In a phase II trial reported in the Journal of Clinical Oncology, Julie E. Bauman, MD, MPH, and colleagues found that the combination of the antihepatocyte growth factor antibody ficlatuzumab and cetuximab was active in patients with cetuximab-resistant, recurrent or metastatic head and neck squamous cell carcinoma. As stated by the investigators, “Aberrant hepatocyte growth factor/cMet pathway activation is an established [cetuximab] resistance mechanism. Dual pathway targeting may overcome resistance.”

Julie E. Bauman, MD, MPH

Study Details

The U.S. multicenter trial included 60 patients with known human papillomavirus (HPV) status, cetuximab resistance (disease progression within 6 months of exposure in the definitive or recurrent/metastatic setting), and resistance to platinum chemotherapy and PD-1 inhibition. Patients were randomly assigned between January 2018 and December 2020 to receive ficlatuzumab at 20 mg/kg every 2 weeks plus cetuximab at 500 mg/m² every 2 weeks (n = 33) or ficlatuzumab alone (n = 27). The primary endpoint was median progression-free survival; a group met significance criteria if the lower bound of the 90% confidence interval (CI) excluded the historical control of 2 months.

Progression-Free Survival

The monotherapy group was closed early for futility. Median progression-free survival was 1.8 months (lower-bound 90% CI = 1.7 months). An objective response was observed in one patient (4%).

The combination group met the prespecified significance criteria with a median progression-free survival of 3.7 months (lower-bound 90% CI = 2.3 months, P = .04); an objective response was observed in six patients (19%), including complete response in two. Median duration of response was 46 weeks (range = 17 weeks to not reached).

Among 16 patients with HPV-positive disease and 16 with HPV-negative disease in the combination group, median progression-free survival was 2.3 months vs 4.1 months (P = .03) and objective response was observed in 0 patients (0%) vs 6 patients (38%; P = .02).

Patients classified as cMet-positive in the combination group had significantly better progression-free survival vs cMet-negative patients (hazard ratio = 0.3, 95% CI = 0.1–0.9, P = .02). cMet-positive status was associated with improved progression-free survival in HPV-negative (P = .03) but not HPV-positive patients (P = .2; P for interaction = .02).

Adverse Events

In patients in the ficlatuzumab monotherapy group, the most common adverse events of any grade were hypoalbuminemia (66%) and edema (25%); the most common grade ≥ 3 adverse events were hyponatremia (8%), pneumonitis (8%), and thromboembolic events (8%). In the combination group, the most common adverse events of any grade were acneiform rash (82%), hypoalbuminemia (76%), and edema (44%); the most common grade ≥ 3 adverse events were hypoalbuminemia (16%), hypokalemia (13%), and headache (9%), with grade ≥ 3 thromboembolic events occurring in 6%. One patient in the monotherapy group died from pneumonitis considered related to treatment; one patient in the combination group died from sudden death–not otherwise specified considered related to treatment.

The investigators concluded, “The ficlatuzumab/cetuximab arm met significance criteria for progression-free survival and warrants phase III development. HPV-negative head and neck squamous cell carcinoma merits consideration as a selection criterion.”

Dr. Bauman, of the Division of Hematology/Oncology, George Washington University and George Washington Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The trial was funded by Aveo Oncology and the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.