Systemic Therapy for Salivary Gland Cancers: A Review of Targeted and Chemotherapeutic Approaches

Systemic therapy for recurrent and metastatic salivary gland malignancies (SGMs) remains a major therapeutic challenge. Traditional chemotherapy offers modest response rates with limited durability, and its role is largely palliative. The most meaningful advances have occurred in biomarker-selected subgroups: androgen receptor blockade for AR-positive salivary duct carcinoma and HER2-directed therapy for HER2-positive tumors have demonstrated superior response rates and survival (often exceeding 50%), compared with the single digit response rates seen with unselected chemotherapy or tyrosine kinase inhibitors. Small-molecule tyrosine kinase inhibitors such as lenvatinib and axitinib may provide disease stabilization in adenoid cystic carcinoma, although tumor shrinkage is uncommon and toxicity limits their long-term use. Immunotherapy as a single agent has been disappointing, but durable responses in select patients and modest activity with combination regimens suggest it may have a future role when rationally paired with other agents. In our practice, comprehensive molecular profiling is essential at the time of recurrence to identify actionable alterations, prioritize targeted therapy where available, and guide clinical trial enrollment. For most patients without a targetable alteration, platinum-based combinations remain the pragmatic choice, though expectations for benefit should be tempered. Future strategies will likely hinge on optimizing biomarker-driven therapies, expanding access to antibody-drug conjugates, and pursuing collaborative trial designs to overcome the rarity and heterogeneity of these tumors.