Importance Adenoid cystic carcinoma (ACC) is a rare salivary gland tumor treated locally with surgery and radiation therapy. Despite high recurrence and distant failure rates, there is no approved systemic therapy for recurrent/metastatic disease. Objective To evaluate amivantamab, a dual-target epidermal growth factor receptor (EGFR)–mesenchymal–epithelial transition (MET) bispecific antibody, as a novel treatment in patients with advanced ACC. Design, Setting, and Participants Between October 2022 and January 2025, this single-arm, open-label, phase 2 nonrandomized clinical trial enrolled patients with recurrent/metastatic ACC at 3 US academic centers. Patients received amivantamab until disease progression or unacceptable toxic effects. Participants were aged 18 years and older with confirmed recurrent/metastatic ACC not amenable to curative-intent therapy, who had progression within 6 months of study enrollment. Participants had at least 1 site of measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), an Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ and marrow function. Intervention Patients received intravenous amivantamab, 1050 mg, if weighing less than 80 kg, or 1400 mg if weighing 80 kg or more, weekly for 1 month, followed by day 1 and 15 dosing every 28 days thereafter until progression. Main Outcomes Primary end point was best overall response rate (ORR) per RECIST 1.1. Results Twenty-one patients enrolled; 18 were efficacy evaluable. The median age was 61 years (range, 36-76 years), and 14 individuals (67%) were male. Most primary sites were the major/minor salivary glands (17 patients 81%), and 13 (62%) had distant metastatic disease. Nine patients (43%) had no prior systemic treatment. Six patients (29%) had 2 or more lines of prior therapy. Of 18 evaluable patients, best ORR was 5.6% (95% CI, 0-27.6%), with 1 partial response (in a patient with type 1 ACC and a somatic EGFR variant). Twelve patients (66.7% 95% CI, 43.6%-83.9%) achieved stable disease. Five patients (27.8% 95% CI, 12.2%-51.2%) experienced disease progression, yielding a clinical benefit rate of 72.2% (95% CI, 48.8%-87.8%). Common treatment-related adverse events (TRAEs) included acneiform dermatitis (18 86%), infusion-related reaction (16 76%), and fatigue (15 71%); 3 patients (14%) experienced grade 3 TRAEs (acneiform dermatitis, mucositis, and elevated alkaline phosphatase). Conclusions While the primary end point of best ORR was not met in this nonrandomized clinical trial, amivantamab was well tolerated, and most patients exhibited disease stabilization. Trial Registration ClinicalTrials.gov Identifier: NCT05074940
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