Setanaxib Plus Pembrolizumab Elicits PFS Benefit in Recurrent or Metastatic HNSCC

The combination of the NOX1/4 inhibitor setanaxib and pembrolizumab (Keytruda) produced progression-free survival (PFS) benefits compared with placebo plus pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to interim data from a phase 2 trial (NCT05323656).¹

Among 16 patients evaluable for PFS between the combination and placebo arms, 7 remained progression free with either a partial response or stable disease. Six of these 7 patients were in the setanaxib arm, and 1 patient was in the placebo arm. Of those 7 patients, 6 remained on study treatment at the data cutoff, including 1 patient in the setanaxib arm who received treatment for 21 weeks.

“Based on the encouraging clinical and transcriptomic results, data clearly support the continuation of the trial, which will read out on tumor size and PFS in the full trial population next year. Also, it is interesting that the transcriptomic results clearly pointed to beneficial impact on 2 fibrosis‑related signaling pathways, supporting the presumed mode of action as well as our pipeline programs.We are excited about the potential of setanaxib in disease areas where today treatment options are limited” Renée Aguiar-Lucander, chief executive officer of Calliditas Therapeutics, stated in a news release.

In preclinical mouse models, an improvement in the penetration of tumor-infiltrating lymphocytes (TILs), slowed tumor growth, and improved survival were observed in cancer-associated fibroblast (CAF)–rich tumors treated with setanaxib plus pembrolizumab compared with tumors treated with either agent alone.²

The ongoing phase 2 proof-of-concept study is enrolling patients at least 18 years of age with histologically or cytologically confirmed recurrent or metastatic HNSCC with or without nodal involvement, and with or without metastatic spread, who are not eligible for surgical resection.³ Patients need to be candidates for first-line treatment for pembrolizumab, per investigator discretion, and they need to have positive CAFs, defined as a CAFs level of at least 5%. Other key inclusion criteria include measurable disease per RECIST v1.1 criteria, a PD-L1 combined positive score (CPS) of at least 1, a life expectancy of at least 6 months, an ECOG performance status of 0 or 1, and adequate organ and bone marrow function.

The study is excluding patients who received prior treatment with either pembrolizumab or setanaxib; treatment with a monoclonal antibody within 4 weeks of study treatment; chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of enrollment; or a diagnosis of immunosuppression, systemic steroid treatment, or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.

Enrolled patients are being randomly assigned to receive 800 mg of oral setanaxib twice per day plus 200 mg of intravenous pembrolizumab once every 3 weeks, or placebo plus pembrolizumab.

The best percentage change in tumor size per RECIST v1.1 criteria is serving as the trial’s primary end point. Secondary end points include PFS, change in CAFs level, change in CD8-positive TILs, change in regulatory T cells, overall response rate, duration of response, disease control rate, overall survival, and safety.

Among 20 patients included in the interim analysis, 16 were evaluable for tumor size and PFS-related results. Additionally, 12 patients were included in a biomarker analysis following tumor biopsies before and after treatment. The biomarker analysis included a transcriptomic analysis and evaluated pathology markers such as SMA, FOXP3 regulatory T cells, and PD-L1 CPS.¹

Findings from the transcriptomic analysis demonstrated that the idiopathic pulmonary fibrosis signaling pathway and the hepatic fibrosis/hepatic stellate cell activation pathway were the most affected by treatment.

The pathology analysis produced preliminary evidence of an increase in immunological activity within tumors of patients treated with setanaxib, including favorable changes in FOXP3 and PD-L1 CPS. No conclusions were made regarding setanaxib’s effect on SMA reduction due to imbalance in SMA levels at baseline between the groups and small numbers of tumor biopsy samples.

“We are pleased with these encouraging interim data in a patient population where additional effective treatments are needed and look forward to completing the study in collaboration with our excellent sites and investigators” Richard Philipson, MD, chief medical officer of Calliditas Therapeutics, said.

References

1. Calliditas announces supportive interim data from phase 2 head and neck cancer trial with lead NOX inhibitor candidate, setanaxib. News release. Calliditas Therapeutics. July 13, 2023. Accessed July 18, 2023. https://www.calliditas.se/en/calliditas-announces-supportive-interim-data-from-phase-2-head-and-neck-cancer-trial-with-lead-nox-inhibitor-candidate-setanaxib/
2. NOX Enzyme Inhibitors: A Novel Approach Across Indications. Calliditas Therapeutics. Accessed July 18, 2023. https://www.calliditas.se/en/our-science/setanaxib/
3. A study of setanaxib co-administered with pembrolizumab in patients with recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). ClinicalTrials.gov. Updated June 23, 2023. Accessed July 18, 2023. https://clinicaltrials.gov/study/NCT05323656