HER2-targeted Therapy for Salivary Gland Cancer

October 6, 2026 by

Salivary gland cancers are a rare and heterogeneous group of tumors that form in the tissues of the glands that make saliva, and account for 3% to 5% of all head and neck cancers.

Since there are different types of salivary glands with varying size, location, and type of fluid produced, and the glands contain multiple types of cells, there are several types of salivary gland cancers (more than 20), including the most aggressive type called salivary duct carcinoma (SDC).

A recent study published in Clinical Cancer Research provided new information that might help inform the clinical practice for treating certain patients with this disease.

The current standard of care for treatment of early-stage salivary gland cancer is surgical resection followed by radiotherapy in patients at high risk of recurrence. Patients with advanced disease face lower survival rates, as there are no standard treatments, and responses to chemotherapy are typically modest.

While there are hundreds of minor salivary glands, the three main pairs of salivary glands are the parotid glands, the sublingual glands, and the submandibular glands.

“There is currently no established standard systemic therapy for recurrent or metastatic salivary gland cancer,” said Winston Wong, MD, a medical oncologist specializing in head and neck cancer at Memorial Sloan Kettering Cancer Center, who was one of the authors of the study. “This is partly due to the rarity and histologic and molecular heterogeneity of these tumors.

“Chemotherapy regimens, including single-agent or combination chemotherapy approaches, have been evaluated in small prospective studies and retrospective series, but the evidence remains limited, and response rates are generally modest,” Wong continued. “As of now, there is a large shift towards treatment that is guided by histologic subtype and molecular alterations, with targeted therapies considered when actionable biomarkers are identified.”

For example, more than 90% of SDCs express the androgen receptor for male sex hormones like testosterone and can be treated with androgen deprivation therapy, similar to that used for prostate cancer.

Overexpression of the HER2 protein is also common in certain histologic subtypes, with prevalence reaching 43% in SDC. In these cases, HER2-directed therapy showed benefit in small studies and case reports. Options evolved from trastuzumab (Herceptin) combined with chemotherapy to trastuzumab-containing antibody-drug conjugates (ADCs). These include ado-trastuzumab emtansine or T-DM1 (Kadcyla), which was originally approved by the U.S. Food and Drug Administration (FDA) for treatment of HER2-positive breast cancer, and trastuzumab deruxtecan (T-DXd, Enhertu), which is approved for breast, lung, and stomach cancer and for HER2-positive solid tumors regardless of the tissue of origin.

In a phase II study, 68.4% of patients with recurrent or metastatic SDC treated with T-DXd experienced tumor shrinkage, with some showing no detectable evidence of disease. Notably, T-DXd demonstrated antitumor activity in patients with low levels of HER2 expression as well.

Further Evidence Supporting Targeting HER2

The new study published in Clinical Cancer Research provided new information in support of the use of T-DM1.

“While not being FDA-approved specifically for salivary gland cancer, T-DM1 is currently being used widely in the U.S. off-label for HER2-positive salivary gland cancer, particularly for SDC, and is listed in the National Comprehensive Cancer Network (NCCN) guidelines as an option for treatment in patients with salivary gland cancer that is HER2 positive,” said Wong.

The study was a phase II basket trial that evaluated the efficacy of T-DM1 in patients with metastatic or recurrent solid tumors with HER2 overexpression, including salivary gland, lung, colorectal, endometrial cancer, and others.

The trial included a cohort of 19 patients with SDC, one of whom had received previous HER2-targeted therapy and seven of whom had not received prior therapy for their cancer.

The investigators found that 11 patients in this cohort (58%) experienced tumor shrinking or disappearance of detectable disease, with progression-free survival longer than 10 months and overall survival longer than 29 months. These results compare favorably with response to chemotherapy, which has led to lower response rates and shorter survival.

“The salivary gland cancer cohort in this basket study adds to the growing body of evidence supporting HER2-directed therapy in patients with HER2-positive salivary gland cancer, particularly SDC,” said Wong. “These findings support the use of and further study of HER2-directed therapy in patients with salivary gland cancer and add T-DM1 as a highly effective treatment option for a disease in which conventional systemic therapies have historically had limited efficacy.”

These findings support the use of and further study of HER2-directed therapy in patients with salivary gland cancer and add T-DM1 as a highly effective treatment option for a disease in which conventional systemic therapies have historically had limited efficacy.

Wong pointed out that both T-DM1 and T-DXd have shown substantial activity in HER2-positive salivary gland cancer, but they have not been directly compared in the context of this disease, and the optimal sequencing of these agents remains unknown. “T-DXd has demonstrated impressive activity, including in patients previously treated with HER2-directed therapy, whereas T-DM1 has also shown durable responses and may have a favorable tolerability profile for some patients,” Wong pointed out. “In particular, gastrointestinal toxicity and interstitial lung disease/pneumonitis are important considerations with T-DXd.”

Therefore, Wong suggested, treatment selection and sequencing should take into account prior therapy, comorbidities, toxicity profiles, and treatment availability. “I would think that all patients with salivary gland cancers that are HER2 positive should be strongly considered for T-DM1 and/or T-DXd, depending on availability of the drug,” he added. “In general, I prefer to start with T-DM1 as the side effect profile is slightly better, and we know that T-DXd can be effective in patients previously treated with HER2-directed therapies.”

Wong further explained that this sequencing strategy is based largely on extrapolation from the broader experience with HER2-directed therapy in breast cancer, and that determining the optimal sequencing of HER2-directed therapies in HER2-positive salivary gland cancer remains an important area of investigation.

The study also reinforced the importance of routine HER2 testing in patients with this cancer. “The expanding number of effective HER2-directed therapies means that identifying HER2-positive disease can directly affect treatment selection,” Wong concluded. “Given the historically limited activity of unselected systemic therapy in advanced salivary gland cancer, identifying an actionable HER2 alteration can provide patients with substantially more effective and rationally selected treatment options.”