in patients treated with chemotherapy alone was 23%, it was 37% in all patients treated with chemotherapy plus trastuzumab and 26% in patients treated with chemotherapy and both antibodies.
The next important results were progression free and overall survival. In the overall population both progression free and overall survival showed non-significant benefits in the patients treated with chemotherapy plus trastuzumab with a hazard ratio of 0.84 and 0.89. These survival benefits were not significant and we have to say that survival results are immature because we couldn’t follow up the patients as long as we wanted because of budget constraints.
The interesting thing is that when the results of progression free and overall survival were split up according to the chemotherapy backbone, the patients treated before the amendment with a doublet chemotherapy had these non-significant advantages while patients treated after the amendment with FLOT as chemotherapy backbone did not have a survival advantage by adding trastuzumab to chemotherapy. This may have multiple reasons. One possible reason is that the overall survival at three years in the patients treated with chemotherapy alone was 75% which is really excellent when compared to the FLOT4 trial where overall survival at three years was 56%. In patients treated with chemotherapy plus trastuzumab overall survival at three years was 77%. Therefore it might be that this lack of benefit of the patients in terms of overall survival in the patients treated with chemotherapy and trastuzumab is just due to an unusually high survival in the patients treated with chemotherapy alone which is, as I said, much higher than patients in other trials treated with perioperative chemotherapy alone.
Another major important finding is that both relapse free and overall survival were significantly better and this was really the only statistically significant advantage. So patients with a major pathologic response rate had a significantly better relapse free survival with a hazard ratio of 0.26 which was highly significant. Regarding overall survival, patients with a major pathologic response had a better overall survival with a hazard ratio of 0.25 as compared to those who had no major pathologic response rate. However, the p-value was 0. 0041.
So in conclusion the addition of both antibodies did not have any advantage, neither in terms of response rate nor in terms of survival as compared to chemotherapy alone. It has to be noted that the addition of these two antibodies increased toxicity, especially diarrhoea, which was the reason why the chemotherapy dose intensity in this trial was lower. The addition of both antibodies can therefore not be recommended in patients with gastric cancer in this indication.
Progression free and overall survival results in this trial were numerically improved when adding trastuzumab to the chemotherapy doublet but not after the amendment when patients received FLOT. As I said, survival results are immature, nevertheless on the basis of its very high major pathologic response rate the addition of trastuzumab to chemotherapy may be considered, especially when tumour downsizing is needed to achieve a curative resection.
Is there anything else you would like to add?
What I’d like to add is the significance of this trial is really that this is by far the largest trial which has ever been conducted in this indication. The other trials, the PETRARCA trial had about 80 patients and had to be closed prematurely due to lack of further funding; the Japanese Trigger trial had only about 50 patients and had to be closed prematurely due to slow recruitment. We have included 172 patients.
This trial does not allow to draw any definitive conclusions. Further research on this topic is necessary but I think we have shown that it is worth conducting further trials with this question on this indication.
