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.

• Ruxolitinib (Drug), also known as Janus kinase inhibitors: Ruxolitinib administered orally on an intermittent schedule in combination with pembrolizumab.
• Pembrolizumab (Drug), also known as Immune checkpoint inhibitor: Pembrolizumab administered as standard-of-care immune checkpoint inhibitor therapy.

Primary outcomes

• 6-Month Progression-Free Survival Rate (R/M cohort only) [6 months after enrollment]: Progression-free survival is defined as the time from enrollment to the first documented disease progression or death from any cause, whichever occurs first. The outcome measure is the proportion of participants who are alive and progression-free 6 months after enrollment.

Secondary outcomes

• Change in systematic inflammation (Neutrophil-to-Lymphocyte Ratio, NLR) [R/M cohort: at screening within 21 days before start of ruxolitinib or at week 6 (baseline) and at week 12. Neoadjuvant cohort: at screening within 21 days before start of ruxolitinib or at week 3 (baseline), at week 5 and at week 12.]: Percentage of participants achieving normalisation of the neutrophil-to-lymphocyte ratio (NLR) after completion of JAK-inhibition treatment. NLR is calculated as the absolute neutrophil count divided by the absolute lymphocyte count. Participants are considered to have achieved NLR normalisation if the post-treatment NLR meets the protocol-defined threshold for a normal NLR value.
• Adherence to Planned JAK-Inhibition Treatment (R/M cohort only) [From initiation of ruxolitinib treatment to Week 12 (up to 6 weeks of treatment).]: Proportion of participants who complete the planned JAK-inhibition treatment duration. Participants are considered adherent if they receive JAK-inhibition according to the protocol-defined treatment schedule and duration without premature discontinuation.
• Tumour response (R/M cohort only) [Week 12]: Best tumour response at week 12 by investigator assessment (objective response rate). Rationale: early signal of anti-tumour activity
• Overall survival (R/M cohort only) [From enrollment until death from any cause or until the end of study follow-up (up to approximately 5 years).]: Overall survival is defined as the time from enrollment to death from any cause. Survival status will be assessed during follow-up and recorded every 6 months.
• Quality of Life Assessed by EORTC QLQ-C30 (R/M cohort only). [At screening, week 12 and week 18]: Change in quality of life measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Scores are transformed to a 0-100 scale according to the EORTC scoring manual. Higher functional-scale scores indicate better functioning, whereas higher symptom-scale scores indicate greater symptom burden.
• Quality of Life Assessed by EORTC QLQ-H&N43 (R/M cohort only) [At screening, week 12, week 18]: Change in head and neck cancer-specific quality of life measured using the uropean Organization for Research and Treatment of Cancer Quality of Life Head and Neck Module (EORTC QLQ-H\&N43) questionnaire. Scores are transformed to a 0-100 scale according to the EORTC scoring manual. Higher symptom scores indicate greater symptom burden.

Other outcomes

• Plasma Inflammatory Biomarkers [Baseline and after completion of JAK-inhibition treatment.]: Change in circulating inflammatory biomarkers, including plasma cytokines and other soluble factors, from before initiation of JAK-inhibition to after completion of JAK-inhibition treatment, measured using multi-analyte plasma assays.
• ≥20% Increase in T Cell Richness or Diversity [Before initiation of ruxolitinib treatment and after completion of ruxolitinib treatment (Week 6 and Week 12 in the R/M cohort; Week 3 and Week 5-6 in the neoadjuvant cohort).]: Percentage of participants achieving a relative increase of at least 20% in peripheral blood T cell richness or diversity between initiation and completion of JAK-inhibition treatment, measured by T cell receptor next-generation sequencing (TCR-NGS).
• ≥20% Decrease in T Cell Clonality [Before initiation of ruxolitinib treatment and after completion of ruxolitinib treatment (Week 6 and Week 12 in the R/M cohort; Week 3 and Week 5-6 in the neoadjuvant cohort).]: Percentage of participants achieving a relative decrease of at least 20% in peripheral blood T cell clonality between initiation and completion of JAK-inhibition treatment, measured by T cell receptor next-generation sequencing (TCR-NGS).
• T Cell Richness, Diversity, and Clonality [Before initiation of ruxolitinib treatment and after completion of ruxolitinib treatment (Week 6 and Week 12 in the R/M cohort; Week 3 and Week 5-6 in the neoadjuvant cohort).]: Levels of peripheral blood T cell richness, diversity, and clonality measured by T cell receptor next-generation sequencing (TCR-NGS) before initiation and after completion of JAK-inhibition treatment.
• Safety and Tolerability [From initiation of ruxolitinib treatment through completion of safety follow-up (Week 6 to Week 18 in the R/M cohort; Week 3 to Week 12 in the neoadjuvant cohort)]: Number of participants experiencing adverse events and serious adverse events. Adverse events will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 6.0, including Grade 3 to 5 events.

Sex: All, ages: 18 Years to any

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)

• Anna Brandt, PD Dr., Principal investigator, University Hospital, Basel, Switzerland