Neoadjuvant Sintilimab Plus Chemotherapy for cT2N0M0 Oral Squamous Cell Carcinoma

Overview

This study is a superiority multi-center, open-label, phase III randomized controlled trial. It will further verify the clinical value of xidili single-antibody combined with chemotherapy (albumin paclitaxel and carboplatin) in neoadjuvant treatment for operable cT2N0M0 early oral squamous cell carcinoma (Oral Squamous Cell Carcinoma, OSCC) patients in terms of improving long-term survival and pathological remission. The study subjects are patients aged 18-75 years, diagnosed with cT2N0M0 stage (8th edition AJCC staging as stage II) OSCC by pathology, with ECOG score of 0-1, good organ function, and meeting laboratory standards (ANC ≥ 1.5 × 10⁹/L, Hb \> 90g/L, CrCl ≥ 60ml/min, ALT/AST ≤ 2.5 × ULN); Exclusion criteria include previous immunotherapy with immune checkpoint inhibitors, active autoimmune diseases, poorly controlled comorbidities, high viral load infection of HBV/HCV, etc.; Patients with surgical resection conditions and signing informed consent will be enrolled. The subjects were randomly divided into two groups at a ratio of 1:1: The experimental group received neoadjuvant treatment with xidili single-antibody combined with albumin paclitaxel and carboplatin for 2-3 cycles followed by surgery (primary lesion resection + I-III region cervical lymph node dissection), while the control group received standard treatment (direct surgery). The primary endpoint of the study is the 3-year event-free survival rate (Event-Free Survival rate, EFS rate), and secondary endpoints include overall survival rate (Overall survival rate, OS rate), major pathological response rate (Major Pathological Response, MPR), complete pathological response rate (Complete Pathological Response, pCR), objective response rate (Objective Response Rate, ORR), safety analysis (Treatment-Related Adverse Event, TRAE), and postoperative lymph node positive rate (Lymph Node Positivity rate, LNP rate). The sample size was calculated based on the Log-rank test, referring to the prospective clinical baseline data of standard surgical treatment for early oral cancer, setting the 3-year EFS rate of the control group at 80%, assuming that the experimental group can be improved to 90% (HR = 0.47), setting a two-sided α = 0.05, efficacy 80%, and follow-up dropout rate 10%, a total of 300 patients (150 in each group) need to be enrolled. This study will provide high-quality evidence-based evidence for optimizing the treatment strategy for cT2N0M0 early high-risk oral squamous cell carcinoma, improving the pathological response rate and long-term recurrence-free survival.

OSCC accounts for over 90% of oral malignancies and is one of the most common malignant tumors in the head and neck region. According to the latest global cancer statistics from GLOBOCAN 2022, there are approximately 389,000 new cases of OSCC worldwide each year, with about 188,000 deaths. In China, there are approximately 37,000 new cases, and the incidence and mortality rates are among the highest globally . Currently, authoritative guidelines such as NCCN/CSCO recommend the implementation of extended resection of the primary lesion and prophylactic neck lymph node dissection for the standard treatment of early OSCC (cT1-2N0M0). However, this classic local regional control strategy is facing clinical bottlenecks that are difficult to overcome. Firstly, even for early patients who were highly dependent on imaging assessment as cN0 before surgery, the rate of occult cervical lymph node metastasis confirmed by postoperative pathology still reaches 20%-40% . Studies have shown that tumor invasion depth (Depth of Invasion, DOI) is a key independent indicator for predicting lymph node metastasis, and when DOI \> 4mm, the risk of occult metastasis increases . Therefore, elective neck dissection (END) can reduce the mortality risk by 36% compared to salvage neck dissection, establishing the standard status of END ; although subsequent studies have confirmed that the navigation strategy of sentinel lymph node biopsy (SLNB) is not inferior to traditional END in local control , lymph node metastasis remains the most significant driving factor for postoperative recurrence and deterioration of survival. More importantly, whether END or SLNB, they are essentially local anatomical clearance methods that cannot effectively reverse the already existing systemic micro-residual disease (Minimal Residual Disease, MRD) in the peripheral blood or lymph circulation. Data show that even after standard primary lesion resection and END, 20%-30% of early patients still experience local regional recurrence or distant metastasis during follow-up . Real-world studies and systematic reviews further indicate that the 5-year OS of early OSCC patients under the current model can reach 75%-85%, but the 5-year disease-free survival rate (Disease-Free Survival, DFS) is only 60%-80%. Compared to I/II stage breast cancer (5-year OS reaching 93.1%-99.2%) or early lung cancer (5-year OS reaching over 92%), the long-term cure rate of early OSCC is significantly lagging behind. Even more challenging is that the recurrence of early OSCC mainly occurs within 3 years after surgery, and survival deteriorates sharply after recurrence, with the 5-year OS after salvage treatment being less than 30% . Therefore, how to implement systemic treatment at the initial stage to eliminate occult micro-metastases, reduce the risk of postoperative recurrence, is a key scientific issue for further improving the survival of early OSCC patients. In recent years, immune checkpoint inhibitors (ICIs) have become an important breakthrough in the treatment of malignant tumors. ICIs such as PD-1/PD-L1 inhibitors, due to their good safety and wide indications, show better clinical application prospects and significant clinical benefits in various solid tumors. Unlike traditional cytotoxic drugs, PD-1/PD-L1 inhibitors relieve the immune suppression mediated by tumor cells, restore the anti-tumor activity of T cells, and thereby achieve continuous anti-tumor effects. More and more studies suggest that, compared with the advanced disease stage, early resectable tumors are also suitable as the window period for immunotherapy intervention. The intact primary tumor can continuously provide abundant tumor antigens, promoting dendritic cell antigen presentation and the clonal expansion of tumor-specific T cells, and facilitating the early clearance of imaging-undetectable micrometastases and the establishment of long-term immune memory . This concept of "perioperative immunotherapy" has become an important development direction in the field of solid tumor treatment. In the field of non-small cell lung cancer (NSCLC), the CheckMate-816 study first confirmed that nivolumab combined with chemotherapy as neoadjuvant treatment could significantly increase the pCR rate (24.0% vs 2.2%) and MPR rate, and significantly improve EFS . Subsequently, KEYNOTE-671 and AEGEAN studies further confirmed that the perioperative treatment mode based on PD-1/PD-L1 inhibitors could continuously improve EFS and OS, promoting perioperative immunotherapy to become an important treatment strategy for resectable early NSCLC . In the field of triple-negative breast cancer (TNBC), the KEYNOTE-522 study showed that pembrolizumab combined with neoadjuvant chemotherapy could increase the pCR rate from 51.2% to 64.8%, and significantly improve long-term survival outcomes. Further follow-up results showed that the combined treatment group had better 5-year EFS and OS than the control group, with a reduction in death risk of approximately 34%, ultimately establishing the standard treatment position of perioperative immunotherapy in early high-risk TNBC . These successful cases collectively indicate that in early solid tumors with a chance of radical cure, moving immunotherapy forward to the perioperative stage not only improves the pathological response rate but can directly translate into long-term survival benefits. In the field of head and neck squamous cell carcinoma (HNSCC), the front line of immune systemic treatment has also experienced a rapid advancement from late rescue to perioperative placement. Initially, the KEYNOTE-048 study first established the dominant position of pembrolizumab monotherapy or combined with platinum + 5-FU chemotherapy as the first-line standard treatment for recurrent/metastatic HNSCC, which significantly prolonged the OS of patients compared to the traditional EXTREME regimen, and this regimen was also recommended by international guidelines such as NCCN and ESMO. After achieving a milestone breakthrough in the first-line treatment of recurrent/metastatic cases, the academic community began to explore the timing of immunological intervention to be moved forward to the "locally advanced resectable" stage. The landmark KEYNOTE-689 randomized controlled clinical study published in The New England Journal of Medicine (NEJM) officially ushered in a historic breakthrough. This study confirmed that in resectable locally advanced HNSCC patients, using perioperative pembrolizumab (2 cycles of preoperative neoadjuvant + 15 cycles of postoperative adjuvant) combined with standard treatment (surgery ± postoperative radiotherapy and chemotherapy) could significantly prolong the EFS of patients, without increasing the risk of surgery delay or postoperative complications . Based on the epoch-making breakthrough achieved by the KEYNOTE-689 study, this perioperative immunotherapy combination has been officially included in the NCCN head and neck tumor clinical practice guidelines (version 1, 2026), establishing its position as the first-line standard treatment for locally advanced resectable HNSCC . This major guideline update not only fully validates the biological and pharmacological rationality of applying PD-1 inhibitors during the perioperative period for head and neck squamous cell carcinoma on an international scale, but also provides the most solid top-level evidence-based medical basis for further advancing immunotherapy to earlier stages of OSCC with potential latent metastasis and high-risk recurrence characteristics. Based on the above scientific frontiers, our center has conducted a two-stage, progressive, and prospective single-center exploratory clinical study on neoadjuvant immunotherapy for early OSCC. In the first stage of the exploration, we initiated a single-center study ("2-cycle PD-1 monoclonal antibody combined with chemotherapy neoadjuvant treatment + local extended resection (without routine neck dissection) for early oral squamous cell carcinoma") (NCT06130332). The results showed that the experimental group achieved better pathological and survival benefits: ORR reached 85.0%, and the MPR rate was as high as 95.0% . During the follow-up, the 2-year EFS rate of the experimental group reached 94.7%, and the 2-year OS rate reached 100.0% , successfully achieving the preset non-inferiority endpoint. In addition, the safety of neoadjuvant treatment was excellent, and the incidence of postoperative complications was significantly lower than that of the control group undergoing direct surgery, and it also had better quality of life and health economics benefits. To fully eliminate the potential threat of latent lymph node metastasis to the long-term EFS of patients, our center further conducted an exploratory study in the second stage ("PD-1 monoclonal antibody combined with TP neoadjuvant treatment + radical extended resection + cervical lymph node dissection for cT1-2N0M0 oral squamous cell carcinoma") (NCT07267286). The results further confirmed the excellent efficacy of this combined regimen while maintaining extremely high clinical safety: the postoperative pathological MPR rate of the experimental group was as high as 72.0%, and the 2-year follow-up EFS reached 100.0% . This series of preliminary exploration data not only fully demonstrated the safety of the regimen, but also clearly indicated that preoperative immunotherapy combined with chemotherapy, in combination with the standard primary lesion resection and cervical dissection during surgery, could generate a powerful regional and systemic synergistic control effect. In the study design, this research clearly targeted cT2N0M0 patients in the 8th edition of the AJCC staging system as the research subjects, and strictly excluded cT1N0M0 patients. This screening logic lies in the precise balance of biology and clinical "risk-benefit" of early OSCC. Firstly, this measure can effectively avoid "excessive treatment" and "benefit ceiling" for cT1N0M0 patients. Evidence-based medical data shows that after standard surgical treatment for cT1N0M0 patients, their 5-year OS has reached 85%-90%, and some superficial lesions even approach 95%. This means that the efficacy of routine surgery for this population has reached the "ceiling", and if new adjuvant immunotherapy chemotherapy is blindly added during the perioperative period, not only will it bring more significant survival benefits, but it will also increase the possibility of systemic toxic side effects. On the contrary, this project can precisely target cT2N0M0 patients with potential high-risk characteristics. The latest 8th edition of the AJCC staging system assigns core T stage weight to DOI, precisely because most cT2 patients have DOI \> 4mm accompanied by a 20%-40% high risk of latent lymph node metastasis and high tumor burden . Although these patients are early resectable, their tumor infiltration depth is large and they are at the edge of peripheral micrometastasis, and they are high-risk groups for traditional surgical treatment failure and short-term recurrence. Therefore, the cT2N0M0 population not only has a relatively high probability of clinical cure, but also faces the threat of recurrence due to latent micrometastasis. At this stage, early intervention is most likely to significantly reduce the recurrence rate. This plan selects Xidiliantumab combined with the TP regimen (albumin-bound paclitaxel + carboplatin) as the core for preoperative neoadjuvant therapy, which has a solid basis of molecular pharmacology for synergistic enhancement. Xidiliantumab (development code: IBI308) is a recombinant fully human IgG4-type PD-1 monoclonal antibody, independently developed by Sinopharm Biopharmaceuticals (Suzhou) Co., Ltd. (hereinafter referred to as "Sinopharm Company"). It specifically binds to the PD-1 molecule on the surface of T lymphocytes, thereby blocking the PD-1/PD-L1 pathway that leads to tumor immune tolerance, and reactivates the anti-tumor activity of T lymphocytes to achieve the purpose of treating tumors. Xidiliantumab and nivolumab as well as pembrolizumab target the same target, but have different amino acid sequences. Multiple preclinical in vitro experiments have verified the effect of Xidiliantumab in blocking the PD-1 pathway, and the results of completed preclinical pharmacodynamics, animal pharmacokinetics and toxicology studies have shown that Xidiliantumab has the characteristics of clear target, reliable cell line source and good drug stability. Multiple clinical studies have also confirmed its effectiveness and safety in clinical application, and it has been approved for indications in multiple tumor types such as Hodgkin's lymphoma, non-small cell lung cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, gastric and gastroesophageal junction adenocarcinoma, and endometrial cancer. The clinical research of Xidiliantumab in the HNSCC field has accumulated certain evidence. A single-arm prospective study evaluated the efficacy and safety of anlotinib combined with Xidiliantumab in the treatment of recurrent or metastatic HNSCC, including 10 patients, of which 8 cases could undergo radiological assessment . The results showed that the ORR was 50%, the disease control rate reached 100%, the mOS was 4.37 months, and the 1-year OS was 37.5%. In terms of safety, 50% of the patients experienced grade 3 or higher adverse events, the most common being tumor pain (50%), hypertension (37.5%), and tumor bleeding. Another prospective study included 163 patients with locally advanced HNSCC, of which 98 cases received chemotherapy alone, and 65 cases received Xidiliantumab combined with chemotherapy. After a median follow-up of 28.0 months, the ORR of the combined treatment group was significantly higher than that of the chemotherapy alone group (84.6% vs 68.4%, p = 0.019). In addition, the 2-year progression-free survival rate (PFS) of the combined treatment group was 44% (95% CI: 32%-56%), significantly better than that of the chemotherapy alone group (27% (95% CI: 18%-36%), p = 0.041). There was no significant difference in the incidence of grade 3 or higher acute toxic reactions between the two groups (18.5% in the combined group vs 15.3% in the chemotherapy group, p \> 0.05). On the other hand, paclitaxel combined with carboplatin (TP regimen) is a first-line treatment for recurrent or metastatic oral and oropharyngeal squamous cell carcinoma. The induction chemotherapy of carboplatin combined with paclitaxel can provide 8% to 33% and 50% to 85% complete response rates and partial response rates respectively . Immunotherapy combined with chemotherapy has shown better response rates in various tumors and can induce immunogenic cell death to release tumor antigens , generating a strong pharmacological synergy with PD-1 inhibitors. Therefore, Xidiliantumab combined with carboplatin and albumin paclitaxel has strong clinical application prospects in neoadjuvant treatment of oral cancer. Based on this, this project intends to conduct a randomized controlled, open-label, multicenter, phase III clinical study of xidili single-agent combined with chemotherapy for neoadjuvant treatment of cT2N0M0 early-stage oral squamous cell carcinoma. The aim is to further improve the prognosis of cT2N0M0 stage oral cancer patients during the perioperative management, provide new evidence-based guidance for the precise diagnosis and treatment of this population, and potentially promote the update of future clinical treatment guidelines.