NT219 Plus Cetuximab Elicits Responses, Demonstrates Tolerability in Recurrent or Metastatic HNSCC

Second-line treatment with the first-in-class dual IRS1/2 and STAT3 inhibitor NT219 alone and in combination with cetuximab (Erbitux) demonstrated safety and tolerability, and the combination produced confirmed partial responses (PRs) in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC), according to data from the dose-escalation portion of a phase 1/2 study (NCT04474470).¹

Four patients treated with 50 mg/kg of NT219—the highest dose level—in combination with cetuximab were evaluable for efficacy, and 2 of these patients achieved a confirmed PR. Additionally, inhibition of intratumoral IRS1/2 and STAT3 was observed in tissue biopsies.

Additionally, 49 patients with recurrent/metastatic HNSCC or advanced colorectal cancer (CRC) were treated with NT219 monotherapy (n = 27) or NT219 plus cetuximab (n = 22). No dose-limiting toxicities (DLTs) were reported in either cohort, and NT219 was well tolerated both as a single agent and in combination with cetuximab.

“We believe these results are very encouraging given the low response rate to cetuximab as monotherapy in patients with recurrent/metastatic HNSCC in the second– and third-line,” Ari Rosenberg, MD, study investigator and assistant professor of medicine at the University of Chicago in Illinois, stated in a news release. “While still early, we are excited to see responders at the highest NT219 dose level where we expected the appropriate exposure to be attained, along with evidence of on target treatment effect in patients’ biopsies. I look forward to continuing investigating NT219 and seeing more data in this disease setting with urgent need for improved therapies.”

NT219 is a novel small molecule that uniquely targets IRS1/2 and STAT3, which are key cancer drivers and important pathways for drug resistance in hard-to-treat histologies. Notably, preclinical research has demonstrated that NT219 exhibits notable effectiveness in preventing acquired resistance and overcoming tumor resistance, both as a monotherapy or in combination with other agents.²

The open-label, dose-escalation and -expansion, phase 1/2 trial is enrolling patients with previously treated advanced solid tumors in portion 1 and patients with recurrent and/or metastatic HNSCC or stage III/IV colorectal adenocarcinoma in portion 2.³ Patients must have at least 1 measurable lesion according to RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate lab results. Patients with stable brain metastases are allowed to enroll.

Exclusion criteria include evidence of any other invasive cancer (excluding non-melanoma skin cancer) within the past 3 years, no recent radiation or major surgery within 4 weeks of starting the study drug, and no previous treatment with investigational therapies within 30 days or 5 half-lives before screening. Additionally, patients should not have active, untreated central nervous system metastases.

During dose escalation, patients were treated at 1 of 5 dose levels of NT219: 3 mg/kg, 6 mg/kg, 12 mg/kg, 24 mg/kg, and 50 mg/kg.¹ They were given NT219 alone or in combination with cetuximab.

The primary end points are safety (parts 1 and 2) and objective response rate (ORR; part 3).³ Secondary end points include pharmacokinetics of NT219, and efficacy end points for both single-agent and combination treatment, including ORR, duration of response, time to response, disease control rate, progression-free survival, time to progression, and overall survival.

“I am very satisfied with the observed activity of NT219 in [patients with] recurrent and/or metastatic HNSCC. Due to the dire unmet need in this difficult to treat population, we believe that extending these early results through a robust proof of concept study would be meaningful for patients and for Purple Biotech and may lead us to next development steps,” Gil Efron, chief executive officer of Purple Biotech, said in a news release.¹

“We will continue exploring higher dose optimization while designing our next study. We believe that the good tolerability of NT219 in combination with cetuximab can position this combination as a strong candidate to combine with other agents in second-line HNSCC and to achieve better survival for patients. Additionally, as demonstrated by our preclinical data, we believe that this data could potentially pave the way for development of NT219 in combination with EGFR inhibitors or other agents such as PD-1 and KRAS inhibitors, potentially unlocking the full potential of NT219.”

References

1. Purple Biotech reports positive interim and preliminary results from NT219 phase 1/2 study in R/M head & neck cancer. News Release. Purple Biotech. October 3, 2023. Accessed October 3, 2023. https://purple-biotech.com/press-viewer/?i=127249
2. NT219: Overview and mechanism of action. Purple Biotech. Accessed October 3, 2023. https://purple-biotech.com/pipeline/nt219/
3. A study to evaluate NT219 alone and in combination with Erbitux (cetuximab) in adults with advanced solid tumors and head and neck cancer. Updated December 14, 2022. Accessed October 3, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04474470