Ficlatuzumab With Cetuximab Achieves PFS Benefit in Recurrent/Metastatic HNSCC

Julie E. Bauman, MD, MPH

Treatment with ficlatuzumab (AV-299) plus cetuximab (Erbitux) demonstrated a statistical progression-free survival (PFS) result in patients with pan-refractory recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).¹

This result comes from a randomized, phase 2 study (NCT03422536) of ficlatuzumab with or without cetuximab in patients with cetuximab-resistant, recurrent/metastatic HNSCC. According to study investigators led by Julie E. Bauman, MD, MPH, director of the GW Cancer Center, The George Washington University, the findings warrant further research.

In a prior phase 1 study (NCT02277197) of ficlatuzumab plus cetuximab in patients with recurrent/metastatic HNSCC who have biomarker correlatives, the combination induced an objective response rate (ORR) of 15% and showed a median PFS of 5.4 months. These findings served as rationale for the launch of the phase 2 study.^1-3

The phase 1 study also evaluated ORR and PFS in human papilloma virus (HPV)-positive vs HPV-negative patients. There was no response among the HPV-positive population compared with a 38% ORR in the HPV-negative subgroup. The median PFS was 1.9 months in the HPV-positive group vs 2.9 months in the HPV-negative group.

The phase 2 investigation of ficlatuzumab with or without cetuximab involved 58 patients with recurrent/metastatic HNSCC. Patients were randomized 1:1 to receive intravenous (IV) ficlatuzumab over 30-60 minutes, every 2 weeks, or ficlatuzumab combined with IV cetuximab administered over 60-120 minutes, every 2 weeks. Treatment in the study continued until disease progression (PD) or unacceptable toxicity. The reatment course repeated every 4 weeks if there was no PD or unacceptable toxicity.^1,4

In addition to the primary end point of PFS, the study evaluated clinical outcomes in biomarker subgroups, change in quality-of-life, the incidence of adverse events (AEs), overall survival, and response rate as secondary end points.

Baseline characteristics were balanced between the 2 treatment arms. Patients were predominantly male, non-Hispanic/White, and had either the oral cavity or oropharynx as their primary tumor site. The median age in the ficlatuzumab monotherapy arm was 65.0 years (range 55.0-70.0 years) and in the combination arm, the median age was 63.0 years (range, 59.0-71.0 years). Fifty-nine percent of the single-agent arm and 48% of the combination arm had tested negative for HPV, while 41% and 51%, respectively, were positive. There majority of patients in the study had a symptomatic performance status.

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With ficlatuzumab monotherapy, the median PFS was 1.8. months, and the median OS was 6.4 months. In terms of ORR, ficlatuzumab showed a rate of 4% (95% CI, 0.1%-20%). The response was from 1 patient with an HPV-negative tumor, and the response duration was 22 weeks. The single-agent arm was terminated for futility.

Among patients treated with the combination of ficlatuzumab and cetuximab, the median PFS 3.7 months, and the P value for the difference between the arms was .04. The median OS in the combination arm was 7.4 months, and the ORR achieved was 19% (95% CI, 7%-36%). Responses included 2 complete responses and 4 partial responses. The median duration of response to ficlatuzumab/cetuximab was 46 weeks (range, 17 weeks-not reached).

For safety, the most common AEs in the monotherapy arm were hypoalbuminemia (66%) and edema (25%), which were expected with HGF/c-MET inhibition. In addition, 12% of patients in the monotherapy arm experienced acneiform rash. In the combination arm, the most common AEs were acneiform rash (82%), hypalbuminemia (76%), and edema (44%). Acneiform rash was expected.

Infections occurred more commonly with ficlatuzumab/cetuximab, but 25 infections that occurred are known effects of cetuximab alone. There were 3 cases of pneumonitis, 2 of which occurred in the monotherapy arm.

Biomarker analysis was conducted in 32 patients. The analysis investigated the impact of c-MET positivity on efficacy outcomes. c-MET positivity was shown to significantly lower risk of disease progression in HPV-negative patients (P = .03), but not in those who were positive for HPV (P = .02). Positive HGF expression in HNSCC tumors was not determined to be associated with PFS or HPV status.

Bauman et al consider the biomarker findings to be noteworthy and encourage prospective analysis of these markers in future studies. Moreover, the investigators urge consideration of ficlatuzumab/cetuximab as a treatment option for pan-refractory, recurrent/metastatic HNSCC, considering the limited treatment options that currently exist.

_REFERENCE:

_{1. Cauman JE, Saba NF, Roe D, et al. Randomized phase ii trial of ficlatuzumab with or without cetuximab in pan-refractory, recurrent/metastatic head and neck cancer. J Clin Oncol. Published online March 28, 2023. Accessed April 5, 2023. doi:10.1200/JCO.22.01994}

_{2. Ficlatuzumab and cetuximab in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). ClincalTrials.gov. Updated April 18, 2019. Accessed April 5, 2023. https://bit.ly/3m53be3}

_{3. Bauman JE, Ohr J, Gooding WE, Phase I study of ficlatuzumab and cetuximab in cetuximab-resistant, recurrent/metastatic head and neck cancer. Cancers (Basel). 2020;12(6):1537. doi:10.3390/cancers12061537.}

_{4. Ficlatuzumab w/wo cetuximab in patients w/cetuximab-resistant, recurrent or metastatic head/neck squamous cell carcinoma. ClinicalTrials.gov. Updated February 5, 2018. Accessed April 5, 2023. https://bit.ly/3UrViw1}