Trastuzumab rezetecan (SHR-A1811) showed high antitumor activity in patients with HER2-high advanced salivary gland carcinoma (SGC) and activity in those with HER2-low disease, according to findings from a biomarker-stratified phase 2 trial (NCT05924256) published in Journal of Clinical Oncology.¹
The confirmed objective response rate (ORR) was 91.7% (95% CI, 73.0%-99.0%), including 4 complete responses (CRs), in the HER2-high cohort (n = 24) and 45.5% (95% CI, 24.4%-67.8%), with no CRs, in the HER2-low cohort (n = 22). The disease control rate (DCR) was similar between cohorts, at 95.8% (95% CI, 78.9%-99.9%) and 95.5% (95% CI, 77.2%-99.9%), respectively.
Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached (NR) in the HER2-high cohort at a median follow-up of 21.9 months (95% CI, 16.9-26.9). In the HER2-low cohort, at a median follow-up of 11.3 months (95% CI, 6.9-15.7), the median DOR was 11.9 months (95% CI, 1.4-22.3), median PFS was 12.7 months (95% CI, 4.4-21.0), and median OS was 21.3 months (95% CI, NR).
Trastuzumab Rezetecan in Advanced Salivary Gland Carcinoma: Key Findings
- Confirmed ORR reached 91.7% in the HER2-high cohort, including 4 CRs, vs 45.5% in the HER2-low cohort, which had no CRs.
- Median DOR, PFS, and OS were not reached in the HER2-high cohort after 21.9 months of follow-up; in the HER2-low cohort, median PFS was 12.7 months and median OS was 21.3 months.
- Grade 3 or higher TRAEs occurred in 41.3% of patients, most commonly neutropenia; interstitial lung disease occurred in 6.5% of patients, all grade 1, with no treatment-related deaths.
How was the phase 2 trial designed?
The single-center, open-label trial enrolled patients with unresectable locally advanced or recurrent/metastatic SGC into 2 prospectively defined, independently evaluated arms following a Simon optimal two-stage design: a HER2-high cohort (IHC 3+ or IHC 2+/ISH+) and a HER2-low cohort (IHC 1+ or IHC 2+/ISH–), classified per ASCO/College of American Pathologists breast cancer HER2 testing guidelines. Eligible patients were 18 to 75 years old with an ECOG performance status of 0 or 1 and at least 1 measurable lesion per RECIST 1.1 criteria; prior systemic therapy, including HER2-targeted agents, was permitted after a washout period.1,2
Trastuzumab rezetecan was administered intravenously at 4.8 mg/kg once every 21 days. The primary end point was confirmed ORR per RECIST 1.1 criteria; secondary end points included DCR, DOR, time to response (TTR), PFS, OS, and safety.
Of the 46 treated patients, salivary duct carcinoma was the predominant histologic subtype in both the HER2-high (79.2%) and HER2-low (63.6%) cohorts.
What additional efficacy data were reported across subgroups?
Median TTR was shorter in the HER2-high cohort at 1.7 months (95% CI, 1.2-2.0) vs 3.0 months (95% CI, 2.5-3.2) in the HER2-low cohort. Among the 9 patients with an IHC 2+ score, 3 were ISH-positive and 6 were ISH-negative, with confirmed partial responses (PRs) observed in 2 and 3 patients, respectively. In the HER2-low cohort, response was observed across IHC 1+ (7 of 16 PRs) and IHC 2+/ISH– (3 of 6 PRs) subgroups, and durable disease control, including a median DOR of 11.9 months, was seen despite the absence of CRs. As of the March 5, 2026, data cutoff, treatment remained ongoing in 15 patients (62.5%) in the HER2-high cohort and 10 patients (45.5%) in the HER2-low cohort; disease progression was the most common reason for discontinuation among the 21 patients who came off treatment.
What was the safety profile of trastuzumab rezetecan?
Treatment-related adverse effects (TRAEs) of any grade occurred in 97.8% of patients, including grade 3 or higher events in 41.3%. The most common hematologic TRAEs were decreased neutrophil count (82.6%; grade 3-4, 32.6%), anemia (67.4%; grade 3-4, 10.9%), and decreased white blood cell count (58.7%; grade 3-4, 15.2%); 7 patients with grade 3-4 neutropenia received secondary prophylactic growth factor support. The most common nonhematologic TRAEs, including vomiting (50.0%), fatigue (47.8%), and increased gamma-glutamyltransferase (30.4%), were grade 1-2. Interstitial lung disease occurred in 3 patients (6.5%), all grade 1, and no decline in left ventricular ejection fraction was observed.
Serious TRAEs occurred in 2 patients (4.3%), consisting of grade 3 infectious pneumonia and grade 3 febrile neutropenia. TRAEs led to dose interruption in 20 patients (43.5%) and dose modification in 15 (32.6%), but none resulted in treatment discontinuation or death.
The study authors concluded that the findings do not establish HER2-low SGC as a definitive treatment category but support further evaluation of HER2-low disease as a target population for HER2-directed antibody-drug conjugate therapy, favoring a graded rather than strictly binary approach to assessing HER2 expression in SGC, an approach relevant to the ongoing NRG-HN010 trial (NCT05408845), which includes both HER2-expressing and HER2-low SGC.
References
- Chen GL, Guo Y, Liu X, et al. Biomarker-stratified phase II trial of trastuzumab rezetecan in advanced salivary gland carcinoma across cohorts with high and low human epidermal growth factor receptor 2 expression. J Clin Oncol. Published online August 11, 2026. doi:10.1200/JCO-26-00671
- A Phase II Study of Advanced Salivary Gland Carcinoma Based on Molecular Typing. ClinicalTrials.gov. Updated April 2, 2026. Accessed August 13, 2026. https://clinicaltrials.gov/study/NCT05924256
