Tag: Gastric and GE Junction Cancer

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

RR

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

RR

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

RR

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

RR

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

RR

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).

VYLOY® (Zolbetuximab-clzb)

RR

The FDA on October 18, 2024, approved VYLOY®, a Claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with Fluoropyrimidine- and Platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic Human Epidermal growth factor Receptor 2 (HER2)-negative Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. VYLOY® is a product of Astellas Pharma US, Inc.

FDA Approves VYLOY® with Chemotherapy for Biomarker Positive Gastric or GEJ Adenocarcinoma

RR

SUMMARY: The FDA on October 18, 2024, approved Zolbetuximab-clzb (VYLOY®), a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with fluoropyrimidine and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic Human Epidermal growth factor Receptor 2 (HER2)-negative Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. The FDA also approved the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to identify patients with Gastric or GEJ adenocarcinoma who may be eligible for treatment with Zolbetuximab.

The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 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.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients with metastatic disease is approximately 6%. These patients frequently are treated with platinum containing chemotherapy along with a fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed on the surface of the cancer cells and accessible to targeted therapies with antibodies. CLDN18.2 is expressed in 30-40% of Gastric adenocarcinomas.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. This study met the Primary endpoint and the median Progression Free Survival (PFS) was 10.6 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The Overall Survival (OS) was also significantly improved (18.23 versus 15.54 months, HR=0.75; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population.

GLOW trial is a global, multi-center, double-blind, randomized Phase III study, conducted to assess the efficacy and safety of Zolbetuximab plus CAPOX (N=254) versus placebo plus CAPOX (N=253) as a first-line treatment for patients with CLDN18.2-positive/HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. In this trial, 507 eligible patients were randomly assigned 1:1 to receive Zolbetuximab 800 mg/m2 IV as a loading dose on cycle 1, day 1, of the first 21-day cycle, followed by 600 mg/m2 IV on day 1 of subsequent cycles, along with CAPOX regimen consisting of Capecitabine 1000 mg/m2 orally twice daily on days 1-14 of each cycle and Oxaliplatin 130 mg/m2 IV on day 1 of each cycle, or the same CAPOX regimen plus placebo. CAPOX was given for 8 cycles in both treatment groups and patients could continue beyond 8 cycles with Zolbetuximab or placebo plus Capecitabine at investigator’s decision, and treatment continued until disease progression or unacceptable toxicities. CLDN18.2 positive was defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18.2 staining and patients were stratified by region (Asia versus non-Asia), number of organs with metastases, and prior gastrectomy (yes versus no). The median patient age was 60 years, majority of patients were male from Asia, not having prior gastrectomy, having stomach as the primary tumor site, and having an ECOG performance status of 1. Basline characteristics were similar in both treatment groups. The Primary end point was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), and Safety.

At a median follow up of 12.6 months, the combination of Zolbetuximab plus CAPOX significantly improved PFS, and the median PFS was 8.2 months, compared with 6.8 months for those given placebo plus CAPOX (HR=0.68; P=0.0007). The median OS was 14.4 months versus 12.2 months respectively (HR=0.77; P=0.01). The PFS and OS benefits were sustained at 24 months, and the benefits were observed across most subgroups. The most common side effects were nausea and vomiting and the authors recommended increasing the infusion duration time, or splitting the dose over a 2 day period, in addition to the administration of prophylactic antiemetics.

The researchers concluded that the addition of first-line Zolbetuximab to CAPOX significantly improved PFS and OS in patients with CLDN18.2-positive, HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. The authors added that Zolbetuximab plus CAPOX represents a potential new first-line therapy for this patient group. Taken together, both GLOW and SPOTLIGHT trials showed a similar reduction in the risk of disease progression or death and a similar reduction in the risk of death with the addition of Zolbetuximab to chemotherapy, when compared with placebo plus chemotherapy.

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Shah MA, Shitara K, Ajani JA, et al. Nature Medicine 2023; 29:2133–2141

Bispecific Immune Checkpoint Inhibitor Improves Survival in Gastric and GEJ Cancer Regardless of PD-L1 Status

RR

SUMMARY: The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 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.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 15%. These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

Cadonilimab (AK104) is a human, bispecific IgG1 antibody with high binding avidity especially to high density of PD-1 and CTLA-4 due to its tetravalent design, and could simultaneously bind different cells expressing PD-1 and CTLA-4, respectively. By effective blocking both PD-1 and CTLA-4 pathways, Cadonilimab activates T cells by increasing interleukin-2 (IL-2) and interferon-gamma secretion to similar extent, as compared with anti-PD-1 and anti-CTLA-4 combination.

COMPASSION-15 is a double-blind, randomized, multicenter, Phase III trial that enrolled 610 patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. They were randomly assigned 1:1 to receive either Cadonilimab in combination with Oxaliplatin and Capecitabine chemotherapy, or placebo plus the same chemotherapy. Chemotherapy with Oxaliplatin and Capecitabine was given every 3 weeks for up to six cycles. Capecitabine was administered at 1000 mg/m2 orally twice daily on days 1 through 14 every 3 weeks and Oxaliplatin IV at 130 mg/m2 every 3 weeks. Cadonilimab 10 mg/kg IV or placebo was given on day 1 of each cycle every 3 weeks. Following the 6 cycles, patients then received Cadonilimab 10 mg/kg IV monotherapy or placebo every 3 weeks. Stratification factors included ECOG performance status (0 versus 1), PD-L1 expression (CPS 5% or more, or less than 5%), and the presence or absence of liver metastasis. The Primary endpoint was Overall Survival (OS) in the Intent to Treat (ITT) population.

The researchers herein presented the interim analysis data of COMPASSION-15 trial. The results revealed a significant improvement in Overall Survival with Cadonilimab combination therapy compared to placebo. The median OS was 15.0 months with Cadonilimab combination, compared with 10.8 months for those in the placebo arm (HR=0.60; P<0.001). The 18-month Overall Survival rate was 45.8% in the Cadonilimab group versus 25.5% in the placebo group.

Subgroup analysis based on PD-L1 expression levels (CPS 5% or more, or less than 5%) also demonstrated favorable outcomes with Cadonilimab across all strata. Among patients with a PD-L1 CPS of less than 5%, Cadonilimab combination achieved a median OS of 14.8 months, compared with 11.1 months in the placebo group. The 18-month OS rates were 44.1% compared with 27.5%, respectively.

Progression-Free Survival (PFS), another critical measure of treatment efficacy, showed consistent benefits with Cadonilimab combination compared to placebo plus chemotherapy, irrespective of PD-L1 expression. Median PFS was 7 months versus 5.3 months in the ITT population, with similar trends observed in CPS 5% or more, and less than 5% subgroups.

The safety analysis revealed no new safety signals. However, Grade 3 or higher treatment-related adverse events were more commonly reported in the combination therapy group compared to the placebo group. Treatment-related adverse events leading to therapy discontinuation were also more frequent in the Cadonilimab group.

It was concluded from this study that Cadonilimab is the first PD-1/CTLA-4 bispecific antibody to demonstrate substantial improvements in Overall Survival and Progression-Free Survival benefit in combination with chemotherapy, offering a potential new standard of care for patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. This study represents a significant milestone in the quest for improved first-line treatments for gastric and GEJ cancers, even for patients with low PD-L1 expression tumors.

Cadonilimab plus chemotherapy versus chemotherapy as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (COMPASSION-15): A randomized, double-blind, phase 3 trial. Ji J, Shen L, Li Z, et al. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA.