Practice-Changing Updates in Upper Gastrointestinal Cancers From ASCO GI 2026

Vaishali Deenadayalan, MD Roswell Park Comprehensive Cancer Center

Key Points

• Zanidatamab-based therapy demonstrated superior efficacy over trastuzumab-based regimens in first-line HER2–positive gastroesophageal adenocarcinoma, positioning it as a potential new standard of care pending regulatory approval.

• Claudin 18.2 (CLDN18.2) has emerged as a clinically actionable biomarker, with zolbetuximab-containing combination regimens showing meaningful activity in HER2–negative gastric and gastroesophageal junction (GEJ) cancers.

• Combination strategies integrating targeted therapy, chemotherapy, and immune checkpoint blockade are redefining first-line treatment paradigms in biomarker-selected upper gastrointestinal (GI) malignancies.

Recent Advances Redefining Upper GI Cancer Care

Over the last several years, the treatment landscape for upper GI cancers spanning esophageal, gastroesophageal, and gastric adenocarcinoma has rapidly evolved. Key milestones include the approval of zolbetuximab in CLDN18.2–positive disease, the integration of durvalumab following the MATTERHORN study, and the recent HERIZON-GEA-01 data presented at the 2026 ASCO Gastrointestinal Cancers Symposium (ASCO GI 2026). Together, these advances highlight a broader paradigm shift toward next-generation antibody platforms and biomarker-selected triplet regimens, underscoring the growing potential for durable survival benefit in this historically challenging disease space.

These trends were thoughtfully explored during the Oncology Brothers panel discussion with three GI experts: Richard Dunne, MD, MS, of University of Rochester; Nicholas Hornstein, MD, PhD, of Northwell Health; and Timothy Brown, MD, of UT Southwestern Medical Center.

HERIZON-GEA-01: Redefining HER2–Positive First-Line Therapy

The phase 3 HERIZON-GEA-01 trial evaluated zanidatamab, a bispecific anti-HER2 antibody targeting two distinct HER2 epitopes, in combination with chemotherapy with or without the PD-1 inhibitor tislelizumab, compared with standard trastuzumab-based chemotherapy in patients with previously untreated, locally advanced or metastatic HER2–positive gastroesophageal adenocarcinoma.¹

Zanidatamab-based regimens demonstrated a significant improvement in progression-free survival (PFS), with a median PFS of 12.4 versus 8.1 months in the control arm. Median overall survival (OS) reached 26.4 months in patients receiving zanidatamab plus tislelizumab and chemotherapy. While OS data for the zanidatamab plus chemotherapy arm were not statistically significant at the time of analysis, a favorable survival trend was observed. The most common serious adverse events reported in the zanidatamab arms included diarrhea, hypokalemia, and anemia.

Collectively, these results strongly suggest that zanidatamab has the potential to replace trastuzumab as the preferred HER2-targeted backbone in the first-line treatment of HER2–positive gastroesophageal adenocarcinoma.

ILUSTRO: Expanding Targeted Therapy in HER2–Negative Disease

For patients with HER2–negative gastric and GEJ adenocarcinoma, attention has increasingly focused on CLDN18.2, a tight-junction protein aberrantly expressed in a subset of tumors. The phase 2 ILUSTRO study evaluated zolbetuximab, a CLDN18.2-targeting monoclonal antibody, in combination with modified FOLFOX-6 (leucovorin, fluorouracil, and oxaliplatin) and nivolumab in patients with HER2–negative locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma expressing CLDN18.2.² At ASCO GI 2026, the combination demonstrated a median PFS of 14.8 months, with outcomes strongly influenced by biomarker expression.

Patients with high CLDN18.2 expression achieved a median PFS of 18 months compared with 6.7 months in those with intermediate expression. Within the CLDN18.2-high subgroup, PD-L1 combined positive score of 1 or more was associated with longer PFS (23.6 vs 12.1 months). Objective responses were frequent and durable, with an overall response rate (ORR) of 62.1%, rising to 68.1% in CLDN18.2-high tumors. OS data were immature at the time of analysis. 

These findings reinforce CLDN18.2 as a therapeutically actionable biomarker, particularly in biomarker-enriched combination regimens incorporating immunotherapy.

LUCERNA: Phase 3I Validation of CLDN18.2-Directed Therapy

Building upon earlier phase studies, the phase 3 LUCERNA trial is evaluating zolbetuximab in combination with pembrolizumab and chemotherapy versus placebo plus pembrolizumab and chemotherapy as first-line treatment for CLDN18.2–positive, PD-L1–positive, HER2–negative locally advanced unresectable or metastatic gastric and GEJ adenocarcinoma,³ The primary end point is OS, with key secondary end points including PFS and ORR per RECIST v1.1. Enrollment is ongoing across global sites. If positive, LUCERNA could establish zolbetuximab-based triplet therapy as a new first-line standard in this molecular subset.

Moving the Field Forward

ASCO GI 2026 marked a pivotal moment in the management of upper GI cancers. In tumors with overlapping PD-L1 positivity and CLDN18.2 expression, current first-line options include zolbetuximab, approved in October 2024, and immunotherapy with chemotherapy backbones. 

During the panel discussion, experts were divided on optimal sequencing strategies. Some favored prioritizing immunotherapy upfront, citing the prolonged infusion times and toxicity associated with zolbetuximab, whereas others supported the use of zolbetuximab in the first-line setting to potentially reserve immunotherapy for later lines of treatment. 

Results from ILUSTRO and the ongoing LUCERNA trial are expected to further inform treatment sequencing, moving the field toward biomarker-driven, combination-based strategies that define first-line therapy in upper GI cancers.

References

1. Zanidatamab and Chemotherapy Can Slow Cancer Growth, Extend Survival in Some People With Gastroesophageal Adenocarcinoma. ASCO. Published January 6, 2026. www.asco.org/about-asco/press-center/news-releases/zanidatamab-and-chemotherapy-can-slow-cancer-growth?cid=DM26684&bid=574040902
2. Shitara K, Yamaguchi K, Shoji H, et al. Phase 2 trial of zolbetuximab in combination with mFOLFOX6 and nivolumab in patients with advanced or metastatic claudin 18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas. J Clin Oncol. 2026;44(suppl 2):LBA284.
3. Shitara K, Enzinger PC, Lordick F, et al. Zolbetuximab + pembrolizumab and chemotherapy as first-line treatment for patients with CLDN18.2-positive, HER2-negative, PD-L1-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma: Phase 3, double-blind, randomized trial (LUCERNA). J Clin Oncol. 2026;44(suppl 2):TPS473. doi:10.1200/JCO.2026.44.2_suppl.TPS473