A phase 1/1b study of lenvatinib and cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma.

BACKGROUND

Despite overexpression of EGFR in head/neck squamous cell carcinoma (HNSCC), cetuximab monotherapy has limited benefit. Lenvatinib is a multi-targeted receptor tyrosine kinase inhibitor with activity against FGFRs1-4, involved in resistance to EGFR inhibition. We evaluated lenvatinib in combination with cetuximab in recurrent/metastatic (R/M) HNSCC.

METHODS

This phase 1/1b, single-institution trial (2018-2022) investigated dose de-escalation in patients with advanced HNSCC and cutaneous squamous cell carcinoma (cSCC) treated with standard cetuximab dosing and lenvatinib in 3 dose levels (0 [24 mg], -1 [20 mg], -2 [14 mg]) orally daily in 3 + 3 design. The primary objective was to determine maximum tolerated dose (MTD) of lenvatinib plus cetuximab. The expansion phase included additional patients with HNSCC receiving MTD. Exploratory endpoints included objective response rate (ORR) and median progression-free survival (mPFS) in HNSCC patients receiving MTD.

RESULTS

The dose de-escalation phase included 12 evaluable patients. There were no dose-limiting toxicities (DLTs) on level 0; 3/6 patients were removed following the 28-day DLT period due to toxicities (all with HNSCC). At level -1, 0/6 pts (5 HNSCC/1 cSCC) had a DLT, establishing level -1 as MTD. The expansion phase included 5 evaluable patients. Of 10 evaluable HNSCC patients receiving MTD, 7 had a partial response (70 % ORR; mPFS, 4.1 m [range 1.4-17.5]). Related grade 3 adverse events included hypertension, oral mucositis, dysphagia, oral cavity fistula, and pharyngeal fistula.

CONCLUSIONS

The MTD of lenvatinib 20 mg daily with cetuximab appears active in R/M HNSCC with an impressive preliminary ORR, warranting further evaluation of this combination.