Anna-Dorothea Wagner, MD, University Hospital of Lausanne, Switzerland, shares insights from the INNOVATION trial. This phase 3 study found the addition of trastuzumab, with or without pertuzumab, to FLOT chemotherapy did not improve progression-free survival (PFS) or overall survival (OS) in comparison to FLOT alone among patients with HER2-positive gastric cancers.

Transcript:

I am Anna-Dorothea Wagner, senior lecturer and consultant at the University Hospital and University of Lausanne, where I'm head of the Gastrointestinal Cancer Outpatient Clinic. I'm also one of the leads of the EORTC [European Organisation for Research and Treatment of Cancer) Gastric Cancer Task Force. 

What is the rationale for the INNOVATION trial?

Background for the INNOVATION trial are two major effects. The first is we know for many years that 20% of all gastric cancers are HER2-positive. We have, in breast cancer since about 25 years ago, the patients with HER2-positive breast cancers are treated with targeted therapies, which is a paradigm for the benefits of targeted treatments in oncology and in patients with locally advanced breast cancer. The addition of trastuzumab to neoadjuvant chemotherapy improved survival by about 10%. The question was whether we can observe similar benefits in gastric cancer by adding the targeted treatments to perioperative treatment of localized gastric cancer. 

In 2010, the ToGA trial showed that, in patients with metastatic gastric cancer, overall survival can be significantly improved by adding trastuzumab to chemotherapy. Since that time, we have a validated target, we have a cheap drug which is well tolerated in the majority of the patients, but we use it only when the patients have metastatic disease and not when there's a chance to cure them. This is something I found really not acceptable as a medical oncologist and wanted to change. 

This is why we designed the EORTC-1203 INNOVATION trial, which stands for the integration of trastuzumab with or without pertuzumab into perioperative chemotherapy of HER2-positive stomach cancer. 

What were the methods of the INNOVATION trial?

This trial was a randomized open-label phase 2 trial, an investigator-initiated trial, which was led by EORTC and conducted in collaboration with the Korean Cancer Study Group and Dutch Upper GI Cancer Group. It was 1-to-2-to-2 randomization. One arm was chemotherapy alone, one arm was chemotherapy plus trastuzumab, and one arm was chemotherapy plus trastuzumab and pertuzumab.  A primary endpoint was major pathologic response rate as evaluated by 2 senior expert pathologists and with discrepancies resolved by a third senior expert pathologist. 

What is important to know about this trial is, when we started it was in 2015, the results of the FLOT-4 trial were not yet available. This is why patients were treated with platinum [plus] 5-FU as a chemotherapy backbone. After 2019 and the publication of the FLOT-4 trial, we made an amendment and then patients were treated with FLOT as a chemotherapy backbone.

What were the findings from this trial?

I think the most interesting finding is the fact that the addition of trastuzumab to FLOT improves major pathologic response rate by 20%, from 33% to 53%. This major pathologic response rate really stands out in comparison to the other treatment arms. Overall, patients clearly have an advantage by adding trastuzumab to chemotherapy with the overall response. Major pathologic response rate in patients treated with chemotherapy alone was 23%, while it was 37% in the patients treated with chemotherapy plus trastuzumab. However, in the double-antibody arm, major pathologic response rate was 26%, really there was no relevant difference between the arm treated with the double-antibody and chemotherapy alone. 

This was a surprising finding for us, but we found the reason why this is the case is probably due to toxicity. The relative dose intensity in the patients treated with FLOT was not sufficient. So the number of patients, or the percentage of patients who were treated with 4 cycles of FLOT was 93% in patients treated with chemotherapy alone as well as in chemotherapy plus trastuzumab, but it was only 80% in patients treated in a double-antibody arm. And the relative dose intensity of the chemotherapy in the patient treated with 5-FU, for example, was only 82% in this double-antibody arm, for docetaxel only 85% as compared to 99% and 94% in the other arms. 

Really this addition of both antibodies resulted in a drop in both of the number of cycles which could be safely administered preoperatively, and the dose intensity of those cycles that were administered. And probably it is for this reason that there was no advantage for the patients treated with this treatment arm. 

In contrast, we have to say that those patients had significantly more grade 3/4 diarrhea, 26% in the patients treated with a double antibody arm. This is something which has as well been observed in the PETRARCA trial, by Salah-Eddin Al-Batran [University Cancer Center Frankfurt] and Ralf Hofheinz [University Medical Center Mannheim] and this is why in their conclusion they write that this regimen should not be recommended outside clinical trials, and this is something what we can confirm. The rate of neutropenia was approximately the same, roughly in all treatment arms. You can give growth factors, but the rate of diarrhea increased importantly from around 5%, or less than 5% in the arm of patients treated with chemotherapy alone and chemotherapy plus trastuzumab to over 25% in the patients treated with this double-antibody arm. 

Regarding the primary endpoint, I already said that in terms of major pathologic response rates, chemotherapy plus trastuzumab clearly stands out with 53% major pathologic response rate in patients treated with FLOT plus trastuzumab. This major pathologic response rate was only 37% in the patients treated with chemotherapy and the double-antibody combination. Overall, the benefit from changing the chemotherapy backbone from the double-antibody combination to FLOT was evident, but this benefit could further be increased by adding trastuzumab alone. 

In terms of progression-free and overall survival, we found that in the overall patient population for the patients treated with chemotherapy plus trastuzumab, there was a non-significant survival advantage, with a hazard ratio of 0.84. But it is important to understand that this survival benefit was first of all, not significant. The trial was not powered to detect overall survival and survival results were immature because the trial had to be stopped prematurely due to a lack of further funding. 

If you analyze the progression-free and overall survival in the patients treated before and after the amendment, you see that the patients before the amendment had a greater benefit from the addition of trastuzumab, whereas patients treated after the amendment had perhaps minor benefit in terms of progression-free, but no benefit in overall survival. This may have different reasons. One possible reason, for me, is that the patients who were treated with chemotherapy alone in this arm in this study, the percentage of patients who survived at 3 years was 73%, which is very high compared to the other trial. I mean in the FLOT-4 trial, the percentage of patients who survived at 3 years was 56%. And you can say that this is another patient population as we included only patients with HER2-positive disease, but HER2-positivity is not a positive prognostic factor. It has no impact on the prognosis. This number of patients who has been treated with chemotherapy alone and with FLOT as chemotherapy backbone, these were only 19 patients. So this is a very small number, and it might be that just due to chance these small number of patients had such a good overall survival results, which is better than the literature. But I mean with chemotherapy and trastuzumab as well, you have more than 70% overall survival at 3 years, which is what we want. 

If you look at the subgroup analysis, it seems that patients over the age of 60 had perhaps no benefit from the addition of the targeted drug. So this is something which has to be considered. Another major finding of this trial is that really those patients in whom a major pathologic response could be obtained, had a significant advantage in terms of both relapse-free and overall survival with a hazard ratio of 0.26 and 0.25. Really this benefit is very clear. Curves separately separate really nicely, this is what we want. 

What is the significant of these results?

In conclusion, the addition of both trastuzumab and pertuzumab to chemotherapy was not associated with any advantage in our trial. Toxicity was significant and there was even a survival disadvantage. Progression-free and overall survival were numerically improved when trastuzumab was added to the chemotherapy doublet, but not after the amendment when the patients received FLOT, for the reason I explained. The survival results are immature and median is not reached. Nevertheless, in my personal view, on the basis of its very high, major pathologic response rate, the addition of trastuzumab to chemotherapy may be considered, especially in patients where downsizing is needed to achieve a curative resection. 

What I did not say yet, this is the largest trial ever conducted in patients for the perioperative treatment of HER2-positive gastric and [gastroesophageal] junction tumors. In total, we included 172 patients. This trial could unfortunately not provide a definite answer to the question, but I think we made a first step or we made an important step on this way, and further trials are needed. 

What are the future steps for this research?

There are different future steps planned. One is that we are currently working on a meta-analysis, including the data of the PETRARCA trial, as well from the Japanese Trigger trial, which included patients with limited metastatic disease with lymph node metastases and also observed a significant survival benefit, although the trial was underpowered. The meta-analysis is one step. Another step is to work with pathologists to try to identify pathologic characteristics of patients who have a major pathologic response rate. Apart from the treatment, this is sort of work ongoing and in progress. Next thing, I hope that other countries, and I do hope especially in China, I think this is the biggest country which has a good infrastructure and they're doing a lot of interesting clinical trials right now. I hope that they'll be able to do other trials in this indication if possible as well with trastuzumab, so that we can really get more evidence on the true magnitude of the benefit of the treatment with trastuzumab alone in these patients. 

Source:

Wagner AD, Grabsch HI, Mauer ME, et al. EORTC-1203 GITC “INNOVATION”: Integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy of HER-2 positive stomach cancer: Overall survival results. Presented at the 2025 ASCO Gastrointestinal Cancers Symposium. January 23-25, 2025; San Francisco, CA. Abstract LBA331.