Low-dose Radiotherapy Plus Tislelizumab in Combination With Afatinib for Neoadjuvant Treatment of Surgically Resectable Head and Neck Squamous Carcinoma

The purpose of this study was to evaluate the safety and tolerability of low-dose radiotherapy plus tislelizumab in combination with afatinib neoadjuvant therapy for patients with surgically resectable squamous carcinoma of the head and neck.

Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy of the head and neck. More than 60% of patients with HNSCC have locally advanced or metastatic disease at the time of diagnosis, with a 5-year overall survival rate of less than 60%. The clinical outcomes of those patients still need to be improved.

Neoadjuvant therapy theoretically can reduce tumor volume, increase organ retention rate, and reduce distant metastasis rate. However, in addition to nasopharyngeal carcinoma, results from several phase III clinical trials have not proved a significant survival benefit of neoadjuvant chemotherapy for patients with resectable HNSCC. It is urgent to explore new neoadjuvant treatment options to improve the prognosis of patients with HNSCC.

Immunotherapy such as PD-1/PD-L1 inhibitors have shown excellent efficiency in the treatment of malignancies. Anti-PD-1 therapy is approved as the first-line treatment of recurrent/metastatic HNSCC. Neoadjuvant immunotherapy for the treatment of locally advanced and resectable HNSCC has been demonstrated to be feasible in some trials.

Afatinib, as an irreversible ErbB tyrosine kinase inhibitor (TKI), has been used as the second-line treatment for recurrent and/or metastatic HNSCC. However, there is a lack of high-level evidence-based medical evidence for the use of afatinib in preoperative therapy for HNSCC. A previous study published in 2018 confirmed that afatinib can be administered safely before surgery.

Radiotherapy is the standard or adjuvant treatment for most patients with head and neck cancer. In HNSCC, combining radiotherapy with immunotherapy has been shown to induce effective anti-tumor immune responses. The mechanism may be that, in addition to direct cytotoxic effects on cancer cells, radiotherapy remodels the tumor microenvironment and affects the number and composition of tumor-infiltrating immune cells, thereby altering the response to immune checkpoint inhibitor therapy.

However, conventional radiation therapy is often associated with adverse effects, such as dry mouth, dysphagia, oral mucositis, and pain, which will lead to a reduction in the quality of life of the patient, and severe adverse effects can even lead to interruption of treatment. Low-dose radiotherapy (LDRT) is usually defined as radiotherapy with ≤2 Gray (Gy) per fraction and a total dose of up to 10 Gy, and is considered to be a non-ablative treatment.LDRT has less impact on the patient compared to conventional radiation therapy, and its low toxicity makes it suitable for tumor lesions that are not amenable to stereotactic radiation therapy.In addition to its low radiotherapy toxicity, LDRT has been shown to cause tumor regression by reprogramming the tumor immune microenvironment.

In conclusion, the researchers designed this study to investigate the efficacy and safety of low-dose radiotherapy plus the anti-PD1 immunotherapy teslizumab in combination with an epidermal growth factor receptor-TKI (afatinib) as a neoadjuvant treatment option for patients with resectable HNSCC, with the aim of providing a new therapeutic option for these patients.

Eligibility Criteria:
Inclusion Criteria:

1. Age 18 years or above.
2. Patients with pathologically confirmed HNSCC (except for nasopharyngeal carcinoma) and meet the following condition:

   * were newly diagnosed and without distant metastasis;were deemed surgically
   * resectable evaluated by a head and neck surgeon;
   * were willing to undergo surgery.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
4. Adequate organ and bone marrow function:

   * absolute neutrophil count ≥ 1.5 × 10\^9/L, hemoglobin ≥ 80 g/L, platelets ≥ 80 × 10\^9/L;
   * ALT, AST and ALP \< 2.5× upper limit of normal (ULN), total bilirubin ≤ 2×ULN; albumin≥ 2.8 g/dL；
   * creatinine clearance ≥ 60 ml/min；
   * INR≤ 1.5, APTT≤ 1.5×ULN.
5. Written informed consent.

Exclusion Criteria:

1. History of other malignancies (except for the history of malignant tumors that have been cured and have not recurred within 5 years, such as skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, in situ cervical cancer, and gastrointestinal mucosal cancer, etc.）
2. Have an active autoimmune disease requiring systemic treatment or a documented history of clinically severe autoimmune disease.
3. Any history of allergic disease, or a sever hypersensitivity reaction to drugs, or allergy to the study drug components.
4. Any of prior therapy with:

   * anti-PD-1, anti-PD-L1/2, anti-CTLA-4 antibody, anti-EGFR antibody or EGFR-TKIs；
   * antitumor vaccine;
   * any active vaccine against an infectious disease within 4 weeks prior to the first dose or planned during the study period;
   * major surgery or serious trauma within 4 weeks before the first dose;
   * toxicity from prior antitumor therapy has not recovered to ≤ CTCAE Version 5.0 Grade 1 or the level specified by the inclusion/exclusion criteria.
5. With serious medical diseases, such as grade II and above cardiac dysfunction (NYHA criteria), ischemic heart disease, supraventricular or ventricular arrhythmia, poorly controlled diabetes mellitus, poorly controlled hypertension, echocardiographic ejection fraction \< 50%, etc.
6. With interstitial pneumonitis, non-infectious pneumonitis, active pulmonary tuberculosis, or history of pulmonary tuberculosis infection that were not controlled by treatment.
7. With hyperthyroidism, or organic thyroid disease.
8. With active infection, or unexplained fever during the screening period or 48 hours before the first dose.
9. With active hepatitis B or C, or known history of positive HIV test, or acquired immunodeficiency syndrome.
10. History of a clear neurological or psychiatric disorder.
11. History of drug abuse or alcohol abuse.
12. Women who are pregnant or breastfeeding, or have a reproductive plan from the screening period to 3 months after the end of the study, or have sex without contraceptive measures, or are unwilling to take appropriate contraceptive measures.
13. Received any investigational drug within 4 weeks prior to the first dose, or concurrently enrolled in another clinical trial.
14. Any other factors that are not suitable for inclusion in this study judged by investigators.