Safety and Efficacy of Ruxolitinib in Patients With HNSCC and High NLR Treated With Pembrolizumab - The Phase 2 InflammaSTOP Trial

Head and neck squamous cell carcinoma (HNSCC) remains associated with poor outcomes in a substantial proportion of patients despite the introduction of immune checkpoint inhibitors. An elevated neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, has been associated with reduced survival in patients receiving immune checkpoint inhibitor therapy and may identify a subgroup of patients at increased risk of poor treatment outcomes.

Janus kinase (JAK) inhibition represents a potential strategy to modulate cancer-associated systemic inflammation and the tumor immune microenvironment. Ruxolitinib, a JAK1/2 inhibitor, has demonstrated anti-inflammatory effects and may enhance the activity of immune checkpoint inhibition by reducing inflammatory signaling pathways that could contribute to treatment resistance.

This study uses a biomarker-driven treatment approach in patients with PD-L1-positive recurrent, metastatic, or locally advanced HNSCC who have evidence of increased systemic inflammation prior to treatment initiation. The study is designed to investigate the effects of combining pembrolizumab with intermittent ruxolitinib and to evaluate whether this approach can favorably influence systemic inflammation and immune responses while maintaining acceptable tolerability.

Patients with advanced HNSCC are frequently frail and may be unable to tolerate the toxicities associated with conventional chemotherapy-based treatment approaches. Consequently, there is a need for treatment strategies that are both effective and well tolerated in patients with reduced performance status. The present study therefore focuses on a population with an inflammatory high-risk phenotype and seeks to generate clinical and translational evidence to support future treatment development.

In addition to evaluating the clinical activity and tolerability of the combination regimen, the study will characterize treatment-associated changes in systemic inflammation and adaptive immune responses. The findings are intended to provide a better understanding of the relationship between inflammatory biomarkers, immune modulation, and clinical outcomes in HNSCC, and to inform the design of future randomized studies evaluating JAK inhibition in combination with immune checkpoint blockade.

Inclusion criteria

• Histologically confirmed diagnosis of R/M HNSCC without local treatment options planned for treatment with pembrolizumab monotherapy (R/M cohort) or locally advanced HNSCC planned for perioperative treatment with pembrolizumab (neoadjuvant cohort)
• PD-L1 CPS≥1
• ECOG-performance score 0-2
• NLR >4 before start of pembrolizumab treatment
• Signed and dated written informed consent

Exclusion criteria

• Participation in another interventional study simultaneously and within the last 30 days prior to inclusion
• Concurrent malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome
• Active, known, or suspected autoimmune disease requiring systemic treatment, a concomitant therapy with systemic immune suppression, up to 5 mg/d prednisolone equivalent is allowed
• Patients with severely reduced liver function (Child-Pugh Class C)
• Known allergy or hypersensitivity reaction to ruxolitinib
• Pregnancy and lactation
• Any other serious or unstable medical condition that, in the Investigator's judgment, would compromise participant safety or interfere with study conduct; an active infection requiring systemic antimicrobial, antiviral, or antifungal therapy within 14 days before enrolment; or known HIV infection, active hepatitis B (HBsAg positive or detectable HBV DNA), or active hepatitis C (detectable HCV RNA)
• Thrombocytopenia (platelet count <100,000/microL) or neutropenia (absolute neutrophil count <1000/mcroL)
• Any condition that would require postponement of the planned curative surgical resection to accommodate the neoadjuvant ruxolitinib period (neoadjuvant cohort)
• Anticipated inability to observe the minimum treatment-free interval of at least 48 hours between the last ruxolitinib dose and surgery (neoadjuvant cohort)