853MO - Setanaxib plus pembrolizumab for the treatment of recurrent or metastatic squamous cell carcinoma of the head & neck: Results of a randomized, double-blind phase II trial

Background

Myofibroblastic cancer-associated fibroblasts (myCAFs) exclude CD8+ T cells from tumours and promote resistance to anti-PD-1 therapy (Ford K. Cancer Res. 2020;80:1846-60). NOX4 regulates myCAF differentiation; preclinical data show that the NOX1/4 inhibitor setanaxib (STX) overcomes myCAF-mediated immunotherapy resistance (Ford K. Cancer Res. 2020;80:1846-60). Pembrolizumab (PMB) is used as first-line monotherapy for patients (pts) with recurrent or metastatic head & neck squamous cell carcinoma (rmHNSCC), where ∼85% of tumours have moderate/high myCAF levels (≥5%) and response rates are low (Harrington KJ. J Clin Oncol. 2023;41:790-802; Marsh D. J Pathol. 2011;223:470-81).

Methods

This randomized, double-blind phase II trial (NCT05323656) evaluated the effect of STX added to PMB in adult pts with rmHNSCC, a combined positive score ≥1, and tumour CAF levels ≥5%. Randomization was 1:1 (stratified by HPV status) to oral STX 800 mg BID or placebo, on top of PMB 200 mg IV every 3 weeks, for ≤24 months. Primary endpoint was best % change from baseline in tumour size (RECIST v1.1); secondary endpoints included PFS, OS, and change from baseline in biomarkers, incl. intratumoural CD8+ T cells.

Results

N=55 pts were randomized. No difference in the primary endpoint was seen but PFS and OS were both statistically significantly greater in the STX arm, with nominal p values below the 0.2 significance threshold level set for this study (Table). No difference in the overall incidence of Grade ≥3 adverse events was seen; mild/moderate hypothyroidism was more common with STX (8 vs 3 pts). Paired biopsy transcriptomic analyses showed statistically significantly more CD8+ T cells in tumour tissue from STX pts. Table: 853MO

Conclusions

STX added to PMB showed statistically significant effects on PFS and OS in pts with rmHNSCC. STX was well tolerated. This combination could have utility in targeting myCAF-rich, ‘immune-excluded’ tumours.;

Clinical trial identification

NCT05323656; EudraCT 2021-004627-33 Sponsor's protocol number: GSN000400.

Editorial acknowledgement

Editorial assistance was provided by Maria Vidal-Rohr and Geraint Owens of Chameleon Communications International, UK, funded by Calliditas Therapeutics.

Legal entity responsible for the study

Calliditas Therapeutics.

Funding

Calliditas Therapeutics.

Disclosure

J. Fayette: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Innate Pharma, Merck Serono, Roche, Pfizer, Hookipa; Non-Financial Interests, Principal Investigator: AstraZeneca, MSD, Pfizer, Meru, Calliditas, Isa. G. Thomas: Financial Interests, Institutional, Research Grant, PI programme grant: Cancer Research UK; Financial Interests, Institutional, Research Grant, PI Boehringer Ingelheim-funded academic research grant: Boehringer Ingelheim; Financial Interests, Institutional, Funding, PI AstraZeneca-funded PhD studentship: AstraZeneca; Financial Interests, Institutional, Research Grant, PI Gilead-funded academic research grant: Gilead Sciences iNC; Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy: Calliditas Therapeutics, Bristol Myers Squibb. A. Daste: Financial Interests, Personal, Advisory Board: Merck, Bristol Myers Squibb, MSD, Merus. A. Levine: Financial Interests, Institutional, Full or part-time Employment: Calliditas Therapeutics AB. R.S. Philipson: Financial Interests, Institutional, Full or part-time Employment: Calliditas Therapeutics AB; Financial Interests, Institutional, Stocks or ownership: Calliditas Therapeutics AB. K.J. Harrington: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Merck, MSD, Pfizer, Replimune, Oncolys, Vyriad, Idera; Financial Interests, Institutional, Other, Honoraria for lectures: Amgen, AstraZeneca, BMS, Boehringer Ingelheim; Financial Interests, Institutional, Advisory Board, Advisory board for CD47 assets: Arch Oncology; Financial Interests, Institutional, Advisory Board, Development of DDR assets: ARTIOS; Financial Interests, Institutional, Advisory Board, Development of exosomal STING agonist: Codiak; Financial Interests, Institutional, Advisory Board, Development of oncolytic adenovirus: PsiVac; Financial Interests, Institutional, Funding, Research: AstraZeneca, Boehringer Ingelheim, MSD; Financial Interests, Institutional, Funding, Development of oncolytic HSV platform: Replimune; Non-Financial Interests, Leadership Role, Chair of Steering Committee: ART NET; Non-Financial Interests, Other, Member of Global Steering Committee: MR - Linac. All other authors have declared no conflicts of interest.