Durvalumab immunotherapy approved for gastric or gastroesophageal junction adenocarcinoma

Author: Grace Stroman

Editor: Tiffany Ko

Today’s article will discuss the Food and Drug Administration (FDA) approval of durvalumab for gastric (GC) and gastroesophageal junction adenocarcinoma (GEJC) as a result of the multinational MATTERHORN study. On November 25th, 2025 durvalumab (Imfinzi) in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) standard of care chemotherapy was approved for neoadjuvant and adjuvant treatment in adults with resectable GC and GEJC.1 The MATTERHORN trial primary endpoint was event-free survival (EFS) and secondary endpoints were overall survival (OS) and pathological complete response (pCR).2 Developed by AstraZeneca, durvalumab is an FDA approved immune-checkpoint inhibitor that targets programmed death-ligand 1 (PD-L1) to enhance tumor clearance, and is the first immunotherapy approved for GC/GEJC with a demonstrated OS survival benefit when combined with standard of care.

Key points

  • MATTERHORN is the first global phase III study demonstrating superior EFS by combining an immunotherapy agent, durvalumab, and chemotherapy standard of care for localized, early-stage GC/GEJC.
  • EFS was not reached for durvalumab plus FLOT therapy while OS and pCR favor durvalumab but are not mature.
  • Durvalumab is an FDA approved PD-L1 antibody for multiple solid cancers and promotes T-cell mediated tumor clearance. 

What is gastric cancer?

Stomach cancer, including GC and GEJC, is the sixth most common and seventh leading cause of cancer related deaths globally in 2022 making it a health-care challenge.3 The highest number of cases occur in Asian, South American, and eastern European populations and is twice as prevalent in males than females.3 However, early-onset (i.e., <50 years of age) sporadic GC is rising in females and is attributed to behavioral, nutritional, microbial, and environmental factors mirroring a trend observed in other gastrointestinal cancers.4-6 GC is divided into two anatomic subsites with unique molecular subtypes and risk factors.7 Upper stomach GC and GEJC, where the esophagus and stomach intersect, is linked with Helicobacter pylori infection, obesity, and gastroesophageal reflux. Lower stomach GC is associated with chronic H. pylori infection, alcohol, tobacco use, and a high-sodium diet.7,8

Current treatment paradigms and clinical trial learning points

GC/GEJC patients generally undergo surgery and chemotherapy. In east Asia, standard treatment involves adjuvant chemotherapy regimens following stomach and surrounding lymph node resection.8 These chemotherapies vary based on tumor staging and can include S-1 (tegafur, gimeracil, and oteracil), CAPOX (capecitabine and oxaliplatin), SOX (S-1 and oxaliplatin), or docetaxel and S-1.8 FLOT neoadjuvant chemotherapy prior to surgery is standard of care for operable cancers outside of Asia.8 However, cancer recurrence is common (~60%) after curative resection and the 5-year OS rate is 25% worldwide.9 Therefore, additional therapeutic intervention is recommended for stage IB or higher.10,11 Radiotherapy and chemoradiotherapy are generally no longer recommended after the ESOPEC trial demonstrated adjuvant FLOT superiority over chemoradiation with carboplatin and paclitaxel for resectable GC and GEJC.12 As a result, surgery with neoadjuvant and adjuvant FLOT remains the primary treatment paradigm for resectable GC/GEJC.

Looking beyond chemotherapies, targeted therapy and immunotherapy regimens have been investigated but have faced clinical setbacks. Phase II trials targeting human epidermal growth factor receptor 2 using trastuzumab and pertuzumab showed improved pCR rates but did not establish a clear survival benefit over placebo.13-15 Additionally, immunomodulating antibodies against programmed cell death protein 1 (PD-1) (i.e., pembrolizumab, nivolumab) or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) (i.e., ipilimumab) combined with chemotherapy did not demonstrate enhanced clinical efficacy over chemotherapy alone.16-18 The phase II DANTE trial was the first to demonstrate improved histopathological regression over placebo when combining the PD-L1 antibody atezolizumab plus FLOT in neoadjuvant resectable esophagogastric adenocarcinoma.19

MATTERHORN study design and results

Despite previous immunotherapy setbacks, investigation of durvalumab, an FDA approved anti-PD-L1 antibody, was evaluated in the MATTERHORN trial for treatment of GC/GEJC. Durvalumab received FDA approval for multiple solid cancers and several indications including non-small cell lung, small-cell lung, hepatocellular carcinoma, bile duct and gallbladder, and endometrial cancers.20-24 Moreover, elevated PD-L1 is detected in ~50% of GC and is correlated with poor prognosis underscoring the clinical potential of anti-PD-L1 therapy.25 The randomized, double-blind, phase III MATTERHORN (NCT04592913) study sought to address the efficacy of durvalumab in combination with FLOT in the neoadjuvant and adjuvant settings. The trial enrolled previously untreated, non-metastatic, and resectable stage II-IVa GC/GEJC and measured EFS, OS, and pCR. The global study spanned 156 locations across North and South America, Europe, and Asia and enrolled 474 patients in both study arms. Participants were generally well balanced in each study arm by age, demographic, sex, and cancer type, however, the trial organizers recognized that Black patients were underrepresented.2

The study was designed to administer durvalumab or placebo in combination with FLOT before and after surgery and measure EFS, OS, and pCR (Figure 1). FLOT chemotherapy plus durvalumab or placebo was administered for a total of 4 cycles- 2 cycles of neoadjuvant therapy and 2 cycles of adjuvant therapy. After the last cycle, durvalumab or placebo was administered every 4 weeks. Patients underwent surgery 4-8 weeks after they received their final neoadjuvant dose, and adjuvant dosing began 4-12 weeks after surgery. Treatment continued until 1 year from the start of adjuvant therapy, 12 total cycles of adjuvant therapy, or withdrawal of study consent or participating investigator. The study was not designed to determine if durvalumab therapy had an effect in the neoadjuvant or adjuvant phases. The primary endpoint measured was EFS, defined as disease progression, recurrence, or death. The main secondary endpoints were OS from study randomization to death and pCR, defined by the lack of viable tumor cells in the resected origin or lymph node tissues. Additional secondary endpoints were disease-free survival, metastasis-free survival, disease-specific survival, and health-related quality of life. Finally, analyses were performed on subgroups within the participants including sex, age, geographic region, lymph-node status, PD-L1 expression, tumor location, Eastern Cooperative Oncology Group score, histologic type, and microsatellite instability status.2

The primary endpoint indicated that durvalumab performed significantly better than placebo, but the secondary endpoints require more data points to make definitive calls. The median EFS was not reached in the durvalumab arm and was 32.8 months for the placebo arm. At 24 months, the EFS rates were 67% for durvalumab and 59% for placebo. Both the OS and pCR endpoints have not been reached for either study arm, however, the data are trending to favor the addition of durvalumab. The OS rate was 76% with durvalumab and 70% with placebo at 24 months, and the pCR rate was 19% with durvalumab compared to 7% with placebo. As the study continues to mature and follow secondary endpoints, these analyses will be reevaluated and finalized. All subgroups tested also tended to favor durvalumab plus FLOT over placebo, although not all analyses were significant due to patient subgroup size. Importantly, the addition of durvalumab did not raise any additional safety concerns beyond FLOT standard of care.2

Mechanism of durvalumab

Durvalumab is a human monoclonal antibody selective for PD-L1 and blocks the interaction between PD-L1 and PD-1, thereby enhancing effector T-cell function for tumor cell clearance. One mechanism by which tumors can evade immune system elimination is through the upregulation of PD-L1, a regulator of T-cell activation.26 Binding between tumor PD-L1 and T-cell PD-1 shuts down T-cell activation thereby blocking tumor elimination. Durvalumab can be used as a monotherapy or in synergy with chemotherapeutics.27 The development of monoclonal antibodies against the checkpoint proteins PD-L1, PD-1, and CTLA-4 provide an avenue to modulate the immune system and override disease microenvironment signals.26

Ongoing GC/GEJC trials

Looking ahead, additional clinical trials and therapeutic modalities are being investigated to improve GC/GEJC outcomes. These include targeted kinase inhibitors, antibodies (i.e., monoclonal, antibody-drug conjugates, bispecific), and T-cell therapies (i.e., chimeric antigen receptors, bispecific engagers).8

References

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