NT219 Delivers Safety Responses in SCCHN

Targeted Therapies in OncologyMay I, 2024
Volume 13
Issue 6
Pages: 35

In a phase 1/2 trial of NT219 with cetuximab in patients with squamous cell carcinoma of the head and neck, safety and tolerability responses were encouraging.

Interim safety and tolerability responses from a phase 1/2 trial (NCT04474470) evaluating NT219 in combination with cetuximab (Erbitux) in patients with squamous cell carcinoma of the head and neck (SCCHN) were encouraging, said Ari J. Rosenberg, MD, during the European Society for Medical Oncology Targeted Anticancer Therapies Congress 2024.1

The dose expansion study demonstrated that NT219, a dual inhibitor of STAT3 and IRS1/2, in combination with cetuximab, was well tolerated and demonstrated a manageable safety profile. Dose levels at 50 mg/kg and 100 mg/kg were equivalent to effective dose levels in animal models. Further, patients who received the 50- and 100-mg/kg dose levels had an objective response rate (ORR) of 28.6% and a disease control rate of 71.4%.

“Preliminary observations also suggest antitumor activity at these dose levels, particularly in patients with human papillomavirus (HPV)– negative disease,” Rosenberg, an assistant professor of medicine at University of Chicago Medicine in Illinois, said during a presentation of the data.


Both STAT3 and IRS1/2 are intimately involved in cancer therapeutic drug resistance. IRS 1 and 2 are scaffold proteins that regulate major survival pathways including β-catenin and PI3K/ AKT. The STAT3 pathway is required for TGFβ- induced epithelial-mesenchymal transitions, metastasis, and angiogenesis and is a major player in tumor immune evasion.

Patients were enrolled in 5 dose level cohorts of 6-, 12-, 24-, 50-, and 100-mg/kg of NT219 plus the standard dose of cetuximab, and the study used a 3+3 design. Patients received both agents weekly until disease progression, unacceptable toxicity, or withdrawal. The primary objectives were safety, tolerability, and determination of recommended phase 2 dose of NT219. Secondary objectives were pharmacokinetics, ORR, duration of response, progression-free survival, and overall survival.

At the cutoff date of January 25, 2024, 17 patients with SCCHN were enrolled and 15 patients were evaluable. To participate in the dose escalation phase of the study, patients had to have an ECOG performance status less than 2.

All patients (N = 17) were male with a median age of 58 years (range, 28-65) and the majority were White (95%). Seventy-six percent had a tumor in the oral cavity, 18% had it in the pharynx, and 6% had it in the larynx.

“The vast majority of patients had received 2 prior lines of systemic therapy in the recurrent metastatic setting,” Rosenberg said, “with almost all patients having progressed on a prior immune checkpoint inhibitor as well as prior platinum- based chemotherapy.”

The most frequently observed treatment emergent adverse events (AEs) were infusion-related reactions (76%) and nausea (35.3%), followed by fatigue (29.4%), headache (23.5%), and rash (23.5%). “All of these were managed with supportive care,” Rosenberg said. Investigators reported no treatment- related grade 4/5 AEs.

Among 7 patients at the highest dose levels of 15 mg/kg and 100 mg/kg, 2 had confirmed disease progression and 3 had stable disease. At a median follow-up of 9.4 months (95% CI, 3.4-10.0), 2 patients in the 50-mg/kg and 100-mg/kg cohort were still undergoing treatment.

The clinical response to the combination of NT219 and cetuximab was also encouraging. Investigators noted 2 patients with neck lesions, 1 of whom remained on therapy for 6 weeks but withdrew because of immune-related AEs with a partial response of about 60%, and the other with a duration of therapy of 40 weeks that is ongoing and with a partial response of about 48%. Rosenberg also pointed out a patient with HPV had neck cancer with distant lung metastases who had progressed on multiple lines of PD-1 therapy as well as platinum-based chemotherapy in the recurrent metastatic setting. This patient experienced regression of his distant lung metastases with a duration of treatment of 27 weeks and stable disease (about 29%).

“The recommended phase 2 dose was determined to be 100 mg/kg in combination with cetuximab,” Rosenberg said. “A subsequent phase 2 study is planned,” he concluded.

1. Rosenberg AJ, Kato S, Johnson D, et al. Interim results of a phase 1/2 trial of NT219 in combination with cetuximab in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Ann Oncol. 2024;9(suppl 1):1-7. doi:10.1016/esmoop/esmoop102270
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