Nature Medicine | Phase 2 Trial of Perioperative Pembrolizumab, Trastuzumab, and FLOT in HER2-Positive Localized Esophagogastric Adenocarcinoma

This study evaluated the feasibility and anti-tumor activity of the combination therapy with pembrolizumab, trastuzumab, and FLOT in patients with HER2-positive localized esophagogastric adenocarcinoma. The results showed a high pathological complete response rate, providing important evidence for future randomized trials.

 

Literature Overview

This article, 'Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial', published in Nature Medicine, reviews a phase 2 clinical trial assessing the safety and efficacy of perioperative treatment with pembrolizumab, trastuzumab, and FLOT chemotherapy in patients with HER2-positive localized esophagogastric adenocarcinoma. The study demonstrated that this combination regimen achieves significant pathological response rates, offering important references for future treatment strategies.

Background Knowledge

Esophagogastric adenocarcinoma is one of the leading causes of cancer-related mortality globally, with the HER2-positive subtype accounting for approximately 10-20% of all gastric cancers. For operable patients, the FLOT regimen has become the standard perioperative treatment. In recent years, PD-1 and HER2-targeted therapies have shown significant efficacy in metastatic gastric cancer, but their application in the perioperative setting remains limited. Combining perioperative anti-PD-1 and anti-HER2 therapy with chemotherapy may enhance anti-tumor immunity through dual targeting, potentially improving pathological complete response (pCR) rates; however, its feasibility and safety remain to be confirmed. Based on this context, this study aimed to evaluate the efficacy of the triple therapy in HER2-positive localized esophagogastric adenocarcinoma to further optimize perioperative treatment strategies.

 

 

Research Methods and Experiments

The IKF/AIO PHERFLOT phase 2 trial was conducted across 11 centers in Germany and enrolled 31 patients with HER2-positive, resectable esophagogastric adenocarcinoma. The treatment regimen included three preoperative cycles of pembrolizumab and trastuzumab combined with FLOT chemotherapy, followed by surgery, and then four additional postoperative cycles of combination therapy. Patients subsequently received up to 11 cycles of pembrolizumab and trastuzumab monotherapy. The primary endpoints were pathological complete response rate (pCR) and 2-year disease-free survival (DFS). Secondary endpoints included R0 resection rate, feasibility, and safety. Exploratory endpoints analyzed clinical responses across molecular subgroups, including PD-L1 combined positive score (CPS) and HER2 expression levels.

Key Conclusions and Perspectives

• In the intention-to-treat population, 48.4% of patients achieved a pathological complete response, and 19.4% achieved near-complete response, with a total major pathological response rate of 67.7%.
• The pCR rate was 52.0% in patients with HER2 IHC 3+, compared to 33.3% in those with HER2 2+/ISH+, suggesting a correlation between HER2 expression level and treatment response.
• Patients with PD-L1 CPS ≥10 achieved a pCR rate of 63.6%, while those with CPS 0 still achieved a 33.3% pCR rate, indicating that even patients with low PD-L1 expression may benefit from this regimen.
• Despite a high rate of postoperative complications (26.7% required reoperation), all patients achieved R0 resection, with no treatment-related deaths observed.
• Approximately 48.4% of patients experienced ≥grade 3 treatment-related adverse events, primarily attributed to chemotherapy agents (e.g., FLOT), and the toxicity profile was consistent with the known safety profiles of the individual drugs.

Research Significance and Prospects

This study supports the feasibility of combining HER2 and PD-1 targeted therapy in the perioperative setting, showing potential for improved pCR rates compared to historical controls. Future large-scale randomized controlled trials are needed to confirm long-term survival benefits. Additionally, this study provides preliminary evidence for organ-preserving strategies, particularly in patients achieving complete response, potentially reducing surgical morbidity. The findings may also inform combination therapies for other gastrointestinal cancers.

 

 

Conclusion

This study published in Nature Medicine systematically evaluated the efficacy and safety of a perioperative regimen combining pembrolizumab, trastuzumab, and FLOT in HER2-positive localized esophagogastric adenocarcinoma. The results demonstrated good feasibility and a significant improvement in the pathological complete response rate (48.4%), suggesting potential advantages in perioperative treatment. Despite a high incidence of postoperative adverse events, overall tolerability was acceptable, with no treatment-related deaths observed. These findings provide new evidence for individualized treatment of HER2-positive gastric cancer and lay the foundation for future phase 3 randomized trial designs. Importantly, the study highlights the significance of molecular subgroups (e.g., PD-L1 CPS and HER2 expression) in predicting treatment response, which may guide the development of precision medicine strategies.

 

Alexander Stein, Eray Goekkurt, Salah-Eddin Al-Batran, Mascha Binder, and Joseph Tintelnot. Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial. Nature Medicine.