Background: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. Patients and methods: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab þ trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). Results: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab þ trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progressionfree survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab þ trastuzumab, n ¼ 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n ¼ 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n ¼ 1/1, PFS 18.5 months), and high TMB (atezolizumab, n ¼ 1/1, PFS 5.5þ months). No unexpected toxicity occurred. Conclusions: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.