3-Year Survival Rate Reaches 69% with Durvalumab Combination Therapy Before and After Surgery in Resectable Gastric Cancer
Background
Gastric and gastro-oesophageal junction cancers are highly fatal malignant tumors, ranking among the top causes of cancer death worldwide. Even in resectable locally advanced stages, surgery alone makes it difficult to control micrometastases, resulting in a high risk of recurrence for patients. Consequently, the medical community has established treatment strategies involving perioperative chemotherapy to improve survival rates, with the FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) being a representative prescription.
While perioperative cytotoxic chemotherapy has established itself as the standard of care through existing multi-center phase 3 trials, improvements in long-term patient prognosis have remained stagnant. This is because a limitation persists in which approximately half of the patients who faithfully complete drug therapy relapse and die within a few years. This created an urgent need for the introduction of drugs with new mechanisms to dramatically improve tumor treatment outcomes.
In the field of treating advanced or metastatic gastric cancer, clear progress has already been observed. It has been confirmed that using immune checkpoint inhibitors (ICI), which block programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1), in combination with platinum-based chemotherapy significantly increases patient survival time. Notably, the drug response rate was significantly higher in patients with high PD-L1 expression within the tumor microenvironment. These clinical results served as a decisive catalyst for researchers to shift their focus to a new paradigm: administering immune checkpoint inhibitors preemptively to patients with resectable, non-metastatic disease.
Key Findings
Researchers of the MATTERHORN study, a global phase 3 clinical trial, evaluated the efficacy of perioperative immunotherapy in patients with resectable locally advanced gastric cancer and gastro-oesophageal junction adenocarcinoma using a randomized, double-blind method. Participating patients were randomized to a trial group receiving durvalumab, an anti-PD-L1 immune checkpoint inhibitor, added to the perioperative FLOT regimen, or to a control group receiving a placebo.
The final aggregated clinical data showed that the addition of perioperative immunotherapy was significantly superior in both tumor regression and survival rate improvement. The rate of pathological complete response (pCR), where residual cancer cells completely disappeared in tumor biopsies, reached 24% in the durvalumab combination group, more than 2.5 times higher than the 9% in the placebo group. As the rate of completely eliminating tumors through preoperative neoadjuvant therapy increased significantly, it resulted in a virtuous cycle where the success rate of surgical complete resection (R0 resection) also rose accordingly.
A clear gap was also observed in long-term survival indicators. The durvalumab combination group reduced the risk of death by 22% compared to the control group, recording a hazard ratio (HR) of 0.78. The overall survival (OS) at the 3-year mark of administration reached 69% in the durvalumab combination group, clearly surpassing the 62% in the placebo group. Along with the concomitant improvement in event-free survival (EFS), this survival benefit was observed consistently regardless of PD-L1 expression status, and analysis indicates that the treatment benefit is even more pronounced in high-risk patients with positive lymph node metastasis.
Significance and Outlook
This study is recognized for bringing immune checkpoint inhibitors, previously confined to palliative care for end-stage patients, to the forefront of perioperative treatment with curative intent. The immunological mechanism, in which anti-cancer immunotherapy is administered prior to surgery while the tumor tissue remains intact, inducing T cells in the body to extensively learn tumor antigens, led to actual improvements in survival rates. Accordingly, international clinical guidelines, including the National Comprehensive Cancer Network (NCCN) in the United States, are expected to rapidly revise the first-line standard treatment recommendations for patients with locally advanced gastric cancer.
However, the challenges to be managed for on-site implementation are by no means trivial. Clinical protocols to closely monitor immune-related adverse events (irAEs) and overlapping toxicities arising from the addition of immunotherapy to intensive chemotherapy are essential. This is because close multidisciplinary collaboration between surgery and medical oncology is essential to prevent planned surgical schedules from being disrupted by severe autoimmune diseases or surgical complications. The burden of medical costs for patients due to the combination of expensive immunotherapies, along with the issue of their inclusion in national health insurance coverage, remains the primary variable determining treatment accessibility.
Gastric and gastro-oesophageal junction cancers are among the most common causes of cancer-related deaths.1 In patients with operable tumours, several phase 3 trials established the value of perioperative chemotherapy.2–4 In parallel, phase 3 studies in advanced disease confirmed a survival advantage for anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors in combination with platinum doublet chemotherapy, particularly in PD-L1 expressing tumours.5 Thus, examination of whether immune checkpoint inhibitors could improve outcomes in patients who are non-metastatic was warranted.
The data presented by the MATTERHORN study serves as strong evidence for reconstructing the treatment workflow in actual clinical practice. When a patient is diagnosed with locally advanced gastric cancer, surgeons and medical oncologists will follow a treatment pathway of administering durvalumab in combination with FLOT therapy as neoadjuvant treatment before establishing a surgical plan to reduce tumor size and address micrometastases. The scenario of maximizing the patient's chance of cure by continuing adjuvant therapy after surgery to prevent recurrence of residual lesions is becoming a reality.
This is also expected to bring significant ripple effects to the pharmaceutical and biotech industries. This is because it has provided an opportunity to significantly expand the market scope of immune checkpoint inhibitors, which were previously prescribed mainly for patients with metastatic disease, to include operable early-stage cancer. The development of subsequent drugs is also likely to focus on combination immunotherapy pipelines before and after surgery rather than monotherapy.