Tag: Gastric and GE Junction Cancer

HERIZON-GEA-01 and the Future of HER2-Targeted Therapy in Gastroesophageal Adenocarcinoma

RR

Written by: Benjamin L. Kitchens, MD
Sponsored by: Jazz Pharmaceuticals

Gastroesophageal adenocarcinoma (GEA) includes cancers of the gastroesophageal junction (GEJ) and stomach.  In 2026, U.S. estimates project 31,510 new cases of gastric cancer and 22,530 new cases of esophageal cancer [1,2].  Gastric and GEJ cancer are often diagnosed at advanced stages due to lack of screening programs in the US; this portends a poor prognosis.  The 5-year relative survival for gastric cancer is 78.1% for localized disease, 39.0% for regional disease, and 8.1% for distant metastatic disease [1].  Similarly, esophageal cancer 5-year relative survival rates are 48.6% for localized disease, 29.1% for regional disease, and 5.3% for distant metastatic disease [2].  The poor prognoses for patients with metastatic GEA underscore the need for continued advances in early detection and innovative therapies to improve outcomes.

Biomarker-driven therapy has transformed the treatment landscape for metastatic GEA.  Approximately 14 to 22% of GEAs are HER2-positive [3-5], and HER2-targeted therapy has become central to treatment.  First line therapy for advanced GEA currently consists of FOLFOX plus trastuzumab, with the addition of pembrolizumab for PD-L1 positive (combined positive score ≥ 1) disease, based on the Keynote-811 trial [6].  This trial showed a median overall survival (OS) of 20 months for pembrolizumab added to trastuzumab and chemotherapy, versus 16.8 months for trastuzumab and chemotherapy alone.  Median progression-free survival (PFS) was 10.0 versus 8.1 months, respectively [6].  HER2-directed therapy remains relevant in the second line setting, with the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) available.  While these treatments reflect impactful progress, there remains a critical need for advanced HER2-directed therapies that deliver deeper and more durable responses.  Zanidatamab is a dual HER2-targeted bispecific immunoglobulin G1-like antibody that binds to two separate extracellular domains of HER2 (domains 2 and 4) [7].  Zanidatamab has already received accelerated approval for previously treated unresectable or metastatic HER2-positive biliary tract cancer, and is under investigation for the treatment GEA [7].

The ongoing Herizon-GEA-01 study is a phase 3 randomized trial evaluating first-line zanidatamab in combination with chemotherapy, plus or minus anti-PD-1 immunotherapy [8].  Participants were 18 years or older with histologically confirmed unresectable, locally advanced, recurrent or metastatic HER2-positive GEA [8].  HER2 positivity consisted of a HER2 immunohistochemistry (IHC) score of 3+, or IHC2+ with positive in situ hybridization.  Other inclusion criteria were an ECOG performance status of 0 or 1, assessable disease defined by RECIST 1.1 criteria, adequate organ function, and left ventricular ejection fraction at least 50%.  Select exclusion criteria were untreated or symptomatic CNS metastases, prior treatment for locally advanced/metastatic GEA, prior HER2-targeted treatment, and prior immunotherapy including anti-PD-1 and anti-PD-L1 agents.

In Herizon-GEA-01, 914 patients were stratified based on geographic region, HER2 status, and ECOG performance status.  Participants were randomly assigned 1:1:1 to one of three treatment arms [8,9].  Arm A patients received trastuzumab plus physician’s choice of chemotherapy (CAPOX or FP).  Arm B received IV zanidatamab 1800mg (weight <70kg)/2400mg (weight ≥70kg) Q3W plus physician’s choice of chemotherapy.  Arm C received IV zanidatamab plus IV tislelizumab 200mg Q3W plus physician’s choice of chemotherapy.

Patients continued treatment until death, disease progression, or unacceptable toxicity.  Chemotherapy could be discontinued after 6 cycles.  The median age in the treatment arms ranged from 62.5 to 64.  Most patients were male (77.3 to 80.8%), ECOG performance status of 1 (55.9 to 61%), metastatic disease (94 to 97.1%), HER2 IHC 3+ (82.6 to 83.1%) and with a PD-L1 tumor area positivity (TAP) score of 1% or greater (58.6 to 61.9%) [10].  Dual primary endpoints were PFS by blinded independent central review and OS.  Secondary endpoints included objective response rate, duration of response, safety, health-related quality of life, and pharmacokinetics.

Interim analysis of HERIZON-GEA-01 demonstrates deeper and more durable responses in the zanidatamab arms than those seen in the trastuzumab plus chemotherapy control arm [10,11].  The median PFS was 12.4 months in both zanidatamab-treated arms compared to 8.1 months in the control arm.  Median overall survival was 24.4 months in the zanidatamab plus chemotherapy arm, and 26.4 in the zanidatamab plus tislelizumab plus chemo arm, compared to 19.2 months in the control arm.  Objective response rates were 65.7% in the control arm, 69.6% in the zanidatamab plus chemotherapy arm, and 70.7% in the zanidatamab plus tislelizumab plus chemotherapy arm.  Median duration of response was 8.3 months in the control arm, 14.3 months in the zanidatamab plus chemotherapy arm, and 20.7 months in the zanidatamab plus tislelizumab plus chemotherapy arm.

Safety data from HERIZON-GEA-01 interim analysis reveals expected results and a manageable zanidatamab toxicity profile.  Diarrhea was the most common adverse event across all three arms, occurring in 82% and 76% of patients in the zanidatamab-treated arms [10].  Other common adverse events across all groups included nausea, vomiting and decreased appetite [11].  Of note, diarrhea prophylaxis was mandatory for patients treated with zanidatamab.  Therefore, appropriate antidiarrheal prophylaxis in the clinic will be very important.  This trial is ongoing and we anticipate further survival data in the future.

This pivotal data from HERIZON-GEA-01 is anticipated to have a meaningful impact on this patient population.  This is particularly in light of the deeper and more long-lasting responses.  Over time, we will see if this translates into statistically significant overall survival and progression-free survival benefits.

References:

  1. Cancer Stat Facts: Stomach Cancer. National Cancer Institute. Surveillance, Epidemiology, and End Results Program.  https://seer.cancer.gov/statfacts/html/stomach.html.  Accessed May 13, 2026.
  2. Cancer Stat Facts: Esophageal Cancer. National Cancer Institute. Surveillance, Epidemiology, and End Results Program.  https://seer.cancer.gov/statfacts/html/esoph.html.  Accessed May 13, 2026.
  3. Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer.  Gastric Cancer.  2015;18(3):476-484.  doi:10.1007/s10120-014-0402-y.
  4. Janjigian YY, Werner D, Pauligk C, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis.  Ann Oncol.  2012;23(10):2656-2662.  doi:10.1093/annonc/mds104.
  5. Kim WH, Gomez-Izquierdo L, Vilardell F, et al. HER2 Status in Gastric and Gastroesophageal Junction Cancer: Results of the Large, Multinational HER-EAGLE Study.  Appl Immunohistochem Mol Morphol.  2018;26(4):239-245.  doi:10.1097/PAI.0000000000000423.
  6. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab in HER2-Positive Gastric Cancer.  N Engl J Med. 2024;391(14):1360-1362.  doi:10.1056/NEJMc2408121.
  7. Ziihera ® (zanidatamab-hrii) | Official Website for US Healthcare Professionals. Jazz Pharmaceuticals.  https://www.ziiherahcp.com/.  Accessed May 13, 2026.
  8. A Study of Zanidatamab in Combination With Chemotherapy With or Without Tislelizumab in Subjects With HER2-positive Unresectable Locally Advanced or Metastatic Gastroesophageal Adenocarcinoma (GEA). gov.  https://clinicaltrials.gov/study/NCT05152147.  Accessed May 13, 2026.
  9. Tabernero J, Shen L, Elimova E, et al. HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma.  Future Oncol.  2022;18(29):3255-3266.  doi:10.2217/fon-2022-0595.
  10. Elimova E, Rha SY, Shitara K, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): Primary analysis from HERIZON-GEA-01.  J Clin Oncol.  2026;44(2 suppl):LBA285.  doi:10.1200/JCO.2026.44.2_suppl.LBA285.
  11. Zanidatamab With or Without Tislelizumab Yields Clinically Meaningful Survival Benefit in HER2-Positive Advanced Gastroesophageal Adenocarcinoma. ASCO Daily News.  https://dailynews.ascopubs.org/do/zanidatamab-without-tislelizumab-yields-clinically-meaningful-survival-benefit-her2.  Accessed May 13, 2026.

Redefining First-Line Therapy in HER2-Positive Gastroesophageal Adenocarcinoma with Zanidatamab-Based Combinations

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Persistent Unmet Need in HER2-Positive Disease

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 20% of patients with GastroEsophageal Adenocarcinoma (GEA), encompassing gastric, gastroesophageal junction, and esophageal adenocarcinomas, harbor HER2-positive tumors. Despite the incorporation of HER2-directed therapy into first-line management more than a decade ago, long-term outcomes remain suboptimal. With Trastuzumab (HERCEPTIN®) plus chemotherapy, median Progression-Free Survival (PFS) has historically hovered around 10 months, and median Overall Survival (OS) around 20 months.

More recently, the addition of immune checkpoint inhibition has modestly improved outcomes in selected patients. Based on KEYNOTE-811, Pembrolizumab (KEYTRUDA®) plus Trastuzumab and chemotherapy is now standard for PD-L1–positive tumors. However, early relapse, often within the first year, remains common, underscoring the need for more effective HER2-targeted strategies.

Zanidatamab: A Next-Generation HER2-Targeted Approach

Zanidatamab (ZIIHERA®) is a novel, humanized IgG1 bispecific monoclonal antibody designed to bind two non-overlapping extracellular domains of HER2 (ECD2 and ECD4). This biparatopic binding leads to enhanced HER2 receptor clustering, internalization, and downregulation, resulting in more complete inhibition of HER2 signaling compared with single-epitope antibodies. Beyond direct signal blockade, Zanidatamab’s unique binding geometry promotes robust immune-mediated antitumor activity, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP).

Preclinical and clinical data suggest greater antibody saturation on HER2-expressing tumor cells than with Trastuzumab or Pertuzumab (PERJETA®). Zanidatamab’s clinical momentum was reinforced by its FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, highlighting the platform’s broader relevance across HER2-driven gastrointestinal malignancies.

Rationale for Combining HER2 Blockade and Immunotherapy

The HERIZON-GEA-01 trial explored synergy between dual HER2 targeting and immune checkpoint inhibition. Tislelizumab (TEVIMBRA®), a humanized IgG4 anti-PD-1 monoclonal antibody, is engineered to minimize Fc-gamma receptor binding on macrophages, potentially reducing antibody-dependent clearance of activated T cells. Tislelizumab received FDA approval in March 2024 for previously treated metastatic esophageal Squamous Cell Carcinoma, supporting its activity in upper gastrointestinal cancers.

HERIZON-GEA-01: Trial Design and Patient Population

HERIZON-GEA-01 (NCT05152147) is a global, open-label, Phase III study evaluating Zanidatamab-based regimens versus standard Trastuzumab plus chemotherapy in the first-line setting for HER2-positive metastatic GEA (GastroEsophageal Adenocarcinoma).

A total of 914 patients with unresectable, locally advanced, recurrent, or metastatic disease were enrolled between December 2021 and February 2025. More than two-thirds had gastric primaries. Patients had received no prior systemic therapy, HER2-targeted therapy, or immunotherapy in this setting.

Participants were randomized 1:1:1 to:

  • Arm A: Trastuzumab plus chemotherapy (N=308)
  • Arm B: Zanidatamab plus chemotherapy (N=304)
  • Arm C: Zanidatamab plus Tislelizumab plus chemotherapy (N=302)

CAPOX was the chemotherapy backbone in approximately 90% of patients. Zanidatamab-based regimens in Arm B and Arm C were compared with standard Trastuzumab plus chemotherapy in Arm A. The median age was 63 yrs, about 53% were Asian, and 60% had PD-L1 status 1% or more.  The dual Primary endpoints were Progression-Free Survival (PFS) by Blinded Independent Review and Overall Survival (OS).

Efficacy Results: Clinically Meaningful and Practice-Changing

At the interim analysis (data cutoff October 2025; median follow-up 26 months), there was a clear and consistent improvement in PFS with Zanidatamab-based therapy compared with Trastuzumab plus chemotherapy. Median PFS reached 12.4 months with Zanidatamab plus chemotherapy and 12.4 months with Zanidatamab plus Tislelizumab and chemotherapy, compared with 8.1–8.2 months in the Trastuzumab control arm. These gains translated into a 35–37% reduction in the risk of disease progression or death, with Hazard Ratios of 0.65 for Zanidatamab plus chemotherapy and 0.63 for the triplet regimen (both P<0.0001). Importantly, the separation of the PFS curves was maintained over time, highlighting the durability of benefit. The estimated 18-month PFS was 38.0% with Zanidatamab plus chemotherapy and 43.9% with the triplet, versus 20.9% with Trastuzumab-based therapy. These findings mark the first time a majority of patients receiving first-line HER2-targeted therapy remain progression-free at one year, a notable advance in a disease historically characterized by early relapse.

Median OS improved from 19.2 months with Trastuzumab plus chemotherapy to 24.4 months with Zanidatamab plus chemotherapy and 26.4 months with Zanidatamab plus Tislelizumab and chemotherapy. The addition of Tislelizumab yielded a statistically significant 28% reduction in the risk of death (HR 0.72; P =0.004). While OS data for Zanidatamab plus chemotherapy alone were not yet statistically significant at this interim analysis (HR 0.80; P =0.06), the observed survival extension of more than five months suggests meaningful clinical activity, with further analyses planned as follow-up matures. The 2-year OS was 50.3% with Zanidatamab plus chemotherapy and 54.3% with the triplet, versus 38.8% with Trastuzumab-based therapy. The 30-month OS was 42.2% and 43.8%, respectively, compared with 30.0% in the Trastuzumab group.

Notably, the triplet regimen is the first HER2-directed first-line strategy to achieve median Overall Survival exceeding two years in a randomized phase III trial. Further, the benefits in both PFS and OS were consistent across key subgroups, including geographic region and PD-L1 status, an especially notable finding given that checkpoint inhibitor benefit has traditionally been restricted to PD-L1–positive tumors.

Depth and Durability of Response

Zanidatamab-based regimens also produced deeper and more durable responses. Confirmed Objective Response Rates approached 70% in both Zanidatamab arms, with Complete Response rates nearing 20% when Tislelizumab was added. Median duration of response was particularly striking, exceeding 20 months with the triplet regimen and substantially longer than the 8-month duration observed with Trastuzumab plus chemotherapy.

Safety and Tolerability

The safety profiles of Zanidatamab and Tislelizumab were consistent with their known toxicities. Grade ≥3 treatment-related adverse events occurred in approximately 74% of patients receiving Zanidatamab plus chemotherapy and 83% with the addition of Tislelizumab, compared with 74% in the Trastuzumab arm.

Diarrhea was the most common toxicity across all arms, typically occurring early and resolving within several weeks. Rates of HER2-targeted therapy discontinuation due to adverse events were higher with Zanidatamab-based regimens but remained manageable, with no new safety signals identified.

Clinical Implications and Future Directions

HERIZON-GEA-01 represents a landmark study in HER2-positive gastroesophageal adenocarcinoma. It is the first Phase III trial to demonstrate superiority of a novel HER2-targeted agent over Trastuzumab in the first-line metastatic setting, and the first to achieve median PFS beyond one year and median OS beyond two years in this population.

While cross-trial comparisons should be interpreted cautiously, outcomes with Zanidatamab plus Tislelizumab and chemotherapy compare favorably with historical results from KEYNOTE-811. The observation of benefit irrespective of PD-L1 status further broadens the potential impact of this strategy.

As longer follow-up matures and guideline bodies evaluate these data, Zanidatamab, particularly in combination with immunotherapy appears poised to redefine the standard of care for HER2-positive metastatic gastroesophageal adenocarcinoma, offering patients a meaningful extension of disease control and survival.

Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer. Shitara K, Elimova E, Liu T, et al. for the HERIZON-GEA-01 Investigators. N Engl J Med 2026;394:2002-2014.

Advanced Gastroesophageal Cancer: ASCO Guideline Update

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SUMMARY:  Gastroesophageal cancers, including gastric, esophageal, and gastroesophageal junction (GEJ) malignancies are among the most common gastrointestinal cancers worldwide. The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer and 22,530 new cases of esophagus cancer will be diagnosed in 2026, and about 10,740  and 16,290 people respectively, will die of the disease.

The burden of disease varies geographically, with gastric cancer occurring more frequently in East Asian populations, while adenocarcinoma of the gastroesophageal junction has shown a rising incidence in Western countries. Squamous cell carcinoma remains the predominant histologic subtype of esophageal cancer globally, although adenocarcinoma is increasingly common in North America and Europe.

One of the major clinical challenges associated with gastroesophageal cancers is that early-stage disease is frequently asymptomatic. As a result, many patients present with unresectable locally advanced or metastatic disease at the time of diagnosis, contributing to persistently poor long-term survival outcomes. Despite advances in multimodal therapy, the overall 5-year survival rate for advanced gastroesophageal cancer remains low.

The rapidly evolving treatment landscape for advanced gastroesophageal cancer has increasingly emphasized biomarker-driven therapy. In 2023, the American Society of Clinical Oncology published guideline recommendations for first-line treatment strategies based on biomarkers such as PD-L1 and HER2 expression, while also addressing the use of targeted agents and immunotherapy in later treatment lines. More recent updates have incorporated emerging evidence from phase III randomized controlled trials evaluating novel immunotherapeutic combinations, targeted therapies, and precision oncology approaches. These updates also highlight the importance of comprehensive biomarker testing and shared decision-making, particularly for patients whose tumors demonstrate multiple actionable biomarkers.

To support these recommendations, ASCO convened an Expert Panel that conducted a systematic review of contemporary evidence in advanced gastroesophageal malignancies. The updated guideline incorporated findings from multiple newly published and updated Phase III clinical trials involving patients with unresectable locally advanced, recurrent, or metastatic disease. Collectively, these studies reflect the continued transition toward individualized treatment strategies aimed at improving survival outcomes and quality of life for patients with advanced gastroesophageal cancer.

Mandatory Biomarker Testing

1.1. Testing to determine the presence of predictive biomarkers PD-L1, dMMR/MSI-H, CLDN18.2, and HER2 in gastroesophageal adenocarcinoma is recommended, and PD-L1 and dMMR/MSI-H status should be tested for ESCC. Clinicians should consider broad-based NGS testing, which includes pan-tumor biomarkers. The results of predictive biomarker testing should be available as soon as possible to inform treatment decision making.

First-Line Therapy

pMMR/MSS HER2-negative gastric/GEJ and esophageal adenocarcinoma

2.1. For patients with pMMR/MSS HER2-negative gastric/GEJ or esophageal adenocarcinoma with PD-L1 expression ≥1 and absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy in combination with immunotherapy may be recommended.

Qualifying statements for Recommendation 2.1:
Immunotherapy benefit has shown a positive association with higher PD-L1 expression (eg, greater benefit with PD-L1 expression ≥10). Not all possible PD-L1 cutoff scores have been assessed. Therefore, the optimal PD-L1 cutoff score balancing benefits and harms is unknown.
Recommended immunotherapy agents include Pembrolizumab, Nivolumab, or Tislelizumab. These agents are considered to have similar efficacy. Selection of a specific agent should be based on dosing schedule, cost considerations, toxicity, and method of administration.
Taking into account the clinical situation, clinicians should avoid withholding the start of chemotherapy while awaiting biomarker testing results.

2.2. For patients with pMMR/MSS HER2-negative gastric/GEJ adenocarcinoma with PD-L1 expression <1 and positive CLDN18.2 expression, fluoropyrimidine and platinum-based chemotherapy combined with Zolbetuximab should be offered.

2.3. For patients with pMMR/MSS HER2-negative gastric/GEJ adenocarcinoma with PD-L1 expression ≥1, and CLDN18.2 expression positivity, fluoropyrimidine and platinum-based chemotherapy combined with immunotherapy or Zolbetuximab may be offered on a case-by-case basis.

Qualifying statement for Recommendation 2.3:
Choice of therapy should take into consideration degree of PD-L1 expression, toxicity profile, burden of symptoms, and anticipated improvement in symptoms associated with response to treatment, patient comorbidities, and prior medical and treatment history.

2.4. For patients with pMMR/MSS HER2-negative gastroesophageal adenocarcinoma, PD-L1 expression <1, and absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy should be offered.

pMMR/MSS HER2-positive gastric/GEJ adenocarcinoma

3.1. For patients with pMMR/MSS HER2-positive gastric/GEJ adenocarcinoma with PD-L1 expression ≥1, Pembrolizumab plus Trastuzumab should be offered, in combination with fluoropyrimidine- and Oxaliplatin-based chemotherapy.

3.2. For patients with pMMR/MSS HER2-positive gastric/GEJ adenocarcinoma with PD-L1 expression <1, Trastuzumab should be offered in combination with fluoropyrimidine and Oxaliplatin-based chemotherapy.

dMMR/MSI-H gastric/GEJ or esophageal adenocarcinoma or ESCC

4.1. Immunotherapy in combination with fluoropyrimidine and Oxaliplatin-based chemotherapy may be offered.

4.2. Immunotherapy alone is an additional treatment option that may be offered on a case-by-case basis.

ESCC that is locally advanced unresectable and not amenable to definitive chemoradiation, advanced or metastatic

5.1. For patients with pMMR/MSS ESCC and PD-L1 expression ≥1, first-line therapy with immunotherapy in combination with fluoropyrimidine and platinum-based chemotherapy or Nivolumab plus Ipilimumab may be offered.

Qualifying statement for Recommendation 5.1:
Immunotherapy benefit has shown a positive association with higher PD-L1 expression (ie, greater benefit with PD-L1 expression ≥10). Not all possible PD-L1 cutoff scores have been assessed. Therefore, the optimal PD-L1 cutoff score balancing benefits and harms is unknown.

5.2. For patients with pMMR/MSS ESCC with PD-L1 expression <1, first-line therapy with fluoropyrimidine and platinum-based chemotherapy may be offered.

Qualifying statement for Recommendations 2.1 to 5.2:
Chemotherapy alone may be offered to patients who express predictive biomarkers but are not considered candidates for targeted therapy or immunotherapy.

Second or Third Line Therapy

pMMR/MSS HER2-negative gastric/GEJ adenocarcinoma

6.1. For patients with pMMR/MSS advanced gastroesophageal adenocarcinoma whose disease has progressed after first-line therapy, Ramucirumab plus Paclitaxel may be offered.

Qualifying statements for Recommendation 6.1:
Ramucirumab plus FOLFIRI may be an option for patients who have previously been treated with Docetaxel or experienced neurotoxicity with first-line treatment.
Although outside the scope of this review, for patients with gastric or GEJ adenocarcinoma, Trifluridine and Tipiracil may be offered after progression on second-line therapy.
Note for Recommendation 6.1:
CLDN18.2 inhibitor Zolbetuximab has not been studied as second-line therapy for previously treated patients with gastroesophageal adenocarcinoma and is therefore not recommended for this patient population.

pMMR/MSS HER2-positive gastric/GEJ adenocarcinoma

6.2. For HER2-positive patients with gastric/GEJ adenocarcinoma and progressive disease after first-line therapy, Trastuzumab Deruxtecan should be offered.

Note for Recommendation 6.2:
Repeat tumor testing after progression on Trastuzumab is recommended to ensure that the tumor maintains HER2 expression after progression on first-line HER2-directed therapy.

ESCC

6.3. For patients with ESCC whose disease has progressed after first-line combination chemotherapy without immunotherapy and with PD-L1 ≥1, Nivolumab or Tislelizumab may be offered, and for patients with PD-L1 ≥10, Pembrolizumab may be offered.

Note to Recommendation 6.3:
This is expected to be a rare circumstance as patients who are candidates for immunotherapy should receive it as first-line therapy.

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update. Shah MA, Kennedy EB, Deighton D, et al. J Clin Oncol. 2026; 44:1145-1165.

Late Breaking Abstract – ASCO GI: 2026. Identifying a Less Neurotoxic First-Line Backbone in Metastatic Esophagogastric Cancer: Insights from the LyRiCX Trial

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Background

First-line systemic therapy for metastatic or unresectable esophagogastric adenocarcinoma has traditionally relied on platinum-based chemotherapy, most commonly Oxaliplatin-containing regimens combined with fluoropyrimidines. While these regimens have demonstrated meaningful activity, cumulative peripheral neuropathy remains a significant treatment-limiting toxicity. Oxaliplatin-induced neurotoxicity can adversely affect patient quality of life and frequently restricts the duration of therapy or the ability to deliver subsequent lines of treatment.

With the integration of immune checkpoint inhibitors such as Nivolumab into the first-line management of selected patients with advanced gastroesophageal cancers, the choice of chemotherapy backbone has become increasingly relevant. Selecting regimens that maintain antitumor efficacy while minimizing long-term toxicity is particularly important, in a treatment landscape where patients may receive multiple sequential therapies.

The Phase II LyRiCX trial was designed to address this challenge by comparing three first-line chemotherapy backbones in patients with HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, with a focus on balancing efficacy and neurotoxicity.

Study Design and Patient Population

LyRiCX was a multicenter, open-label, randomized Phase II study conducted across medical centers in the Netherlands. Adults with previously untreated, pathologically confirmed HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, with no pre-existing neuropathy more than Grade 1, were eligible for enrollment.

Participants were randomized to one of three chemotherapy regimens:

  • F-Nal-Iri: Nanoliposomal Irinotecan 70 mg/m2, Leucovorin 400 mg/m2, and Fluorouracil 2400 mg/m2 every 2 weeks
  • CapCar: Capecitabine 1000 mg/m2 plus Carboplatin AUC5 every 3 weeks
  • CapOx: Capecitabine 1000 mg/m2 plus Oxaliplatin 130 mg/m2 every 3 weeks

Before the regulatory approval of Nivolumab (OPDIVO®) in this setting (through August 2022), patients were randomized in a 2:2:1 ratio to F-Nal-Iri, CapCar, or CapOx. After immunotherapy became available, treatment allocation incorporated PD-L1 status as measured by the Combined Positive Score (CPS):

  • CPS <5 or contraindication to Nivolumab: randomized to chemotherapy alone (F-Nal-Iri, CapCar, or CapOx; 2:2:1).
  • CPS ≥5: randomized to CapCar or CapOx combined with Nivolumab (2:1).

The trial employed a predefined “pick-the-winner” strategy to determine the most favorable regimen. The co–Primary endpoints were:

  • Incidence of Grade 2–4 neurotoxicity
  • Progression-Free Survival (PFS)

Between September 2019 and January 2025, 320 patients were enrolled. The median age was 65 years and 81% of participants were male. Treatment distribution included:

  • F-Nal-Iri: 83 patients
  • CapCar: 157 patients (including 74 receiving Nivolumab)
  • CapOx: 80 patients (including 36 receiving Nivolumab)

The median PFS follow-up was 24.1 months.

Neurotoxicity Outcomes

The most striking finding from LyRiCX was the dramatic difference in neurotoxicity rates across treatment arms.

Grade 2–4 neurotoxicity occurred in:

  • 0% of patients receiving F-Nal-Iri
  • 2.5% of patients receiving CapCar ± Nivolumab
  • 46.3% of patients receiving CapOx ± Nivolumab

Statistical analysis showed no significant difference in neurotoxicity between CapCar and F-Nal-Iri. In contrast, neurotoxicity was significantly higher with CapOx compared with both alternative regimens (P<0.001 for both comparisons).

These findings highlight the substantial neurologic toxicity burden associated with oxaliplatin-based therapy in this patient population.

Efficacy Results

Despite marked differences in neurotoxicity, efficacy outcomes were broadly comparable across treatment arms.

Median Progression-Free Survival was:

  • 4.5 months with F-Nal-Iri
  • 5.7 months with CapCar ± Nivolumab
  • 5.9 months with CapOx ± Nivolumab

Among patients who did not receive immunotherapy, statistical analyses showed no significant differences in PFS between:

  • F-Nal-Iri and CapCar
  • F-Nal-Iri and CapOx

Similarly, comparisons between CapCar ± Nivolumab and CapOx ± Nivolumab did not demonstrate a statistically significant difference in PFS.

Taken together, these data indicate that non-Oxaliplatin regimens reduce neurotoxicity without significantly compromising disease control

Safety and Adverse Events

Overall safety profiles were generally comparable across treatment groups, and no unexpected safety signals were identified. Grade 3–4 adverse events occurred at similar frequencies among the regimens, with the notable exception of neurotoxicity. Anemia was observed across all treatment arms and appeared somewhat more frequently in the CapCar-based group, although this difference did not translate into a clear safety disadvantage.

Importantly, neurotoxicity remained the dominant differentiating toxicity, occurring at markedly higher rates in the CapOx arm relative to the other regimens.

Clinical Implications

The LyRiCX study provides important insight into the optimization of chemotherapy backbones for metastatic esophagogastric adenocarcinoma. While Oxaliplatin-containing regimens remain widely used, the substantial risk of cumulative neuropathy may have significant downstream consequences for quality of life and treatment sequencing.

Both CapCar and F-Nal-Iri demonstrated dramatically lower rates of clinically significant neurotoxicity while maintaining similar Progression-Free Survival compared with CapOx. Among the evaluated regimens, CapCar emerged as the most practical and favorable option, offering several advantages:

  • Minimal risk of treatment-limiting neuropathy
  • Comparable efficacy outcomes
  • No requirement for central venous access
  • Use of widely available off-patent agents, supporting cost efficiency

As treatment strategies continue to evolve with the integration of immunotherapy and additional targeted therapies, selecting chemotherapy backbones that preserve patient function and enable subsequent treatment options will remain a critical component of clinical decision-making.

Key Takeaway for Oncology Practice:

The LyRiCX trial suggests that Capecitabine plus Carboplatin may represent a highly favorable first-line chemotherapy backbone for HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, providing comparable disease control to Oxaliplatin-based therapy while substantially reducing the risk of neurotoxicity.

Liposomal irinotecan, carboplatin or oxaliplatin (LyRICX) with or without nivolumab in the first-line treatment of metastatic or irresectable esophagogastric adenocarcinoma: A randomized phase 2 study. Kamp D, van Velzen M, Kessels R, et al. J Clin Oncol 44, LBA287(2026): DOI: 10.1200/JCO.2026.44.2_suppl.LBA287 

Late Breaking Abstract – 2026 ASCO GI Symposium: Redefining First-Line Therapy in HER2-Positive Gastroesophageal Adenocarcinoma with Zanidatamab-Based Combinations

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Persistent Unmet Need in HER2-Positive Disease

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 20% of patients with GastroEsophageal Adenocarcinoma (GEA), encompassing gastric, gastroesophageal junction, and esophageal adenocarcinomas, harbor HER2-positive tumors. Despite the incorporation of HER2-directed therapy into first-line management more than a decade ago, long-term outcomes remain suboptimal. With Trastuzumab (HERCEPTIN®) plus chemotherapy, median Progression-Free Survival (PFS) has historically hovered around 10 months, and median Overall Survival (OS) around 20 months.

More recently, the addition of immune checkpoint inhibition has modestly improved outcomes in selected patients. Based on KEYNOTE-811, Pembrolizumab (KEYTRUDA®) plus Trastuzumab and chemotherapy is now standard for PD-L1–positive tumors. However, early relapse, often within the first year, remains common, underscoring the need for more effective HER2-targeted strategies.

Zanidatamab: A Next-Generation HER2-Targeted Approach

Preclinical and clinical data suggest greater antibody saturation on HER2-expressing tumor cells than with Trastuzumab or Pertuzumab (PERJETA®).

Zanidatamab (ZIIHERA®) is a novel, humanized IgG1 bispecific monoclonal antibody designed to bind two non-overlapping extracellular domains of HER2 (ECD2 and ECD4). This biparatopic binding leads to enhanced HER2 receptor clustering, internalization, and downregulation, resulting in more complete inhibition of HER2 signaling compared with single-epitope antibodies. Beyond direct signal blockade, Zanidatamab’s unique binding geometry promotes robust immune-mediated antitumor activity, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP).

Zanidatamab’s clinical momentum was reinforced by its FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, highlighting the platform’s broader relevance across HER2-driven gastrointestinal malignancies.

Rationale for Combining HER2 Blockade and Immunotherapy

The HERIZON-GEA-01 trial also explored synergy between dual HER2 targeting and immune checkpoint inhibition. Tislelizumab (TEVIMBRA®), a humanized IgG4 anti-PD-1 monoclonal antibody, is engineered to minimize Fc-gamma receptor binding on macrophages, potentially reducing antibody-dependent clearance of activated T cells. Tislelizumab received FDA approval in March 2024 for previously treated metastatic esophageal Squamous Cell Carcinoma, supporting its activity in upper gastrointestinal cancers.

HERIZON-GEA-01: Trial Design and Patient Population

HERIZON-GEA-01 (NCT05152147) is a global, open-label, Phase III study evaluating Zanidatamab-based regimens versus standard Trastuzumab plus chemotherapy in the first-line setting for HER2-positive metastatic GEA (GastroEsophageal Adenocarcinoma).

A total of 914 patients with unresectable, locally advanced, recurrent, or metastatic disease were enrolled between December 2021 and February 2025. More than two-thirds had gastric primaries. Patients had received no prior systemic therapy, HER2-targeted therapy, or immunotherapy in this setting.

Participants were randomized 1:1:1 to:

  • Arm A: Trastuzumab plus chemotherapy
  • Arm B: Zanidatamab plus chemotherapy
  • Arm C: Zanidatamab plus Tislelizumab plus chemotherapy

CAPOX was the chemotherapy backbone in approximately 90% of patients. Zanidatamab-based regimens in Arm B and Arm C were compared with standard Trastuzumab plus chemotherapy in Arm A. The dual Primary endpoints were PFS by Blinded Independent Review and OS.

Efficacy Results: Clinically Meaningful and Practice-Changing

At the interim analysis (data cutoff October 2025; median follow-up 26 months), there was a clear and consistent improvement in Progression-Free Survival with Zanidatamab-based therapy compared with Trastuzumab plus chemotherapy. Median PFS reached 12.4 months with Zanidatamab plus chemotherapy and 12.4 months with Zanidatamab plus Tislelizumab and chemotherapy, compared with 8.1–8.2 months in the Trastuzumab control arm. These gains translated into a 35–37% reduction in the risk of disease progression or death, with Hazard Ratios of 0.65 for Zanidatamab plus chemotherapy and 0.63 for the triplet regimen (both P <0.0001). Importantly, the separation of the PFS curves was maintained over time, highlighting the durability of benefit. The 1-year PFS was 38.0% with Zanidatamab plus chemotherapy and 43.9% with the triplet, versus 20.9% and 38.2% respectively with Trastuzumab-based therapy. The 2-year PFS was 31.5% and 20.9%, respectively, compared with 15.6% in the Trastuzumab group. These findings mark the first time a majority of patients receiving first-line HER2-targeted therapy remain progression-free at one year, a notable advance in a disease historically characterized by early relapse.

Median OS improved from 19.2 months with Trastuzumab plus chemotherapy to 24.4 months with Zanidatamab plus chemotherapy and 26.4 months with Zanidatamab plus Tislelizumab and chemotherapy. The addition of Tislelizumab yielded a statistically significant 28% reduction in the risk of death (HR 0.72; P =0.0043). While OS data for Zanidatamab plus chemotherapy alone were not yet statistically significant at this interim analysis (HR 0.80; P =0.0564), the observed survival extension of more than five months suggests meaningful clinical activity, with further analyses planned as follow-up matures. The 2-year OS was 50.3% with Zanidatamab plus chemotherapy and 54.3% with the triplet, versus 42.2% and 43.8% respectively with Trastuzumab-based therapy. The 30-month OS was 38.8% and 43.8%, respectively, compared with 30.0% in the Trastuzumab group.

Notably, the triplet regimen is the first HER2-directed first-line strategy to achieve median Overall Survival exceeding two years in a randomized phase III trial. Further, the benefits in both PFS and OS were consistent across key subgroups, including geographic region and PD-L1 status, an especially notable finding given that checkpoint inhibitor benefit has traditionally been restricted to PD-L1–positive tumors.

Depth and Durability of Response

Zanidatamab-based regimens also produced deeper and more durable responses. Confirmed Objective Response Rates approached 70% in both Zanidatamab arms, with Complete Response rates nearing 20% when Tislelizumab was added. Median duration of response was particularly striking, exceeding 20 months with the triplet regimen and substantially longer than the 8-month duration observed with Trastuzumab plus chemotherapy.

Safety and Tolerability

The safety profiles of Zanidatamab and Tislelizumab were consistent with their known toxicities. Grade ≥3 treatment-related adverse events occurred in approximately 59% of patients receiving Zanidatamab plus chemotherapy and 72% with the addition of Tislelizumab, compared with 60% in the Trastuzumab arm.

Diarrhea was the most common toxicity across all arms, typically occurring early and resolving within several weeks. Rates of HER2-targeted therapy discontinuation due to adverse events were higher with Zanidatamab-based regimens but remained manageable, with no new safety signals identified.

Clinical Implications and Future Directions

HERIZON-GEA-01 represents a landmark study in HER2-positive gastroesophageal adenocarcinoma. It is the first phase III trial to demonstrate superiority of a novel HER2-targeted agent over Trastuzumab in the first-line metastatic setting, and the first to achieve median PFS beyond one year and median OS beyond two years in this population.

While cross-trial comparisons should be interpreted cautiously, outcomes with Zanidatamab plus Tislelizumab and chemotherapy compare favorably with historical results from KEYNOTE-811. The observation of benefit irrespective of PD-L1 status further broadens the potential impact of this strategy.

As longer follow-up matures and guideline bodies evaluate these data, Zanidatamab, particularly in combination with immunotherapy appears poised to redefine the standard of care for HER2-positive metastatic gastroesophageal adenocarcinoma, offering patients a meaningful extension of disease control and survival.

Zanidatamab + chemotherapy ± tislelizumab for first-line HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma: Primary analysis from HERIZON-GEA-01. Elimova E, Rha SY, Shitara K, et al. 2026 ASCO Gastrointestinal Cancers Symposium. Abstract LBA285. Presented January 8, 2026.

Durvalumab + FLOT Establishes New Benchmark in Curative-Intent Therapy for Gastric and GEJ Cancers

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SUMMARY: The American Cancer Society estimates that in the US about 30,300 new gastric cancer cases will be diagnosed in 2025 and about 10,780 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factors for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Despite the intent of cure in resectable gastric and GastroEsophageal Junction (GEJ) cancers, long-term survival remains suboptimal, with fewer than half of patients alive at five years. Current perioperative chemotherapy strategies, such as the FLOT regimen (5-FU, Leucovorin, Oxaliplatin, and Docetaxel), are widely accepted as the standard of care, particularly in Western countries. However, recurrence remains a frequent challenge, underscoring the need for enhanced systemic control.

The global, randomized, double-blind Phase 3 MATTERHORN trial evaluated whether adding the immune checkpoint inhibitor Durvalumab to FLOT could improve clinical outcomes in patients with resectable, locally advanced gastric or GEJ adenocarcinoma. This approach leverages prior success of immunotherapy in metastatic settings, where checkpoint inhibitors are already approved in combination with chemotherapy, but expands the strategy into the curative-intent, perioperative context.

Durvalumab (IMFINZI&reg;) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells.

Trial Design and Treatment Protocol
In this study, a total of 948 treatment-naïve patients with Stage II to IVa resectable gastric or GEJ adenocarcinoma were randomized 1:1 to receive either Durvalumab plus FLOT (N=474) or placebo plus FLOT (N=474).  Treatment consisted of Durvalumab 1500 mg or Placebo every 4 weeks (Q4W) on Day 1 + FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel) on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by Durvalumab 1500 mg or Placebo on Day 1 Q4W for 10 cycles. Participants were enrolled across Asia, Europe, North America, and South America, reflecting the global burden of disease. Key stratification factors included geographic region (Asia vs non-Asia), nodal status, and PD-L1 expression. The median age was approximately 62 years, and around 70% of patients had gastric tumors, with the remainder involving the GEJ. Most patients (70%) had node-positive disease at baseline. Treatment groups were well balanced. Treatment was administered perioperatively, consisting of two neoadjuvant and two adjuvant cycles. Durvalumab or placebo was continued post-chemotherapy as monotherapy for 10 additional cycles. The Primary endpoint was Event-Free Survival (EFS), with Secondary endpoints including Overall Survival (OS), pathologic Complete Response (pCR), and Safety.

Efficacy Findings
At a median follow-up of 31.5 months, the addition of Durvalumab to FLOT significantly improved EFS compared to placebo. The median EFS had not yet been reached in the Durvalumab arm, whereas it was 32.8 months in the placebo group (Hazard Ratio [HR] 0.71; 95% CI, 0.58–0.86; P<0.001), translating to a roughly 30% reduction in the risk of progression, recurrence, or death. Importantly, Durvalumab did not delay surgery or adjuvant therapy initiation. Notably, 24-month EFS rates were higher with Durvalumab (67.4%) compared to placebo (58.5%), indicating a durable benefit. Subgroup analyses consistently favored the Durvalumab combination across clinical and demographic variables, including PD-L1 expression status, nodal involvement, and geographic region, although some subgroups lacked sufficient power for statistical significance.

An early OS analysis, though not yet mature, suggested a favorable trend for the Durvalumab arm (HR 0.78; 95% CI, 0.62–0.97), with median OS not reached in that group compared to 47.2 months in the placebo group.

In addition to EFS, the Durvalumab-containing regimen improved pathologic Complete Response rates as well as Major Pathological Response, suggesting more effective eradication of micrometastatic disease with immunotherapy-enhanced perioperative treatment.

The final Overall Survival results from the MATTERHORN trial were presented at the ESMO Congress 2025. In this definitive analysis, perioperative Durvalumab added to FLOT chemotherapy delivered a statistically significant and clinically meaningful survival advantage over placebo plus FLOT (HR=0.78; 95% CI, 0.63–0.96; P=0.021). Notably, the OS benefit was observed across PD-L1 expression levels, with comparable hazard ratios in both the TAP <1% and TAP ≥1% subgroups, suggesting that the activity of Durvalumab in the perioperative setting is not restricted to PD-L1–positive disease.

Durvalumab also enhanced pathological response metrics. Patients treated with Durvalumab achieved substantially higher nodal negativity rates (ypN0, 58.2% vs 44.8%), indicating deeper locoregional tumor clearance and supporting the biologic premise that checkpoint inhibition can potentiate chemotherapy-mediated cytoreduction. Improvements in Event-Free Survival were consistent across the spectrum of pathological response categories including partial, major, and complete responders, highlighting that meaningful clinical benefit extends beyond patients achieving ypCR.

Safety and Tolerability
The addition of Durvalumab did not compromise surgical outcomes or delay the initiation of adjuvant therapy. The incidence of grade 3/4 adverse events was similar between arms (72% with Durvalumab vs 71% with placebo), as were rates of serious adverse events (48% vs 44%) and treatment-related deaths (5% vs 4%). These findings reinforce the safety of incorporating immunotherapy into the perioperative setting without increasing toxicity burden or interfering with multimodal management.

Biomarker Insights and Future Directions
Approximately 90% of patients were PD-L1–positive in both groups, and 5% had MicroSatellite Instability–High (MSI-H) tumors (lower than the rates of 7% to 9% commonly seen). Although these biomarker-defined subpopulations are known to respond favorably to immunotherapy, their relatively small representation in the study suggests the observed benefits were driven by broader immunomodulatory effects rather than biomarker enrichment alone.

The optimal duration of adjuvant Durvalumab remains an open question. In MATTERHORN, Durvalumab was continued for 10 cycles post-chemotherapy, but further investigation may determine whether shorter courses or biomarker-guided de-escalation could yield similar benefits while minimizing toxicity and cost.

Clinical Implications

The MATTERHORN findings reinforce that integrating Durvalumab into the perioperative FLOT regimen confers durable improvements in both Overall and Event-Free Survival for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. Importantly, the magnitude of benefit remained stable across key clinical and biological subgroups, including PD-L1 status and nodal involvement, underscoring the robustness and generalizability of the treatment effect.

Combined with the earlier JCO publication detailing significant gains in Event-Free Survival, these results strengthen the rationale for incorporating immunotherapy into curative-intent treatment pathways for early-stage upper gastrointestinal cancers. Durvalumab + FLOT is poised to emerge as a new global standard of care, reflecting the broader paradigm shift toward perioperative immune-checkpoint blockade in resectable solid tumors.

Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: A randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Tabernero J, Al-Batran, Wainberg ZA, et al. LBA81- Presented at ESMO Congress 2025, Berlin.

DESTINY-Gastric04: Trastuzumab Deruxtecan Improves Survival Over Ramucirumab Plus Paclitaxel in HER2-Positive Gastric and GEJ Cancers

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SUMMARY: The American Cancer Society estimates that in the US, about 30,300 new cases of Gastric cancer will be diagnosed in 2025 and about 10,780 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of advanced Gastric and GastroEsophageal (GE) junction cancers, overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody, Trastuzumab, as there is Overall Survival (OS) benefit with this combination regimen. Upon progression, Paclitaxel plus Ramucirumab (CYRAMZA®), an anti-VEGFR-2 antibody is recommended as second-line therapy, regardless of HER2 expression, based on OS and Progression Free Survival (PFS) data for this combination regimen. 

Trastuzumab Deruxtecan (T-DXd) (ENHERTU®) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike ado-Trastuzumab emtansine (KADCYLA®), T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure.

The DESTINY-Gastric04 study represents the first confirmatory Phase 3 trial evaluating T-DXd as second-line therapy against the current standard, Ramucirumab plus Paclitaxel, in patients with Trastuzumab-pretreated HER2-positive metastatic disease.

Study Design

DESTINY-Gastric04 is a global, randomized, open-label, Phase 3 trial in which 494 patients (N=494) with HER2-positive metastatic gastric or GEJ adenocarcinoma were randomly assigned in a 1:1 ratio to receive T-DXd 6.4 mg/kg IV every 3 weeks (N=246) or Ramucirumab 8 mg/kg IV days 1 and 15 every 28 days along with Paclitaxel 80 mg/m² IV days 1, 8, 15 every 28 days (N=248). Treatment continued until progression or unacceptable toxicity. No crossover was allowed during the trial. The median patient age was 64 yrs, randomized patients had an ECOG performance status of 0–1, documented HER2 positivity on post-trastuzumab tumor biopsy (IHC 3+ or IHC 2+/ISH+) and no prior history of interstitial lung disease (ILD) or pneumonitis. Approximately, two thirds of the patients had the primary tumor location in the stomach whereas one third had tumors at the GE junction. Patients were stratified based on HER2 status (IHC 3+ vs. 2+/ISH+), geographic region, and time to progression on prior therapy. The Primary end point was Overall Survival (OS). Secondary end points included Progression-Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), and safety.

Efficacy Outcomes

Overall Survival (OS):
The Overall Survival was significantly longer with T-DXd than with Ramucirumab plus Paclitaxel with a 30% reduction in the risk of death. The median OS was 14.7 months with T-DXd versus 11.4 months with Ramucirumab–Paclitaxel (HR=0.70; P=0.004). The 24-month OS rate was 29.0% with T-DXd versus 13.9% with Ramucirumab–Paclitaxel

Progression-Free Survival (PFS):
The median PFS was 6.7 months versus 5.6 months (HR=0.74; P=0.007) and 12-month PFS rate was 22.9% versus 13.6%, favoring T-DXd

Objective Response Rate (ORR):
The confirmed ORR was 44.3% with T-DXd versus 29.1% with Ramucirumab–Paclitaxel (P<0.001) and the median duration of response was 7.4 months versus 5.3 months and higher Disease Control Rate was observed in T-DXd group, reflecting both improved response and stable disease.

Safety Profile

Overall Safety:
Grade 3 or more drug-related Adverse Events were 50.0% in the T-DXd group versus 54.1% in the Ramucirumab–Paclitaxel group. Drug discontinuation due to AEs was 11.5% versus 13.3% respectively.

Interstitial Lung Disease (ILD)/Pneumonitis:
ILD occurred in 13.9% of T-DXd recipients (mostly grade 1–2) and 0.4% experienced grade 3 events versus 1.3% in the Ramucirumab–Paclitaxel group (one grade 5 event)

Clinical Interpretation

The DESTINY-Gastric04 trial reinforces the clinical value of Trastuzumab deruxtecan as a second-line option in HER2-positive gastric and GEJ cancers, demonstrating superior survival outcomes and deeper, more durable responses compared to Ramucirumab plus Paclitaxel. Notably, this benefit was achieved even in the absence of protocol-defined crossover, and despite access to post-trial HER2-targeted agents in some regions. ILD remains a recognized risk associated with T-DXd and mandates proactive monitoring and prompt intervention. Nonetheless, the overall safety profile was manageable and consistent with prior studies.

Key Takeaways for Practice

  • Trastuzumab deruxtecan offers a statistically and clinically significant OS advantage over Ramucirumab plus Paclitaxel in the second-line setting for HER2-positive gastric/GEJ cancer.
  • HER2 re-testing after progression on Trastuzumab is crucial, as HER2 loss is documented and impacts therapeutic eligibility.
  • Safety profiles of both regimens are acceptable, though clinicians must remain vigilant for ILD with T-DXd.
  • These results support the positioning of T-DXd as the preferred second-line therapy in eligible patients who retain HER2 positivity.

Future Directions

Given the survival gains observed in this trial, ongoing studies are evaluating T-DXd in earlier lines of therapy and in combination with immunotherapy. Longer follow-up and Real-World Data will further clarify optimal sequencing strategies and management of T-DXd–associated toxicities.

Late Breaking Abstract – ASCO 2025: Durvalumab Plus FLOT Demonstrates Significant EFS Improvement in Resectable Gastric and GE Junction Cancers: Interim Results from the Phase 3 MATTERHORN Trial

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SUMMARY: The American Cancer Society estimates that in the US about 30,300 new gastric cancer cases will be diagnosed in 2025 and about 10,780 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factor for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Despite the intent of cure in resectable gastric and GastroEsophageal Junction (GEJ) cancers, long-term survival remains suboptimal, with fewer than half of patients alive at five years. Current perioperative chemotherapy strategies, such as the FLOT regimen (5-FU, Leucovorin, Oxaliplatin, and Docetaxel), are widely accepted as the standard of care, particularly in Western countries. However, recurrence remains a frequent challenge, underscoring the need for enhanced systemic control.

The global, randomized, double-blind Phase 3 MATTERHORN trial evaluated whether adding the immune checkpoint inhibitor Durvalumab to FLOT could improve clinical outcomes in patients with resectable, locally advanced gastric or GEJ adenocarcinoma. This approach leverages prior success of immunotherapy in metastatic settings, where checkpoint inhibitors are already approved in combination with chemotherapy, but expands the strategy into the curative-intent, perioperative context.

Durvalumab (IMFINZI&reg;) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells.

Trial Design and Treatment Protocol
In this study, a total of 948 treatment-naïve patients with Stage II to IVa resectable gastric or GEJ adenocarcinoma were randomized 1:1 to receive either Durvalumab plus FLOT (N=474) or placebo plus FLOT (N=474).  Treatment consisted of Durvalumab 1500 mg or Placebo every 4 weeks (Q4W) on Day 1 + FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel) on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by Durvalumab 1500 mg or Placebo on Day 1 Q4W for 10 cycles. Participants were enrolled across Asia, Europe, North America, and South America, reflecting the global burden of disease. Key stratification factors included geographic region (Asia vs non-Asia), nodal status, and PD-L1 expression. The median age was approximately 62 years, and around 70% of patients had gastric tumors, with the remainder involving the GEJ. Most patients (70%) had node-positive disease at baseline. Treatment groups were well balanced. Treatment was administered perioperatively, consisting of two neoadjuvant and two adjuvant cycles. Durvalumab or placebo was continued post-chemotherapy as monotherapy for 10 additional cycles. The Primary endpoint was Event-Free Survival (EFS), with Secondary endpoints including Overall Survival (OS), pathologic Complete Response (pCR), and Safety.

Efficacy Findings
At a median follow-up of 31.5 months, the addition of Durvalumab to FLOT significantly improved EFS compared to placebo. The median EFS had not yet been reached in the Durvalumab arm, whereas it was 32.8 months in the placebo group (Hazard Ratio [HR] 0.71; 95% CI, 0.58–0.86; P<0.001), translating to a roughly 30% reduction in the risk of progression, recurrence, or death. Importantly, Durvalumab did not delay surgery or adjuvant therapy initiation. Notably, 24-month EFS rates were higher with Durvalumab (67.4%) compared to placebo (58.5%), indicating a durable benefit. Subgroup analyses consistently favored the Durvalumab combination across clinical and demographic variables, including PD-L1 expression status, nodal involvement, and geographic region, although some subgroups lacked sufficient power for statistical significance.

An early OS analysis, though not yet mature, suggested a favorable trend for the Durvalumab arm (HR 0.78; 95% CI, 0.62–0.97), with median OS not reached in that group compared to 47.2 months in the placebo group. At 24 months, overall survival was 76% with Durvalumab versus 70% with placebo.

Pathologic and Disease-Free Outcomes
In addition to EFS, the Durvalumab-containing regimen improved pathologic Complete Response rates, achieved in 19% of patients versus 7% in the placebo arm. This significant increase in pCR suggests more effective eradication of micrometastatic disease with immunotherapy-enhanced perioperative treatment.

Disease-Free Survival (DFS) results mirrored those of EFS. The median DFS had not yet been reached in the Durvalumab arm and was 39.8 months in the placebo group (HR 0.70; P=0.012). At 24 months, DFS rates were 75% and 66%, respectively.

Safety and Tolerability
The addition of Durvalumab did not compromise surgical outcomes or delay the initiation of adjuvant therapy. The incidence of grade 3/4 adverse events was similar between arms (72% with Durvalumab vs 71% with placebo), as were rates of serious adverse events (48% vs 44%) and treatment-related deaths (5% vs 4%). These findings reinforce the safety of incorporating immunotherapy into the perioperative setting without increasing toxicity burden or interfering with multimodal management.

Biomarker Insights and Future Directions
Approximately 90% of patients were PD-L1–positive in both groups, and 5% had MicroSatellite instability–High (MSI-H) tumors (lower than the rates of 7% to 9% commonly seen). Although these biomarker-defined subpopulations are known to respond favorably to immunotherapy, their relatively small representation in the study suggests the observed benefits were driven by broader immunomodulatory effects rather than biomarker enrichment alone.

The optimal duration of adjuvant Durvalumab remains an open question. In MATTERHORN, Durvalumab was continued for 10 cycles post-chemotherapy, but further investigation may determine whether shorter courses or biomarker-guided de-escalation could yield similar benefits while minimizing toxicity and cost.

Clinical Implications
The interim findings from MATTERHORN, position Durvalumab plus FLOT as a potential new global standard of care for patients with resectable gastric and GEJ adenocarcinoma. The significant improvements in EFS and pCR, coupled with a manageable safety profile, support integration of immunotherapy into the perioperative management paradigm.

These results also underscore the importance of addressing systemic disease early in the treatment course. As Overall Survival data continue to mature, this study highlights the promising role of immunotherapy in curative-intent settings and may shift practice patterns globally.

Event-free survival (EFS) in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). Janjigian Y, Al-Batran S-E, Wainberg Z, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA5).