DANTE Trial: Phase III Recruitment Completed in Gastric and GEJ Cancer

The DANTE trial (NCT03421288) has successfully completed recruitment for its Phase III cohort, an achievement reached in under two years—remarkably fast for a large, multicenter immuno-oncology study. This trial holds a unique position in the global landscape: it is one of only a handful of Phase III studies exploring the role of immune checkpoint inhibition in the perioperative setting for resectable gastric and gastroesophageal junction adenocarcinoma.

Unlike most perioperative immunotherapy trials, DANTE is the only study worldwide specifically designed around biomarker selection, enrolling patients whose tumors demonstrate features that make them more likely to benefit from immunotherapy. This biomarker-driven approach not only enhances the scientific rigor of the study but also reflects a shift toward precision medicine in upper gastrointestinal cancers, where treatment personalization has long lagged behind.

Authors: Sylvie Lorenzen, MD Thorsten Oliver Götze, MD, Peter Thuss-Patience, MD, Matthias Biebl, MD, Nils Homann, MD, Michael Schenk, MD, Udo Lindig, MD, Vera Heuer, MD, Albrecht Kretzschmar, MD, Eray Goekkurt, MD, Georg Martin Haag, MD8, Jorge Riera-Knorrenschild, MD, Claus Bolling, MD, Ralf-Dieter Hofheinz, MD Tianzuo Zhan, MD, Stefan Angermeier, MD, Thomas Jens Ettrich, MD, Alexander Reinhard Siebenhuener, MD, Moustafa Elshafei, MD, Wolf Otto Bechstein, MD, Timo Gaiser, MD, Maria Loose, PhD, Disorn Sookthai, MSc, Christina Kopp, MSc, Claudia Pauligk, PhD, and Salah-Eddin Al-Batran, MD

Salah-Eddin Al-Batran, MD, Director Institute of Clinical Research UCT-University Cancer Center Franfkurt, shared on his Linkedin

“DANTE is one of the few Phase III trials worldwide assessing the role of immunotherapy via immune checkpoint inhibition in operable gastric and gastroesophageal junction tumors, and the only trial specifically designed for patients with a biomarker for immunotherapy.”

Background

Esophagogastric adenocarcinoma (EGA) remains a disease with high global mortality despite advances in multimodality therapy. Perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) has been established as the current standard of care, improving R0 resection rates and overall survival compared with older regimens.

The FLOT4 trial demonstrated a pathologic complete regression rate of 16% and a major regression rate of 37%, but long-term survival outcomes are still unsatisfactory. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have reshaped treatment in advanced EGA, yet their role in the curative perioperative setting remains uncertain. The DANTE trial (IKF-s633, NCT03421288) was designed to evaluate whether the addition of the PD-L1 inhibitor atezolizumab to perioperative FLOT can enhance histopathologic regression and ultimately improve survival.

Design and Methods of the DANTE Phase II/III Trial

The DANTE trial was an investigator-initiated, multicenter study conducted in Germany, Austria, and Switzerland. It began as a Phase II randomized trial before transitioning into a Phase III design with event-free survival as the primary endpoint. The Phase II portion specifically focused on surgical pathology outcomes on an exploratory basis.

Eligibility criteria included patients ≥18 years with histologically confirmed gastric or gastroesophageal junction (GEJ) adenocarcinoma staged ≥cT2 and/or cN+, without evidence of distant metastases. Staging required endoscopy, endoscopic ultrasound, CT or MRI, and diagnostic laparoscopy in higher T stages. Patients needed adequate organ function and ECOG performance status ≤1.

Biomarker testing included central and local evaluation of PD-L1 combined positive score (CPS) and microsatellite instability (MSI)/mismatch repair (MMR) status. Randomization (1:1) was stratified by nodal status, tumor site, and MSI status.

Patients were assigned to two arms:

• Arm A (experimental): FLOT (docetaxel 50 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 2,600 mg/m² 24h infusion, q2w ×4 pre- and ×4 postoperative cycles) combined with atezolizumab (840 mg q2w during chemotherapy), followed by atezolizumab monotherapy (1,200 mg q3w ×8 cycles).
• Arm B (control): Standard perioperative FLOT regimen alone.

Surgery was scheduled 4–6 weeks after preoperative chemotherapy and performed per national standards. The primary endpoints for the Phase II analysis were pathologic regression (TRG1a = complete response) and ypTNM downstaging. Secondary endpoints included R0 resection rate, safety, and surgical morbidity.

Results of the DANTE Phase II/III Trial (2023 Analysis)

Between September 2018 and October 2020, 295 patients were enrolled (146 in Arm A, 149 in Arm B). Baseline characteristics were balanced: median age 61–62 years, ~70–80% male, and most with cT3, cN+ disease. PD-L1 CPS ≥1 was present in 56% (Arm A) and 59% (Arm B), while MSI/dMMR tumors were detected in 6% and 10%, respectively.

Surgery and resection outcomes

• Surgery was performed in 97% (Arm A) and 96% (Arm B).
• R0 resection was achieved in 96% vs 95%, respectively.

Pathologic regression

• Complete regression (TRG1a) occurred in 24% of patients receiving FLOT + atezolizumab vs 15% with FLOT alone (p = 0.032).
• Major regression (TRG1a/b) was achieved in 49% vs 38%.

Downstaging

• ypT0 stage was observed in 23% with FLOT + atezolizumab vs 15% with FLOT alone (p = 0.044)
• ypN0 status occurred in 68% vs 54% (p = 0.012).
• ypT0N0 was achieved in 23% vs 14%.

Biomarker analysis

• Patients with PD-L1 CPS ≥10 derived the greatest benefit: TRG1a in 33% vs 12%.
• In MSI/dMMR tumors, TRG1a reached 63% with FLOT + atezolizumab compared to 27% with FLOT alone.
• Even in PD-L1 CPS <1, response improvements were seen (23% vs 16%).

Safety

The safety population included 292 patients.

• Grade 3–4 hematologic toxicities (neutropenia, leukopenia) were common in both arms: febrile neutropenia 5% vs 1%.
• Non-hematologic grade 3–4 AEs included diarrhea (13% vs 8%), nausea (8% vs 6%), and peripheral neuropathy (7% vs 4%).
• Surgical morbidity was similar: complications in 45% (Arm A) vs 42% (Arm B).
• Postoperative 60-day mortality was 3% vs 2%.

Overall, the addition of atezolizumab did not increase surgical risk or unexpected toxicity.

Clinical Significance of the  DANTE Trial

Although perioperative FLOT chemotherapy has improved outcomes in gastric and gastroesophageal junction cancers, long-term survival remains limited. The integration of immunotherapy into standard curative treatment strategies represents an important next step. By combining immune checkpoint inhibition with chemotherapy, the potential exists to increase pathologic regression rates, achieve deeper tumor downstaging, and ultimately improve survival in this aggressive disease.

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