Background: Recurrent/metastatic adenoid cystic carcinoma (R/M ACC) is a rare salivary gland cancer (SGC) without standard treatments. The multitargeted, antiangiogenic kinase inhibitor lenvatinib (len) has activity in R/M ACC, but immune checkpoint inhibitor (ICI) therapies lack efficacy. Hypothesizing that VEGFR inhibition can enhance ICI-induced responses, we conducted a phase II trial evaluating len plus the programmed death-1 (PD-1) inhibitor pembrolizumab (pem) in two R/M SGC cohorts: ACC and non-ACC. Here we report results from the completed ACC cohort. Methods: Patients (Pts) with R/M ACC were enrolled. RECIST v1.1 measurable disease and evidence of progression on imaging performed within 6 months of enrollment were required; any number of prior therapies was allowed. Pts were treated with len 20 mg orally daily and pem 200 mg intravenously every 3 weeks (21-day cycles). The primary objective was to evaluate best overall response rate (ORR), seeking an ORR improvement with len+pem from 15% (previously reported with len alone) to 35%. In the first stage, > 3 confirmed complete and partial responses (cCRs+ cPRs) were required among 17 pts to continue to the second stage; > 8 responses among 32 total pts would have been considered positive (1-sided alpha 0.1, power 0.9). Secondary objectives included evaluating progression-free survival (PFS) and safety/tolerability per CTCAE v5.0 criteria. Results: 17 R/M ACC pts were enrolled and evaluable for the primary objective. One pt had a cPR for an ORR of 6%, failing to meet the rule for progression to the second stage. Thirteen (76%) pts had stable disease and 2 (12%) progression of disease as best response; 1 pt did not have response assessed. Thirteen (76%) pts experienced some degree of regression in RECIST target lesions (TLs; -1.9% to –42.8%), including 5 (29%) with > -20% regression. Eleven (65%) pts were progression-free for > 24 weeks. Twelve (71%) pts experienced at least one > Grade 3 adverse event related to study treatment. Sixteen pts had at least one treatment interruption or len dose reduction; 2 pts received only 1 cycle of therapy. Five pts were treated beyond first progression without observation of subsequent response. Quality of life data and correlative tissue studies are ongoing. Conclusions: The trial failed to demonstrate that len+pem produces a greater ORR in patients with R/M ACC than what was previously reported with len alone. Further investigation into the biology mediating ICI-resistance and development of novel approaches to augment the efficacy of immune-based therapies in ACC are needed. (Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA provided lenvatinib and pembrolizumab for the study.) Clinical trial information: NCT04209660.