Hengrui's Trastuzumab Rezetecan Achieves 91.7% ORR in HER2-High Advanced Salivary Gland Cancer: Phase II Study Published in JCO

A novel antibody-drug conjugate developed by Hengrui Pharma has demonstrated remarkable efficacy in patients with advanced salivary gland cancer, achieving an objective response rate of 91.7% in those with high HER2 expression, according to results from a landmark phase II clinical trial published in the Journal of Clinical Oncology.

The biomarker-stratified study evaluated trastuzumab rezetecan (development code SHR-A1811), a next-generation HER2-targeted ADC, in patients with advanced salivary gland carcinoma across two independent cohorts based on HER2 expression levels. The research, led by Professors Dongmei Ji and Qinghai Ji from Fudan University Shanghai Cancer Center, represents the first prospective study to systematically assess HER2-targeted ADC efficacy in both HER2-high and HER2-low salivary gland cancer populations.

The findings offer new hope for a rare and aggressive malignancy where treatment options have long been limited. Salivary gland cancers are a heterogeneous group of tumors with poor prognosis in advanced stages. Traditional chemotherapy provides only modest and short-lived benefits with significant toxicity, while immune checkpoint inhibitors have shown objective response rates of just 4.6% to 12% in this population.

A New Therapeutic Paradigm

HER2 overexpression and amplification represent one of the most actionable molecular alterations in salivary gland cancer, particularly in the salivary duct carcinoma subtype, where HER2 positivity rates reach approximately 43% according to a meta-analysis. While previous prospective studies of trastuzumab combined with docetaxel in HER2-positive salivary duct carcinoma showed promising results with a 70.2% objective response rate and median progression-free survival of 8.9 months, such evidence was largely confined to HER2-high populations.

The therapeutic value of HER2 targeting in low-expression salivary gland cancer had remained unexplored until now. Trastuzumab rezetecan, featuring a cleavable tetrapeptide linker and a topoisomerase I inhibitor payload with a drug-to-antibody ratio of 6, has already secured approvals for three indications in lung cancer, breast cancer, and colorectal cancer.

Study Design and Patient Population

The open-label, single-center phase II umbrella study (NCT05924256) enrolled patients with unresectable locally advanced or recurrent/metastatic salivary gland carcinoma between August 2023 and September 2025. Patients were stratified according to ASCO/CAP breast cancer HER2 testing guidelines: the HER2-high cohort included those with IHC 3+ or IHC 2+/ISH+ status, while the HER2-low cohort comprised patients with IHC 1+ or IHC 2+/ISH- status.

Both cohorts employed Simon's optimal two-stage design independently, with initial enrollment of 10 patients per cohort. If confirmed responses numbered two or fewer, the cohort would terminate; with three or more responses, enrollment expanded to 22 patients. Trastuzumab rezetecan was administered intravenously at 4.8 mg/kg every three weeks.

Of 48 patients screened, 46 were enrolled and treated—24 in the HER2-high cohort and 22 in the HER2-low cohort. All patients had an ECOG performance status of 1. Salivary duct carcinoma was more prevalent in the HER2-high group (79.2% versus 63.6%), and all four patients with prior HER2-targeted therapy were in the HER2-high cohort.

Striking Efficacy in HER2-High Population

With a median follow-up of 21.9 months, the HER2-high cohort demonstrated a confirmed objective response rate of 91.7% (95% CI: 73.0-99.0), including four complete responses and 18 partial responses. The disease control rate reached 95.8%. Median duration of response, progression-free survival, and overall survival had not been reached at the data cutoff date of March 5, 2026, while median time to response was just 1.7 months. At the time of analysis, 15 patients (62.5%) remained on treatment.

Meaningful Activity in HER2-Low Population

Perhaps equally significant, the HER2-low cohort—previously considered "HER2-negative" and lacking targeted treatment options—also showed clinically meaningful benefit. With a median follow-up of 11.3 months, the confirmed objective response rate was 45.5% (95% CI: 24.4-67.8), with 10 partial responses and 11 cases of stable disease, yielding a disease control rate of 95.5%. Median duration of response was 11.9 months, median progression-free survival was 12.7 months, and median overall survival was preliminarily estimated at 21.3 months. Ten patients (45.5%) remained on treatment at data cutoff.

Notably, nine patients with IHC 2+ status were distributed across both cohorts based on ISH results: three IHC 2+/ISH+ patients in the HER2-high cohort (two confirmed partial responses) and six IHC 2+/ISH- patients in the HER2-low cohort (three confirmed partial responses). This suggests that regardless of ISH status, the IHC 2+ population derives benefit from treatment.

Favorable Safety Profile

The safety profile was consistent with the known characteristics of ADC therapies. Hematologic toxicity was the predominant adverse event. Interstitial lung disease occurred in 6.5% of patients, all mild in severity. No treatment-related adverse events led to treatment discontinuation, and overall tolerability was favorable.

Implications for Clinical Practice

These results represent an important advance in biomarker-driven treatment of salivary gland cancer. The study challenges the traditional binary classification of HER2 positivity and negativity, suggesting that ADC therapy may enable a more nuanced, graded approach to HER2 assessment in salivary gland cancer.

For the HER2-low population—previously without targeted therapeutic options—trastuzumab rezetecan demonstrated durable responses exceeding one year in median progression-free and overall survival. This finding parallels developments in breast cancer, where HER2-low has emerged as a clinically meaningful treatment category following trials with other HER2-targeted ADCs.

The study provides critical prospective evidence supporting further development of HER2-targeted ADCs in salivary gland cancer across a broader spectrum of HER2 expression, potentially transforming treatment paradigms for this rare but devastating disease.

Disclaimer: This article is intended for informational purposes only and does not constitute medical advice. Treatment decisions should be made in consultation with qualified healthcare professionals.