A phase 1 study of concurrent cabozantinib and cetuximab in recurrent or metastatic head and neck squamous cell cancer

Abstract

Objectives: Epidermal growth factor receptor (EGFR) inhibition with cetuximab is a standard treatment for head and neck squamous cell carcinoma (HNSCC). Activation of the receptor tyrosine kinases AXL, MET and VEGFR can mediate resistance to cetuximab. Cabozantinib, a multikinase inhibitor (MKI) targeting AXL/MET/VEGFR, has demonstrated antitumor activity in preclinical models of HNSCC. This investigator- initiated phase I trial evaluated the safety and efficacy of cetuximab plus cabozantinib in patients with recurrent/metastatic (R/M) HNSCC.

Materials and methods: Patients received cetuximab concurrently with cabozantinib daily on a 28-day cycle. Using a 3 + 3 dose-escalation design, the primary endpoint was to determine the maximally tolerated dose (MTD) of cabozantinib. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) RESULTS: Among the 20 patients enrolled, most had prior disease progression on immune checkpoint inhibitors (95 %), platinum-based chemotherapy (95 %), and cetuximab (80 %). No dose-limiting toxicities were recorded and the MTD for cabozantinib was established to be 60 mg. Grade ≥ 3 adverse events occurred in 65 % of patients (n = 13). ORR was 20 %, with 4 partial responses (PRs). Two PRs were observed in cetuximab-naïve patients (n = 4), with an ORR of 50 % in this subgroup. In the overall population, DCR was 75 %, median PFS was 3.4 months and median OS was 8.1 months.

Conclusion: Cetuximab plus cabozantinib demonstrated a manageable toxicity profile and preliminary efficacy in patients with heavily treated R/M HNSCC. The combination of cetuximab with MKIs targeting the AXL/MET/VEGFR axis warrants further investigation, including in cetuximab-naïve patients.

Keywords: Cabozantinib; Cetuximab; Head and neck squamous cell cancer; Human papillomavirus-associated oropharyngeal squamous cell cancer; Immunotherapy resistance; Platinum resistance.

Figure 1.

Swimmer’s plot from start of study to time of last cabozantinib-cetuximab treatment. Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 evaluation was unavailable for 3 patients, including 1 response unevaluable due to early toxicity, which was categorized as non-RECIST progressive disease (PD) (patient 1 in swimmer’s plot), and 2 cases of early clinical progression, which were categorized as non-RECIST PD (patients 3 and 4 in swimmer’s plot). CTX = prior cetuximab treatment.

Figure 2.

Waterfall plot for best percentage change in target lesion(s) size for patients receiving combination cabozantinib-cetuximab therapy as measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Best percentage change for all 17 evaluable patients (RECIST evaluation was unavailable for 3 patients, including 1 response unevaluable due to early toxicity, which was categorized as non-RECIST progressive disease [PD], and 2 cases of early clinical progression, which were categorized as non-RECIST PD) (A); patients who received an initial cabozantinib dose of 40 mg (B); patients who received an initial cabozantinib dose of 60 mg (C); patients whose primary site was the oropharynx (accompanied by HPV status) (D); and patients with non-oropharyngeal primary sites (E). Red indicates a best response of PD, yellow indicates a best response of stable disease (SD), and green indicates a best response of partial response (PR).