Sintilimab Combined With Chemotherapy as Neoadjuvant Therapy for cT2N0M0 Early-Stage Oral Squamous Cell Carcinoma: A Multicenter, Randomized Controlled, Open-Label, Superiority, Phase III Clinical Trial

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.