Background: Epidermal growth factor receptor (EGFR) targeting with cetuximab (CTX) is a standard therapy for head and neck squamous cell carcinoma (HNSCC). Resistance to CTX can be mediated by activation of the receptor tyrosine kinase AXL. Cabozantinib (cabo) is a tyrosine kinase inhibitor (TKI) of AXL/c-MET/VEGFR which demonstrated antitumor activity in HNSCC preclinical models. We conducted a phase I trial to assess the safety and efficacy of the cabo-CTX combination in recurrent or metastatic (R/M) HNSCC. Methods: Eligibility criteria included RECIST v1.1 measurable disease and incurable R/M HNSCC. Prior treatment with CTX was allowed. Patients received an initial CTX loading dose of 400 mg/m² followed by 250 mg/m² weekly. CTX maintenance dose was later amended to 500 mg/m² biweekly. Cabo was given concurrently on days 1-28 of each 28-day cycle. Primary endpoint was maximally tolerated dose (MTD) of cabo, as identified using a 3+3 dose-escalation design. Tumor responses were assessed every 2 cycles. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Of 22 patients enrolled between 2018 and 2022, 2 did not start therapy. Among treated patients, median age was 59 (range 33-71) and 90% (n = 18) of patients were male. Primary tumor sites included the oropharynx (n = 13), oral cavity (n = 3), larynx (n = 2), hypopharynx (n = 1) and unknown primary (n = 1). p16 antigenic testing for HPV status was positive in 11 oropharyngeal cancers (85%). Most patients were previously treated with immune checkpoint inhibitors (n = 19), chemotherapy (n = 19), CTX (n = 16), or other TKI (n = 2). 12 patients received biweekly CTX dosing at 500 mg/m². Initial cabo dose was 40 mg for the first 11 patients, and 60 mg afterwards (MTD). No dose-limiting toxicity (DLT) was recorded. Common adverse events (AEs) included fatigue (80%), acneiform rash (75%), increased aspartate aminotransferase (AST) (70%), anemia (70%) and hypothyroidism (70%). Grade ≥3 AEs occurred in 65% (n = 13), including increased AST (45%), increased alkaline phosphatase (15%), increased bilirubin (10%) and erythrodysesthesia (10%). AEs led to dose reductions in 20% (n = 4) and treatment discontinuation in 15% (n = 3). In the preliminary efficacy analysis, 4 patients had partial responses (PRs) with an ORR of 20%, including 2 PRs in patients with prior CTX resistance. Disease control rate (DCR) was 75% in the overall population and 75% in those with previous CTX treatment. Median PFS was 3.4 mo and median OS was 8.1 mo. PFS differed according to HPV status, with median PFS 7.1 mo versus 3.1 mo in HPV-positive and -negative patients respectively (p = 0.03). Conclusions: The cabo and CTX combination showed an acceptable toxicity profile with liver toxicity as a common AE. The regimen showed preliminary efficacy data in patients with R/M HNSCC, including those with prior CTX resistance. Clinical trial information: NCT03667482.