Head and Neck Squamous Cell Carcinoma (HNSCC) represents a significant and growing health burden in China, with approximately 60% of new patients diagnosed at locally advanced (Stage III/IV) disease. Despite the application of multidisciplinary team (MDT) approaches, the prognosis for these patients remains poor, characterized by a 2-year recurrence rate of 50%-60%, a 20%-30% rate of distant metastasis, and a 5-year overall survival (OS) rate below 50%. Standard-of-care for locally advanced HNSCC involves surgery ± radiotherapy/chemoradiotherapy for resectable cases and platinum-based concurrent chemoradiotherapy (CRT) for unresectable cases. However, significant unmet therapeutic needs persist.
The advent of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies, has revolutionized treatment for recurrent/metastatic HNSCC, prompting exploration in the neoadjuvant setting. Previous studies suggest that neoadjuvant immunotherapy combined with chemotherapy can improve pathological complete response (pCR) rates in resectable locally advanced HNSCC, potentially increasing operability or reducing the extent of surgery to better preserve organ function. Adebrelimab is a novel, domestically developed humanized anti-PD-L1 monoclonal antibody. It blocks the PD-1/PD-L1 pathway to reactivate anti-tumor immunity and is designed for high specificity towards PD-L1, potentially leading to a favorable safety profile. Its efficacy and safety, combined with chemotherapy, have been demonstrated in cancers like extensive-stage small cell lung cancer and esophagogastric junction adenocarcinoma.
Recent groundbreaking research published in Science (June 2024) highlights a promising strategy to overcome ICI resistance by combining ICIs with JAK inhibitors. This combination can increase anti-tumor T and NK cell numbers and reverse T-cell exhaustion. Crucially, JAK inhibitors can prevent T-cell exhaustion induced by Type I Interferon (IFN-I) signaling. When combined with ICIs, they restore T-cell function, leading to enhanced anti-tumor efficacy. A key finding is that a temporally sequenced administration strategy-delaying the initiation of the JAK inhibitor-can preserve beneficial early immune activation while counteracting resistance mechanisms, as validated in preclinical models. Furthermore, an Interferon-Stimulated Gene (ISG) signature (e.g., IFIT1/MX1) may serve as a predictive biomarker to identify patients with active interferon signaling who are more likely to benefit from this approach.
Based on this compelling rationale, this clinical trial aims to investigate the combination of a JAK1 inhibitor with neoadjuvant chemoimmunotherapy in locally advanced HNSCC. A critical feature of the trial design is the implementation of the temporally sequenced dosing strategy for the JAK inhibitor, initiating it from day 8 of each treatment cycle to optimize the immune response and mitigate resistance.
In summary, this study seeks to address the critical unmet needs in locally advanced HNSCC by evaluating a novel, mechanistically rational combination of a JAK1 inhibitor (sulfamethoxazole) with neoadjuvant chemoimmunotherapy (adebrelimab + nab-paclitaxel/cisplatin), utilizing an innovative timed-sequencing approach. The trial aims to demonstrate improved efficacy and manageable safety, while pioneering biomarker-driven strategies for patient selection in this challenging disease.
