Durvalumab Increases Pathologic Complete Response 2.7-Fold in Operable Gastric Cancer

Immunotherapy Enters the Early-Stage Gastric Cancer Setting

Gastric and gastroesophageal junction adenocarcinomasare among the leading causes of cancer-related death worldwide. Surgery with curative intent remains the primary approach. However, particularly in locally advanced Stage II–IVA disease, patients frequently develop local or distant recurrence after surgery.

Surgery alone is therefore insufficient, and multimodal systemic treatment strategies before and after surgery are needed. For this purpose, perioperative treatmentinvolves chemotherapy and/or immunotherapy both before surgery (neoadjuvant) and afterward (adjuvant). Neoadjuvant treatment reduces tumor volume and improves surgical success, while adjuvant treatment aims to eliminate microscopic residual disease and reduce recurrence risk.

The likelihood of resection (surgery)at diagnosis in gastric cancer varies with geographic region, screening practices, and the health system, but the overall pattern is as follows:

🔍 Overall Situation: Few Early Diagnoses, Advanced Disease Is Common

• Western countries (including Europe, the US, and Türkiye):
  • At diagnosis, approximately 30–40% of patients have operable (localized or locally advanced) disease .
  • The remaining 60–70% of patients have either distant metastases (M1) or very extensive local invasion.
• East Asia (particularly Japan and South Korea):
  • National screening programs allow 50–60% of patients to be diagnosed at an early stage .
  • In these regions, the operability rate at diagnosis can reach 60–70%.

The Previous Standard: Perioperative Chemotherapy with FLOT

Published in 2016, the phase 2/3 FLOT4-AIO studyrepresented a breakthrough for this patient group. Compared with epirubicin + cisplatin + 5-FU/capecitabine (ECF/ECX), the FLOT regimen (5-FU, leucovorin, oxaliplatin, and docetaxel) provided significantly longer survival and better local control.

As a result, perioperative FLOT + surgery was adopted in many countries, particularly in Europe, for Stage II or higher gastric or GEJ adenocarcinoma as standard treatment .

However, recurrence rates remained high even with FLOT, suggesting that microscopic residual disease (MRD) and tumor cells escaping the immune system persisted in some patients. This prompted consideration of integrating immune-activating treatments into this setting.

A New Question: Is FLOT More Effective with Immune Activation?

Immune checkpoint inhibitors (such as anti–PD-1/PD-L1 antibodies) can prolong survival when combined with chemotherapy in advanced gastric and GEJ cancers. Until now, however, they had not been systematically tested in resectable disease treated with curative intent during the perioperative period.

Against this background, the phase 3 MATTERHORN studyinvestigated whether adding the immune-targeting anti–PD-L1 agent durvalumab to standard FLOT could improve survival in the perioperative setting.

This striking study was presented in the Plenary Session at the 2025 ASCO meeting and simultaneously published that day in NEJM .

The MATTERHORN Study: Design and Participants

• Design: Phase 3, multicenter, double-blind, randomized controlled
• Participants: 948 patients (474 durvalumab + FLOT, 474 placebo + FLOT)
• Patient characteristics: Stage II–IVA resectable gastric or GEJ adenocarcinoma, ECOG 0–1
• Treatment schedule:
  • 2 cycles of neoadjuvant durvalumab + FLOT or placebo + FLOT
  • Surgery
  • 2 cycles of adjuvant durvalumab + FLOT or placebo + FLOT
  • Followed by 10 cycles of durvalumab or placebo maintenance

Key Findings: Event-Free Survival (EFS)

• 24-month event-free survival (EFS):
  • Durvalumab + FLOT: 67.4%
  • Placebo + FLOT: 58.5%
• Risk reduction: The risk of an event or death decreased by 29% (HR: 0.71; 95% CI: 0.58–0.86; P<0.001)

🧠 Clinical significance: These findings show that adding durvalumab to FLOT delays recurrence and allows patients to benefit more from curative treatment.

Pathologic Complete Response (pCR) Rates Increased Substantially

• pCR rate:
  • Durvalumab + FLOT: 19.2%
  • Placebo + FLOT: 7.2%
• Relative increase: The likelihood of pCR increased 2.7-fold (RR: 2.69; 95% CI: 1.86–3.90)

📌 Note: Pathologic complete response is a strong biological response directly associated with survival. The increase in these rates clearly demonstrates the contribution of the immune system to treatment.

Overall Survival (OS): A Favorable Trend, but Results Are Not Final

• 24-month median OS:
  • Durvalumab + FLOT: 75.7%
  • Placebo + FLOT: 70.4%
• No difference in the first 12 months, but clear separation after month 12 (HR: 0.67; 95% CI: 0.50–0.90)

📈 Limitation: The OS difference has not yet crossed the statistical significance threshold (P=0.03), but the trend is strong and follow-up is ongoing.

Safety Profile: No Additional Toxicity

• Grade 3-4 adverse event rate:
  • Durvalumab: 71.6%
  • Placebo: 71.2%
• Immune-related adverse events:
  • Durvalumab: 23.2%
  • Placebo: 7.2%

🔒 Reassurance: Adding durvalumab to FLOT did not cause additional serious toxicity. No difference was observed in rates of surgical delay or initiation of adjuvant treatment.

Regional Subgroups: Consistent Benefit Across All Regions, Including Türkiye

Durvalumab + FLOT significantly increased pCR across all regions, including Asia, Europe, North and South America .

Conclusion: Is a New Perioperative Standard Emerging?

In resectable gastric and GEJ cancers, the MATTERHORN study showed that durvalumab + FLOT:

• ✅ Significantly improves event-free survival,
• ✅ Increases the pathologic complete response rate 2.7-fold,
• ✅ Has an acceptable safety profile.

🧬 In conclusion, durvalumab + FLOT is a candidate to become a new worldwide perioperative standard treatment for this patient group.