Setanaxib Plus Pembrolizumab Improves Survival in Recurrent/Metastatic HNSCC

Treatment with the NOX enzyme inhibitor setanaxib (GKT-831) in combination with pembrolizumab (Keytruda) led to statistically significant improvements in progression-free survival (PFS) and overall survival (OS) compared with pembrolizumab plus placebo in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to topline data from a phase 2 trial (NCT05323656).¹

Findings showed that patients treated with the combination experienced a median PFS of 5 months compared with 2.9 months for those given pembrolizumab plus placebo (HR, 0.58). Additionally, setanaxib plus pembrolizumab resulted in 6- and 9-month OS rates of 92% and 88%, respectively, compared with 68% and 58%, respectively, for pembrolizumab plus placebo (HR, 0.45).

Furthermore, patients treated with setanaxib plus pembrolizumab achieved a disease control rate (DCR) of 70% vs 52% for those given pembrolizumab plus placebo. Notably, regarding the trial’s primary end point of best percentage change in tumor size from baseline, no statistical difference was observed between the 2 arms.

“It is very encouraging to see statistical significance on important clinical outcomes in this relatively small study, which provides an excellent basis for advancing setanaxib in this hard-to-treat population,” study investigator Kevin Harrington, BSc, MBBS, MRCP, FRCR, FRCP, PhD, DIC, a professor of biological cancer therapies at The Institute of Cancer Research London, and a consultant clinical oncologist at The Royal Marsden NHS Foundation, stated in a news release.

The randomized, double-blind, placebo-controlled phase 2 study enrolled patients at least 18 years of age with histologically or cytologically confirmed recurrent or metastatic HNSCC that was not eligible for surgical resection. Patients could have HNSCC with or without nodal involvement and metastatic spread. Patients needed to be candidates for first-line treatment with pembrolizumab at the discretion of the investigator.²

Other key inclusion criteria consisted of a positive cancer-associated fibroblast (CAF) level (≥5%), measurable disease per RECIST 1.1 criteria, a PD-L1 combined positive score 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.

Patients were excluded if they had a diagnosis of immunosuppression or received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment; received an anticancer monoclonal antibody within 4 weeks of the first day of study treatment; received chemotherapy, targeted small molecule therapy, or radiation within 2 weeks of study treatment; received any prior treatment with setanaxib or pembrolizumab; had known active central nervous system metastases or carcinomatous meningitis; or had any evidence of current interstitial lung disease (ILD) or pneumonitis, or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.

Enrolled patients were randomly assigned to receive 800 mg of setanaxib twice per day or matching placebo. All patients also received 200 mg of pembrolizumab once every 3 weeks.

Secondary end points included PFS; changes in CAFs, CD8-positive tumor-infiltrating lymphocytes, and regulatory T cells in tumor tissue; overall response rate; duration of response; DCR; OS; safety; and pharmacokinetics.

No clinically relevant differences were observed at baseline between the 2 treatment groups.¹

Additional data from a transcriptomic analysis of biopsy samples demonstrated a statistically significant increase in CD8-positive T cells in tumor tissue from patients treated with setanaxib plus pembrolizumab, pointing to increased tumor immunological activity consistent with the mechanism of action of setanaxib.

Safety data showed setanaxib plus pembrolizumab was well tolerated, and no new safety signals were reported.

“This is a very exciting result which provides clinical evidence of the mode of action of setanaxib in line with our thesis of its anti-fibrotic effects, and with results beyond our expectations for a study of this size. It is exciting that we now have positive clinical evidence in support of our first in class NOX platform” Renée Aguiar-Lucander, chief executive officer of Calliditas Therapeutics, added in the news release.

References

1. Calliditas announces positive topline results of phase 2 head and neck cancer trial with lead NOX inhibitor candidate, setanaxib. News release. Calliditas Therapeutics. May 6, 2024. Accessed May 7, 2024. https://www.calliditas.se/en/calliditas-announces-positive-topline-results-of-phase-2-head-and-neck-cancer-trial-with-lead-nox-inhibitor-candidate-setanaxib/
2. 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 April 23, 2024. Accessed May 7, 2024. https://clinicaltrials.gov/study/NCT05323656