Editor's Note: In this exclusive interview, we speak with Dr. Anna Dorothea Wagner, a leading expert in gastrointestinal oncology, about the evolving landscape of virtual targeted diagnosis and treatment for gastric cancer. She shares insights on the latest clinical advancements, particularly the EORTC-1203 GITC Innovation Clinical Study, and evaluates the performance of trastuzumab and pertuzumab in perioperative chemotherapy. Her discussion sheds light on the potential of targeted therapy to improve survival outcomes and the challenges faced in conducting large-scale clinical trials.Oncology Frontier: Could you please introduce the current status of virtual targeted treatment for gastric cancer?
Dr. Anna Dorothea Wagner: It’s my pleasure to respond to this question. Currently, adding trastuzumab to chemotherapy—either alone or in combination with pembrolizumab—is the standard of care for patients with advanced or metastatic gastric cancers who cannot be cured. Targeting HER2 has also been highly effective in the treatment of both metastatic and localized breast cancer. In breast cancer patients, neoadjuvant trastuzumab improves five-year overall survival by about 10%.
For locally advanced or localized gastric cancer, perioperative chemotherapy is the standard of care in Western countries. The overall survival rate with surgery and perioperative chemotherapy is approximately 50% at five years. The idea behind our trial was to improve survival by incorporating targeted therapy for patients with HER2-positive tumors. It seemed inconsistent to offer HER2-targeted therapy only in the metastatic setting and not when patients have a chance of being cured. Our aim was to increase their likelihood of achieving long-term remission.
Oncology Frontier: What is the design and outcome of the EORTC-1203 GITC Innovation Clinical Study?
Dr. Anna Dorothea Wagner This was an open-label, randomized phase 2 trial with a 1:2:2randomization. The study included patients from 37 centers across Europe, South Korea, and Singapore. The primary endpoint was the major pathologic response rate, which was independently assessed by two senior pathologists, with a third expert reviewing discrepancies. Secondary endpoints included progression-free survival and overall survival.
The trial was designed to evaluate an improvement in the major pathologic response rate from 25% to 45% by adding trastuzumab alone or a combination of trastuzumab and pertuzumab to standard perioperative chemotherapy. The protocol specified that the double-antibody combination would be tested first, and if positive, the single-antibody approach would be examined.
Oncology Frontier: How do you evaluate the performance of trastuzumab and pertuzumab in the study?
Dr. Anna Dorothea Wagner When we initiated the trial in 2015, the standard systemic treatment was a combination of cisplatin and fluoropyrimidine. However, after the publication of the FLOT4 trial in 2019, the chemotherapy backbone was updated to FLOT.
Our findings indicate that adding trastuzumab alone to perioperative chemotherapy increased the major pathologic response rate by 13% overall. Specifically, in patients treated with neoadjuvant FLOT, the response rate improved from 33.3% to 53.3%, which we consider a significant advantage. However, in patients treated with both trastuzumab and pertuzumab, the benefit was marginal, likely due to reduced chemotherapy intensity. Moreover, the double-antibody regimen did not improve overall survival or response rates and was associated with increased toxicity, particularly diarrhea. Therefore, our study does not support the use of this combination.
Conversely, trastuzumab alone demonstrated clear benefits in major pathologic response rate and progression-free survival. In the overall patient population, the hazard ratio for progression-free survival was 0.85, with a notable advantage in patients who received the treatment before the amendment (hazard ratio: 0.64). However, after the amendment, the benefit was not as pronounced (hazard ratio: 1.04). For overall survival, the hazard ratio was 0.89—0.77 before the amendment and 0.99 after.
Relapse-free survival showed a strong correlation with major pathologic response. Patients who achieved a major pathologic response had a hazard ratio of 0.26 for relapse-free survival and 0.25 for overall survival, which is highly significant. However, due to the small sample size and premature closure of the study, the improvement in major pathologic response rate did not translate into a statistically significant overall survival benefit.
Our study should be viewed in the context of two other trials. The Japanese TRIGGER trial demonstrated a survival benefit of trastuzumab for patients with HER2-positive gastric cancer and limited lymph node metastases. Additionally, the HER-FLOT trial, led by Ralf Hofheinz, reported an impressive three-year survival rate of 82% in patients treated with neoadjuvant FLOT plus trastuzumab, which aligns with our findings of 76% survival at three years.
While trastuzumab cannot yet be recommended as a standard addition to perioperative chemotherapy due to the small sample size and lack of significant survival results, its higher response rate suggests that it could be beneficial for patients with large tumors where tumor shrinkage is crucial before surgery. Thus, the decision to add trastuzumab should be made on an individual basis, weighing the potential benefits and risks between doctor and patient.
