ASCO Guideline Update Broadens First-Line Treatment Options for HER2+ Gastroesophageal Cancer

ASCO has updated its living clinical practice guidelines on immunotherapy and targeted therapy for advanced gastroesophageal cancer, broadening first-line recommendations for patients with HER2-positive disease to incorporate a HER2-targeting antibody, with or without an immune checkpoint inhibitor, alongside fluoropyrimidine- and platinum-based chemotherapy, according to a guideline update to be published in the Journal of Clinical Oncology.¹

The revisions were informed by findings from the phase 3 HERIZON-GEA-01 trial (NCT05152147), in which first-line zanidatamab-hrii (Ziihera) plus tislelizumab (Tevimbra) and chemotherapy (n = 302) produced a median overall survival (OS) of 26.4 months (95% CI, 21.5-30.3) vs 19.2 months (95% CI, 16.8-21.8) with trastuzumab (Herceptin) plus chemotherapy (n = 308) in the overall population (HR, 0.72; 95% CI, 0.57-0.90; P = .004).² The median progression-free survival (PFS) by blinded independent central review (BICR) was 12.4 months (95% CI, 9.8-18.5) vs 8.1 months (95% CI, 7.0-8.9), respectively (HR, 0.63; 95% CI, 0.51-0.78; P < .001).²

What updates to the ASCO living guidelines are important to note?

Recommendation 3.1 now advises that patients with mismatch repair–proficient (pMMR)/microsatellite-stable (MSS) HER2-positive gastroesophageal adenocarcinoma and a PD-L1 expression of 1 or greater be offered a HER2-targeting antibody plus immunotherapy in combination with fluoropyrimidine- and platinum-based chemotherapy (evidence quality: moderate; strength of recommendation: strong).¹ The prior recommendation had specified pembrolizumab (Keytruda) plus trastuzumab and chemotherapy for this population.

Recommendation 3.2 now advises that patients with pMMR/MSS HER2-positive disease and a PD-L1 expression below 1 be offered a HER2-targeting antibody in combination with fluoropyrimidine- and platinum-based chemotherapy (evidence quality: moderate; strength of recommendation: strong), broadened from a prior trastuzumab-plus-chemotherapy recommendation on the basis of the PFS superiority of zanidatamab plus chemotherapy vs trastuzumab plus chemotherapy. The expert panel retained trastuzumab as an option to account for patients with contraindications to zanidatamab and for drug availability. The panel noted that, without a head-to-head trial, therapy selection should be individualized based on toxicity tolerance, drug availability and regulatory status, cost, and patient preference.

What additional efficacy data were shown in HERIZON-GEA-01?

HERIZON-GEA-01 was an international, multisite, open-label, phase 3 trial that enrolled 914 patients with previously untreated HER2-positive advanced gastroesophageal adenocarcinoma.² All patients received standard-dose chemotherapy (either capecitabine plus oxaliplatin or fluorouracil plus cisplatin) and were randomly assigned to also receive zanidatamab plus tislelizumab, zanidatamab (n = 304), or trastuzumab in 21-day cycles. The coprimary end points were PFS by BICR and OS.

In the zanidatamab-plus-chemotherapy arm, the median OS was 24.4 months (95% CI, 20.4-30.0), which was not significantly different from that with trastuzumab plus chemotherapy (HR, 0.80; 95% CI, 0.64-1.01; P = .06).² The median PFS in the investigational arm was 12.4 months (95% CI, 9.8-14.5), which was significantly longer than the median PFS with trastuzumab plus chemotherapy (HR, 0.65; 95% CI, 0.52-0.81; P < .001).

PD-L1 status was assessed retrospectively using tumor area positivity (TAP) scores at a cutoff of less than 1% vs 1% or greater. In total, approximately 32% of patients across the 3 arms had TAP scores below 1%, approximately 60% of patients had scores of 1% or greater, and approximately 7% of patients had no score available. Both zanidatamab-containing regimens improved PFS vs trastuzumab plus chemotherapy in the TAP-low and TAP-high subgroups. A significant OS advantage was observed with the triplet regimen vs trastuzumab plus chemotherapy among patients with a TAP score below 1%, whereas no significant OS difference was seen between these regimens in the TAP score of 1% or greater subgroup.

Why did the ESMO expert panel withhold the recommendation of triplet therapy in PD-L1–low gastroesophageal adenocarcinoma?

Although the OS benefit with triplet therapy in the PD-L1 TAP–low subgroup reached statistical significance, the expert panel identified several caveats¹:

• The relevant end points were considered exploratory
• The subgroup confidence intervals were not adjusted for multiplicity
• The biological mechanism underlying the finding is uncertain
• The OS data in this subgroup are inconsistent with prior OS data in the PD-L1–low subgroup from the phase 3 KEYNOTE-811 trial (NCT03615326) of pembrolizumab (Keytruda) plus trastuzumab and chemotherapy in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma; the panel noted that this discrepancy leaves the relative contribution of immunotherapy in the HERIZON-GEA-01 combination unclear

Given these considerations, the panel opted not to incorporate triplet therapy into the main text of recommendation 3.2 and awaits further OS analyses from HERIZON-GEA-01. The panel also concluded there was insufficient evidence at this time to comment on the benefit of the HERIZON-GEA-01 regimen in HER2 2+ vs HER2 3+ subgroups. Since ASCO living guidelines are updated on an 8-week interval, the panel indicated that it is positioned to incorporate results from subsequent analyses of HERIZON-GEA-01 or other newly published trials.

What safety data were reported from HERIZON-GEA-01?

Grade 3 or 4 adverse effects (AEs) were reported in 73.8% of safety-evaluable patients in the zanidatamab/tislelizumab/chemotherapy arm (n = 294), 67.2% of those in the trastuzumab/chemotherapy arm (n = 302), and 65.6% of those in the zanidatamab/chemotherapy arm (n = 305).² Grade 5 AEs occurred in 9.5%, 7.3%, and 8.2% of patients, respectively. Grade 3 or higher diarrhea was the most commonly reported AE across arms, occurring in 24.8% of patients receiving triplet therapy, 20.0% of those receiving zanidatamab plus chemotherapy, and 12.9% of those receiving trastuzumab plus chemotherapy. Grade 3 or higher immune-mediated AEs occurred in 12.2% of patients in the triplet arm.

The HERIZON-GEA-01 study authors noted that limitations of the trial include the risk of false-positive OS and PFS findings in predefined subgroups owing to unadjusted confidence intervals, as well as limited representativeness, as no enrolled patients resided in the United States or the Middle East.

References

1. Shah MA, Marzalik JS, Kennedy EB, et al. Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO Living Guideline, version 2026.1.2. J Clin Oncol. Published online August 17, 2026. doi:10.1200/JCO-26-01944
2. Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. 2026;394(21):2002-2014. doi:10.1056/NEJMoa2517729