New data from MATTERHORN, HERIZON-GEA-01, and DESTINY-Gastric04 are redefining treatment standards in gastric and gastroesophageal cancers. At the 2026 Hawaii Gastrointestinal Cancers Summit, Dr. Emerson Y. Chen outlined how perioperative nivolumab plus FLOT improves survival in resectable disease and how next-generation HER2-directed therapies, including zanidatamab-based combinations and trastuzumab deruxtecan (T-DXd), are reshaping first- and second-line treatment strategies for advanced HER2-positive gastroesophageal adenocarcinoma.

Dr. Emerson Y. Chen is a gastrointestinal oncologist specializing in caring for patients with cancers of the pancreas, liver, bile duct, esophagus, stomach, colon, and rectum at Oregon Health & Science University. At the 2026 Hawaii Gastrointestinal Cancers Summit, Dr. Chen presented a comprehensive overview of emerging treatment strategies in upper gastrointestinal cancers, with particular focus on perioperative chemoimmunotherapy in resectable gastroesophageal adenocarcinoma and HER2-directed therapies in advanced disease.

Take-Home Message

1. Durvalumab with FLOT (D-FLOT) is superior to FLOT alone asperioperative therapy for resectable gastroesophageal adenocarcinoma. Matterhorn: practice-changing
2. Zanidatamab with tislelizumab and chemotherapy doublet (platinum +fluoropyrimidine) combination is superior to 1st line trastuzumab-basedcombination for HER2+ metastatic gastroesophageal adenocarcinoma. HERIZON-GEA-01: likely practice-changing
3. Fam-trastuzumab-deruxtecan-nxki (T-DXd) is superior to 2nd linepaclitaxel/ramucirumab for HER2+ metastatic gastroesophagealadenocarcinoma. DESTINY-Gastric04: practice-affirming

The transcript report below has not been reviewed by the speaker and may contain errors.

Overview of Upper Gastrointestinal Cancers and Key Trials

Upper gastrointestinal (GI) cancers encompass esophageal cancer, gastroesophageal (GE) junction cancer, and gastric cancer. Historically, GE junction tumors have been grouped into either the esophageal or gastric cancer treatment paradigm, and esophageal cancer itself includes both adenocarcinoma and squamous cell histologies. Three pivotal studies were reviewed: one addressing localized adenocarcinoma in the perioperative setting, and two examining HER2-positive advanced disease — one in the first-line and one in the second-line space.

As a high-level summary, the MATTERHORN study demonstrated that nivolumab (OPDIVO) added to FLOT perioperative chemotherapy is superior to FLOT chemotherapy alone for resectable gastroesophageal adenocarcinoma. In the first-line HER2-positive metastatic setting, zanidatamab plus tislelizumab plus chemotherapy is superior to trastuzumab-based regimens. In the second-line HER2-positive setting, trastuzumab deruxtecan (T-DXd) is superior to paclitaxel plus ramucirumab (the "Rainbow" regimen) in HER2-positive metastatic gastric cancer.

The MATTERHORN Study: Perioperative Chemoimmunotherapy for Resectable Gastroesophageal Adenocarcinoma

Background and Study Rationale

Prior to the MATTERHORN study, a number of trials evaluated chemoradiation versus chemotherapy in the perioperative setting. The field had long debated whether perioperative chemotherapy or chemoradiotherapy offered superior survival outcomes. Evidence ultimately established that perioperative chemotherapy achieves better survival benefit than chemoradiation in adenocarcinoma. However, these studies were conducted before the era of immunotherapy. As a result, the opportunity to incorporate immunotherapy into the perioperative chemotherapy framework had not been fully explored. While immunotherapy had been integrated into chemoradiation protocols, such as in the CheckMate 577 trial, an equivalent adjuvant approach had not yet been established within a perioperative chemotherapy backbone. The MATTERHORN study was designed to address this gap.

Study Design

MATTERHORN was a global, randomized, placebo-controlled trial enrolling patients with resectable GE junction and gastric adenocarcinoma. All patients received perioperative FLOT chemotherapy (fluorouracil, leucovorin, oxaliplatin, and docetaxel); half were randomized to receive nivolumab, and the other half received a placebo. The trial included sites in the United States, including Washington and California, as well as international centers. Patients received four cycles of FLOT before surgery, and four cycles after, with nivolumab continued for approximately one year. The primary endpoint was event-free survival (EFS), which incorporated disease progression prior to surgery. Secondary endpoints included overall survival and response rate.

Eligibility Criteria

This was strictly an adenocarcinoma study; squamous cell carcinoma, neuroendocrine histology, and stage I disease were excluded. Patients were required to have at least T2 or node-positive disease by clinical staging. While the protocol technically did not include esophageal adenocarcinoma, the histological principles are broadly applicable across the upper GI adenocarcinoma spectrum. Both MSI-high and MSS patients were eligible, as were patients who were PD-L1 negative — making this an all-comers population, balanced between arms.

Baseline Characteristics and Treatment Delivery

Baseline characteristics were well-balanced between the two arms. Approximately two-thirds of patients had gastric cancer, and one-third had GE junction cancer. Approximately one quarter had T4 disease, and a large proportion were clinical N-positive, representing a population at meaningful risk for recurrence. Regarding treatment delivery, 96% of patients completed all pre-operative FLOT therapy, and 80% achieved an R0 resection following surgery. Notably, only approximately 60% of patients were able to complete all post-operative therapy, a common challenge in the perioperative setting.

Efficacy Results

The primary endpoint of event-free survival was met, demonstrating a statistically significant improvement. The median EFS was not reached in the nivolumab arm versus 32.8 months in the placebo arm; the two-year EFS rate was 67% versus 58%, with a hazard ratio of 0.71. Subgroup analyses demonstrated a consistent EFS benefit across most subgroups, including patients with PD-L1-negative tumors and those with MSS disease. The pathologic complete response (pCR) rate was 19% in the nivolumab arm versus 7% in the placebo arm. Overall survival curves were initially closely aligned but diverged over time, and the final overall survival analysis, reported at ESMO, similarly demonstrated separation favoring the nivolumab arm.

Safety Profile

Given that both arms received FLOT, the most common adverse events — including diarrhea, nausea, neutropenia, and alopecia — were attributable to the chemotherapy backbone and occurred at comparable rates across arms. Immune-mediated adverse events, including colitis and pneumonitis, were observed in the nivolumab arm, as expected with checkpoint inhibitor therapy.

Clinical Takeaway

MATTERHORN establishes nivolumab plus FLOT as superior to FLOT alone for event-free survival and overall survival in resectable gastroesophageal adenocarcinoma. Importantly, the EFS benefit was observed regardless of MSI or PD-L1 status. This study supports the application of perioperative chemoimmunotherapy for patients with stage II or III gastric or GE junction adenocarcinoma who are candidates for surgery.

Zanidatamab Plus Tislelizumab Plus Chemotherapy: First-Line HER2-Positive Advanced Gastroesophageal Cancer

Background and Agent Overview

Zanidatamab is a dual HER2-targeted bispecific antibody. The trial combined zanidatamab with tislelizumab, an anti-PD-1 checkpoint inhibitor, along with chemotherapy (either capecitabine/oxaliplatin or fluorouracil/oxaliplatin). This was a three-arm, global randomized study enrolling patients with HER2-positive disease in the first-line recurrent or metastatic setting. Notably, US sites were not included, as the preferred first-line regimen in the United States at the time of the trial was trastuzumab plus chemotherapy plus a PD-1 inhibitor, based on the ToGA and KEYNOTE-811 data. Despite this, the trial design allows meaningful evaluation of the contributions of both immunotherapy and dual HER2 blockade.

Trial Design

The three treatment arms were: Arm A, chemotherapy plus trastuzumab (control); Arm B, chemotherapy plus zanidatamab; and Arm C, zanidatamab plus tislelizumab plus chemotherapy. This design enables cross-arm assessment of both the anti-HER2 contribution of zanidatamab versus trastuzumab and the immunotherapy contribution of tislelizumab.

Efficacy Results

Progression-free survival (PFS) data demonstrated that zanidatamab plus tislelizumab plus chemotherapy achieved superior PFS compared to trastuzumab-based chemotherapy. When comparing the contribution of zanidatamab without immunotherapy (Arm B) to the control arm, there was also a PFS improvement, though specific time-point values were modestly lower than the triplet arm. Most critically, overall survival was significantly improved with zanidatamab plus tislelizumab plus chemotherapy versus trastuzumab plus chemotherapy, with median overall survival of 26 months versus 19 months and a hazard ratio of 0.72.

Safety and Tolerability

Diarrhea was a notable toxicity in the zanidatamab-containing arms, necessitating prophylactic use of loperamide. This is attributable both to the quadruple regimen including immunotherapy and to zanidatamab's known mechanism-related gastrointestinal effects. Thyroid-related adverse events were also observed, consistent with checkpoint inhibitor toxicity. Standard precautions applied to HER2-directed and immunotherapy combinations — including monitoring for cardiotoxicity, hepatotoxicity, and pneumonitis — remain applicable.

Clinical Takeaway

Zanidatamab plus tislelizumab plus chemotherapy demonstrated a meaningful overall survival benefit compared to conventional trastuzumab-based therapy, establishing it as an appropriate first-line treatment option for HER2-positive gastroesophageal adenocarcinoma. Importantly, this benefit was observed regardless of PD-L1 status — a meaningful distinction given that trastuzumab plus chemotherapy plus pembrolizumab is generally reserved for PD-L1-positive tumors. Full publication data, as well as regulatory and guideline decisions, are anticipated.

DESTINY-Gastric04: T-DXd Versus Paclitaxel Plus Ramucirumab in Second-Line HER2-Positive Gastric Cancer

Background

Trastuzumab deruxtecan (T-DXd) had previously been evaluated in the DESTINY-Gastric01 study, which included both second-line and third-line patients with HER2-positive gastric and GE junction cancer. Prior to DESTINY-Gastric04, the FDA had granted approval for T-DXd in this setting regardless of line of therapy. However, clinical uncertainty remained regarding whether T-DXd was best deployed in the second or third line. DESTINY-Gastric04 was designed specifically to address the second-line setting.

Study Design

Patients with HER2-positive disease who had progressed on first-line HER2-directed therapy, typically trastuzumab-based, were randomized to receive either T-DXd or paclitaxel plus ramucirumab (the Rainbow regimen). HER2 positivity was confirmed as IHC 2+ with FISH-positive or IHC 3+. Baseline characteristics were balanced between arms, and a subset of patients had liver metastases and prior treatment with platinum-based therapy.

Efficacy Results

T-DXd demonstrated superior overall survival compared to paclitaxel plus ramucirumab, with a median OS of 14.7 months versus 11.4 months and a hazard ratio of 0.74. PFS results were consistent with the OS data. The 12-month PFS rate on the T-DXd arm was notably driven by a subset of patients who appeared to derive prolonged benefit from continued HER2-directed therapy — 12-month PFS of [unclear] versus 14% in the comparator arm. Objective response rate was 44% with T-DXd versus 24% with paclitaxel plus ramucirumab, and duration of response was 7.4 versus 5.3 months.

Safety Profile

Patients receiving T-DXd were more likely to experience fatigue and nausea/vomiting. Interstitial lung disease (ILD), a class effect known with T-DXd, was observed and warrants ongoing monitoring. ILD events were predominantly grade 1. The comparator arm carried toxicities associated with paclitaxel and ramucirumab, including hypertension and peripheral neuropathy.

Clinical Takeaway

DESTINY-Gastric04 confirms that for patients with HER2-positive gastric or GE junction cancer who progress on first-line trastuzumab-based therapy and retain HER2 positivity, T-DXd offers superior outcomes compared to the conventional second-line rainbow regimen (paclitaxel plus ramucirumab). The data support prioritizing HER2-directed therapy in the second-line setting for eligible patients.

Summary

Three practice-shaping trials across the gastroesophageal cancer treatment continuum were reviewed at the 2026 Hawaii Gastrointestinal Cancers Summit. In the resectable setting, MATTERHORN establishes nivolumab plus FLOT as a new perioperative standard for stage II–III gastric and GE junction adenocarcinoma, with event-free and overall survival benefit observed across PD-L1 and MSI subgroups. In the first-line advanced HER2-positive setting, zanidatamab plus tislelizumab plus chemotherapy offers a survival advantage over trastuzumab-based therapy, independent of PD-L1 status. In the second-line HER2-positive setting, DESTINY-Gastric04 confirms that T-DXd is superior to the paclitaxel plus ramucirumab regimen, reinforcing the value of continued HER2 targeting in patients whose tumors remain HER2-positive after first-line therapy.