Background: Despite overexpression of EGFR in HNSCC, cetuximab monotherapy has limited benefit. Fibroblast growth factor receptor (FGFR) signaling is a known resistance mechanism to EGFR inhibition. Lenvatinib is a multi-targeted receptor tyrosine kinase inhibitor (RTKI) and has unique activity against FGFR 1,2,3, and 4. We are evaluating inhibition of EGFR and RTKs including FGFR through the combination of cetuximab and lenvatinib in patients (pts) with R/M HNSCC. Methods: In this phase I/Ib, single-institution study, pts with measurable disease per RECIST v1.1 that is incurable with surgery and radiation are eligible regardless of prior cetuximab therapy. The dose de-escalation phase included pts with HNSCC and cutaneous squamous cell carcinoma (cSCC) treated with standard cetuximab dosing and lenvatinib in 3 potential dose levels (DL): (0) 24mg, (-1) 20mg, (-2) 14mg oral daily in a standard 3+3 design. The primary objective was to determine the MTD of lenvatinib in combination with cetuximab. The expansion phase included an additional 5 pts with HNSCC treated at the MTD. Exploratory endpoints include ORR and PFS in HNSCC pts treated at the MTD. Results: 12 evaluable pts were treated on the dose de-escalation phase. There were no DLTs on DL 0; however, 3/6 pts were removed immediately following the 28-day DLT period due to toxicity that included extensive thrombotic events and athlerosclerotic disease. On DL -1, 0/6 pts (5 HNSCC/1 cSCC) had a DLT establishing lenvatinib 20mg daily as the MTD. 7 pts were enrolled onto the expansion phase; 4 are currently evaluable for response and 2 are unevaluable because of withdrawal due to a cetuximab reaction and required surgery. Of the 9 evaluable HNSCC pts treated with lenvatinib 20mg daily, 6 pts had a PR with a 67% ORR. For the 8 pts who have completed treatment, the median PFS is 3.6 months (range 1.6-10.4). Grade 3 AEs regardless of attribution included hypertension (3), oral mucositis (3) and oral cavity fistula (1). The most common AEs were acneiform rash (7), fatigue (6), and hypertension/hypothyroidism/oral mucositis (5 each). Conclusions: The MTD of lenvatinib 20mg daily with cetuximab appears to be active in R/M HSNCC with an impressive preliminary ORR, warranting further evaluation of the efficacy of this combination. Clinical trial information: NCT03524326.