ASCO has released a guideline update addressing advances in the use of immunotherapy and targeted therapy for the treatment of advanced gastroesophageal cancer.1 The guideline, last updated in 2023 to include first-line therapy recommendations for patients with biomarkers such as PD-L1 and HER2, now reflects new targeted therapy options in the first-line setting, providing the most up-to-date treatment information for clinicians.
Manish A. Shah, MD, FASCO
“The need for the update speaks to the pace of drug discovery in the field,” said Guideline Co-Chair Manish A. Shah, MD, FASCO, of Weill Cornell Medicine. “For over 2 decades, we were forced to only consider chemotherapy for first-line treatment, but since the development of trastuzumab in 2010, we have witnessed the approval of several new targeted therapies that have changed the landscape tremendously.”
Biomarker Testing Recommendations Reflect New Treatment Options
One of the most important changes to the guideline is the recommendation that predictive biomarker testing be conducted in patients with gastroesophageal adenocarcinoma. Testing should be done to determine the expression of PD-L1, deficient mismatch repair/microsatellite instability–high, HER2, and CLDN18.2. According to the guideline, testing results should be obtained as soon as possible to inform treatment decision-making.
“It is important to get biomarker testing [done] from the beginning, as it has important implications for therapy,” Dr. Shah said. However, he added, “we would not recommend waiting for the biomarker testing results to start treatment. Start with chemotherapy, and add in biomarker-driven treatment when possible. These are aggressive cancers, and you don’t want the disease to get ahead of you.”
The new recommendation to test for CLDN18.2 reflects the approval of the targeted therapy zolbetuximab, a monoclonal antibody that targets CLDN18.2 protein on cancer cells.2 The guideline recommends zolbetuximab for patients with gastroesophageal adenocarcinoma that is positive for CLDN18.2 expression and has PD-L1 expression < 1.
This recommendation was based on the results of two phase III randomized clinical trials of patients with HER2-negative tumors and CLDN18.2 biomarker expression: SPOTLIGHT and GLOW.3,4 In these trials, patients were randomly assigned to zolbetuximab plus chemotherapy or chemotherapy alone. Across both studies, the hazard ratios (HRs) for overall survival (OS; HR 0.78, 95% CI [0.67, 0.90]) and progression-free survival (PFS; HR 0.71, 95% CI [0.61, 0.84]) both significantly favored the zolbetuximab arm.
The guideline was also updated to include tislelizumab, an immunotherapy treatment which was approved in late 2024 as first-line treatment for adults with unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinomas with PD-L1 expression.5 The updated recommendation is that patients with PD-L1 expression ≥ 1 receive first-line therapy with fluoropyrimidine- and platinum-based chemotherapy in combination with immunotherapy (pembrolizumab, nivolumab, or tislelizumab).
Addressing Multiple Biomarker Expression, Dual Positivity
The guideline also includes recommendations for clinicians regarding what should be considered when selecting appropriate treatment. Choice of therapy should consider the degree of PD-L1 expression, toxicity profile of each treatment, symptom burden, and anticipated improvement in symptoms.
“The biggest area of confusion is when patients have more than 1 biomarker expressed,” said Guideline Co-Chair Lakshmi Rajdev, MD, MS, of Icahn School of Medicine at Mount Sinai. “If someone is PD-L1 positive and claudin positive, for example, that will have to involve a shared decision-making discussion.”
Ongoing studies will look at whether patients with dual-positive disease might benefit from combination therapy with immunotherapies and claudin inhibitors.
Finally, the guideline also provides some clarification on how to measure PD-L1 expression, Dr. Rajdev said.
“There are 2 ways to look at PD-L1 expression: tumor area positivity (TAP) score and combined positive score (CPS),” she explained.
TAP score is determined visually by estimating the area covered by PD-L1–positive tumor relative to the total tumor. CPS is the number of PD-L1–staining cells divided by the total number of viable cancer cells multiplied by 100. TAP score and CPS show notable concordance at PD-L1–positivity thresholds of 1%, 5%, and 10%. Median overall survival and progression-free survival outcomes are comparable between TAP score and CPS, supporting their use in clinical settings.6
Rapid Pace of Discovery
Based on data presented at the 2026 ASCO Gastrointestinal Cancers Symposium, Dr. Shah said that clinicians should not be surprised if this guideline is updated again relatively soon.
“Ongoing rapid drug development in this area means that clinicians need to be able to stay up-to-date as best as possible,” he explained.
For example, results from the phase III HERIZON-GEA-01 trial showed that the combination of zanidatamab plus chemotherapy, with or without tislelizumab, significantly improved progression-free survival in patients with HER2-positive metastatic gastroesophageal adenocarcinoma.7 These results may require a rapid recommendation update, Dr. Shah said.
REFERENCES
1. Shah MA, Kennedy EB, Deighton D, et al: Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO guideline update. J Clin Oncol. Published online February 26, 2026.
2. U.S. Food and Drug Administration. FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA.gov. October 18, 2024. Accessed January 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma.
3. Shitara K, Lordick F, Bang YJ, et al: Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT).. Lancet 401(10389):1655-1668, 2023.
4. Shah MA, Shitara K, Ajani JA, et al: Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med 29(8):2133-2141, 2023.
5. TEVIMBRA® (tislelizumab-jsgr) injection, for intravenous use. Prescribing information. BeiGene; 2024. Accessed January 24, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761417s000lbl.pdf.
6. Moehler M, Oh D-Y, Kato K, et al: Tislelizumab plus chemotherapy vs placebo plus CT in HER2-negative advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma: PD-L1 biomarker analysis from RATIONALE-305. Ann Oncol 35:1s (Abstract 397MO), 2024.
7. Elimova E, Rha SY, Shitara K, et al: Zanidatamab + chemotherapy ± tislelizumab for first-line HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma: Primary analysis from HERIZON-GEA-01. Abstract LBA285. 2026 ASCO Gastrointestinal Cancers Symposium. Presented January 8, 2026.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, February 26, 2026. All rights reserved.
