3 Things You Should Know About the Evolving Therapeutic Landscape of GEA

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Analyze the latest evidence for currently available treatments used in the management of gastric, gastroesophageal junction, and gastroesophageal adenocarcinomas (GEAs)
• Evaluate emerging clinical trial data for targeted treatment strategies across GEAs
• Implement strategies to mitigate and manage the adverse events associated with targeted therapy for GEA

RELEASE DATE: April 9, 2026

EXPIRATION DATE: April 9, 2027

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1. Read this activity in its entirety.

2. Go to https://www.gotoper.com/sfo-gi-gea-postref to access and complete the posttest.

3. Answer the evaluation questions.

4. Request credit using the drop down menu.

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The addition of targeted therapy or immunotherapy to chemotherapy may improve survival rates over chemotherapy alone in patients with gastroesophageal cancers. The majority of patients express at least 1 biomarker made actionable by the advent of these therapies. Here are 3 things you should know about the evolving therapeutic landscape of gastroesophageal adenocarcinoma (GEA).

1) Adding IO to FLOT improves long-term survival in patients with resectable GEA.

Recurrence rates are high in patients with resectable GEA treated with standard-of-care regimens such as perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel).¹ Adding immunotherapy (IO) to FLOT may improve recurrence rates.

The phase 3 MATTERHORN trial (NCT04592913) randomly assigned 948 patients with resectable gastric or gastroesophageal junctioncancer 1:1 to receive FLOT with or without durvalumab. With a median follow-up of approximately 31.5 months, the median event-free survival (EFS) with durvalumab was not reached (NR; 95% CI, 40.7-NR) vs 32.8 months (95% CI, 27.9-NR) with placebo (HR, 0.71; 95% CI, 0.58-0.86).² The 24-month EFS rates were 67% and 59% with durvalumab and placebo, respectively. A total of 19% (95% CI, 15.75%-23.04%) of patients receiving durvalumab plus FLOT achieved pathologic complete response vs 7% (95% CI, 5.02%-9.88%) of participants in the placebo arm (OR, 3.08; 95% CI, 2.03-4.67; P <.001).

Durvalumab with FLOT also yielded a statistically significant and clinically meaningful improvement in overall survival (OS; HR, 0.78; 95% CI, 0.63-0.96; P = .021) after a median duration of follow-up of approximately 43 months.³ The 36-month OS rates were 68.6% and 61.9% with durvalumab and placebo, respectively. This survival benefit appeared to be consistent across both PD-L1–positive and –negative patient subgroups. Approximately 40% of gastroesophageal tumors are positive for PD-L1 (Figure 1).⁴

The adverse events (AEs) reported in the MATTERHORN study align with known safety profiles of durvalumab and FLOT.¹ Treatment-related grade 3 or 4 AEs occurred in 60% of patients receiving durvalumab plus FLOT and 59% of patients receiving placebo plus FLOT. Durvalumab discontinuation due to AEs occurred in 10% of patients; 6% of patients discontinued the placebo due to AEs. Grade 3 or 4 immune-mediated AEs were reported in 7% of patients in the durvalumab arm and 4% of patients in the placebo arm.

2) New options are under investigation for patients with HER2+ disease.

Trastuzumab plus chemotherapy is a standard-of-care treatment for patients with unresectable locally advanced, recurrent, or metastatic GEA whose tumors are HER2-positive (immunohistochemistry [IHC] 3+ or 2+/in situ hybridization [ISH]+).⁵ The phase 3 HERIZON-GEA-01 study (NCT05152147) compared zanidatamab, a novel bispecific HER2-targeting monoclonal antibody, with and without the anti–PD-1 antibody tislelizumab plus chemotherapy as frontline treatment vs trastuzumab plus chemotherapy in 914 patients with HER2-positive, unresectable, locally advanced, recurrent, or metastatic GEA (Figure 2).⁶ Both experimental arms (B and C) provided statistically significant improvements in progression-free survival (PFS), while the zanidatamab plus tislelizumab arm (arm C) also demonstrated a statistically significant improvement in OS.

The median PFS in arm A was 8.1 months (95% CI, 7.0-8.9) vs 12.4 months (95% CI, 9.8-14.5) in arm B (HR, 0.65; 95% CI, 0.52-0.81; P < .0001) and 12.4 months (95% CI, 9.8-18.5) in arm C (HR, 0.63; 95% CI, 0.51-0.78; P < .0001).⁶ The median OS in arm A was 19.2 months (95% CI, 16.8-21.8) vs 24.4 months (95% CI, 20.4-30.0) in arm B (HR, 0.80; 95% CI, 0.64-1.01; P = .0564) and 26.4 months (95% CI, 21.5-30.3) in arm C (HR, 0.72; 95% CI, 0.57-0.90; P = .0043).

Treatment-related grade 3 or greater AEs occurred in 71.8% of patients in arm C, 59.0% of patients in arm B, and 59.6% in arm A. Diarrhea is an AE of particular concern with the combination of zanidatamab plus chemotherapy and occurred at grade 3 or greater in 24.5%, 20.0%, and 12.9% of patients in the C, B, and A arms, respectively. Discontinuation of HER2-targeting therapy occurred in 11.9% of patients in arm C and 8.5% of patients in arm B vs 2.3% of patients in arm A.

3) New actionable targets in gastrointestinal cancers provide patients with additional options.

Up to 35% of patients with gastric or GEA adenocarcinoma express high levels of claudin 18.2 (CLDN18.2), a component of intercellular tight junctions that is not routinely expressed in normal tissue outside gastric mucosa.^4,7 Zolbetuximab, a CLDN18.2-targeting monoclonal antibody, in combination with chemotherapy, is a category 1 preferred first-line therapy for patients with unresectable locally advanced, recurrent, or metastatic CLDN18.2-high (75% or higher by IHC), HER2-negative gastric or esophagogastric junction adenocarcinoma and a category 2A therapy for those with esophageal adenocarcinoma.⁵ Approval for zolbetuximab was based on survival outcomes from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials that assessed mFOLFOX6 or CAPOX plus zolbetuximab or placebo.⁸ In the combined analysis, the median PFS in the zolbetuximab arm was 9.2 months (95% CI, 8.4-10.4) vs 8.2 months (95% CI, 7.6-8.4) with placebo (HR, 0.71; 95% CI, 0.61-0.83). The median OS in the zolbetuximab arm was 16.4 months (95% CI, 15.0-17.9) vs 13.7 months (95% CI, 12.3-15.3) in the placebo arm (HR, 0.77; 95% CI, 0.67-0.89). In the zolbetuximab and placebo arms, nausea was reported in 76.0% and 56.2% of patients, and vomiting was reported in 66.8% and 34.2%, respectively. Figure 3 presents a recommended protocol for the management of nausea and vomiting related to zolbetuximab treatments.⁹

Key References

3. Tabernero J, Al-Batran SE, Wainberg ZAA, et al. 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. Ann Oncol. 2025;36(suppl 2):S1623-S1624. doi:10.1016/j.annonc.2025.09.096

6. 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(suppl 2):LBA285. doi:10.1200/JCO.2026.44.2_suppl.LBA285

8. Shitara K, Shah MA, Lordick F, et al. Zolbetuximab in gastric or gastroesophageal junction adenocarcinoma. N Engl J Med. 2024;391(12):1159-1162. doi:10.1056/NEJMc2409512

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CME Posttest Questions

1. In the phase 3 MATTERHORN study, addition of durvalumab to perioperative FLOT improved which of the following outcomes in patients with resectable gastric or gastroesophageal junction adenocarcinoma?

A. Pathological complete response (pCR) rate only

B. pCR and event-free survival (EFS), but not overall survival (OS)

C. pCR, EFS, and OS

D. No significant improvement in any of these outcomes

2. In the randomized phase 3 HERIZON-GEA01 study enrolling patients with newly diagnosed, HER2-positive gastroesophageal adenocarcinoma, treatment with zanidatamab-chemotherapy with or without tislelizumab improved OS compared with which of the following treatments?

A. Trastuzumab-chemotherapy

B. Chemotherapy

C. Trastuzumab-pembrolizumab-chemotherapy

D. No OS improvement observed

3. A patient with metastatic gastric adenocarcinoma with positive CLDN18.2 expression is undergoing treatment with zolbetuximab plus chemotherapy. They experience nausea and 1 episode of vomiting, both alleviated by slowing the rate of infusion. During the second infusion at the same reduced rate of infusion, the patient begins to experience nausea but no vomiting (yet). What is the next best step at this time?

A. Continue infusion at this rate unless the patient experiences vomiting

B. Stop the infusion until nausea resolves and resume at the same rate

C. Stop the infusion until nausea resolves and resume at a slower rate

D. Stop the infusion and discontinue zolbetuximab

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