Phase II Multi-centered Study of Perioperative Ivonescimab Versus Pembrolizumab Combined with Standard of Care (SOC) in Patients with Resectable, Locally Advanced Head and Neck Squamous Cell Carcinoma

Phase II Multicentered Study of Perioperative Ivonescimab Versus Pembrolizumab Combined with Standard of Care (SOC) in Patients with Resectable, Locally Advanced Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is one of the common malignant tumors in the world. More than 60% of HNSCC patients are locally advanced when first diagnosed. The treatment effect of locally advanced HNSCC is not ideal. About 50-60% of patients will have local recurrence within 2 years, and 20-30% of patients will have distant metastasis. The 5-year disease control rate is approximately 40%, and the 5-year overall survival rate is less than 50%.

In recent years, PD-1 inhibitors have shown significant efficacy in recurrent/metastatic HNSCC. The Keynote 040 and Checkmate 141 studies established the status of PD-1 inhibitors as second-line treatment in recurrent/metastatic HNSCC. The Keynote 048 study further established the value of PD-1 inhibitors alone or in combination with chemotherapy in the first-line treatment of recurrent/metastatic HNSCC. An increasing number of studies have attempted to explore the value of neoadjuvant therapy with PD-1 inhibitors in locally advanced HNSCC. For example,The Checkmate 358 study showed that the clinical objective response rate of neoadjuvant nivolumab monotherapy was 10.2%, and the major pathological response rate (MPR) was 2.9%.

Ivonescimab is a new PD-1/VEGF bispecific antibody drug, which can block both the PD-1 pathway and the VEGF pathway. This dual blocking mechanism is expected to enhance the efficacy of immunotherapy by improving the tumor microenvironment. Ivonescimab has been studied in Phase II to Phase III clinical studies in multiple tumor types such as lung cancer, breast cancer, and head and neck squamous cell carcinoma. For example, the HARMONi-2 study showed that ivocilizumab monotherapy had significantly better progression-free survival (PFS) than pembrolizumab in the treatment of PD-L1-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). In recurrent and metastatic HNSCC, Ivonescimab alone or in combination with the CD47 monoclonal antibody Ligufalimab has better objective response rate (ORR) and disease control rate (DCR) than pembrolizumab.

The aim of this study is to compare the efficacy and safety of perioperative treatment with Ivonescimab and pembrolizumab in surgically resectable locally advanced head and neck squamous cell carcinoma.

Inclusion Criteria:

1. ) Patients who signed the informed consent and were willing to complete the study according to the protocol.

2. ) Age ≥18.

3. ) Patients diagnosed with head and neck squamous cell carcinoma by histology, including those with primary lesions in the oropharynx, oral cavity, larynx, or hypopharynx, or those with head and neck squamous cell carcinoma of unknown primary lesion after comprehensive examination and multidisciplinary discussion.

4. ) Locally advanced head and neck squamous cell carcinoma that can be surgically resected ( AJCC staging 8th edition: stage III-IVB), excluding T4b.

5. ) There was at least one measurable lesion before treatment, which met the requirement of " measurable lesion " in RECIST 1.1 standard.

6. ) Expected survival period: >3 months.

7. ) ECOG score 0-1.

8. ) Good organ function: Meet the following requirements:

   1. Absolute neutrophil count ( ANC ) ≥ 1.5 ×10 9 / L ;
   2. Platelet count ≥ 100 × 10 9 / L ;
   3. Hemoglobin ≥ 9 g/ dL ;
   4. Serum albumin ≥ 2.8 g/ dL ;
   5. Total bilirubin ≤ 1.5 × ULN , ALT , AST and / or ALP ≤ 2.5 × ULN ;
   6. Serum creatinine ≤ 1.5 × ULN and creatinine clearance ≥60 mL/min (Cockcroft-Gault );
   7. Activated partial thromboplastin time ( APTT ) and international normalized ratio ( INR ) ≤ 1.5 × ULN (screening is allowed for patients who are using stable doses of anticoagulant therapy such as low molecular weight heparin or warfarin and whose INR is within the expected therapeutic range of the anticoagulant ).

9. ) Patients with hepatitis B virus ( HBV ) infection and inactive / asymptomatic HBV carriers, or patients with chronic or active HBV , will be allowed to enroll if HBV DNA <500 IU/mL (or 2500 copies/mL ) at screening . Patients with positive hepatitis C antibodies will be allowed to enroll if HCV-RNA is negative at screening .

10. ) Women of childbearing age , who must have a negative urine or serum pregnancy test result within 7 days before treatment . They must use a medically approved contraceptive method (such as intrauterine device, contraceptive pills or condoms) during the study treatment, at least 3 months after the last use of immunotherapy and at least 6 months after the last use of chemotherapy.

11. ) Male subjects who are not sterilized must be willing to use a medically approved contraceptive method (such as intrauterine device, birth control pills or condoms) during the study treatment, at least 3 months after the last use of immunotherapy, and at least 6 months after the last use of chemotherapy.

Exclusion Criteria:

1. Patients who have had or are suffering from other malignant tumors in the past (except for those who have been cured and have survived cancer-free for more than 5 years, such as basal cell carcinoma of the skin, carcinoma in situ of the cervix, and papillary thyroid carcinoma).
2. Received any of the following treatments:a. Received any investigational drug within 4 weeks before the first use of the investigational drug; b. Enrolled in another clinical study at the same time, unless it is an observational (non-interventional) clinical study; c. Subjects who need to be given corticosteroids (≥ 10 mg prednisone equivalent per day) or other immunosuppressants for systemic treatment within 2 weeks before the first use of the study drug, except for the use of corticosteroids for local inflammation and prevention of allergies, nausea and vomiting. Other special cases need to be communicated with the investigator. In the absence of active autoimmune diseases, inhaled or topical steroids and adrenal cortical hormone replacement with a dose of ≥ 10 mg/ day prednisone efficacy dose are allowed; d. Those who have received anti-tumor vaccines or have received live vaccines within 4 weeks before the first administration of the study drug (if the new coronavirus vaccine is received, the interval between the vaccination and treatment must be more than 2 weeks) .
3. Uncontrolled cardiac clinical symptoms or diseases, such as: a. NYHA grade II or above heart failure; b. Unstable angina; c. Myocardial infarction within 1 year; d. Patients with clinically significant supraventricular or ventricular arrhythmias requiring clinical intervention.
4. Severe infection ( CTCAE > 2 ) occurred within 4 weeks before the first use of the study drug , such as severe pneumonia, bacteremia, infectious complications requiring hospitalization, etc.; baseline chest imaging examination indicated active lung inflammation, symptoms and signs of infection within 4 weeks of the first use of the study drug, or the need for oral or intravenous antibiotic treatment.
5. Patients with active autoimmune diseases or a history of autoimmune diseases (such as interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes); but excluding autoimmune-mediated hypothyroidism treated with stable doses of thyroid replacement hormone; type 1 diabetes using stable doses of insulin; patients with vitiligo or healed childhood asthma / allergy who do not require any intervention as adults.
6. Have a history of immunodeficiency, including positive HIV test, or other acquired or congenital immunodeficiency diseases, or have a history of organ transplantation and allogeneic bone marrow transplantation.
7. A history of interstitial lung disease (excluding radiation pneumonitis without hormone treatment) or non-infectious pneumonia.
8. Patients with active pulmonary tuberculosis infection found through medical history or CT examination, or patients with a history of active pulmonary tuberculosis infection within 1 year before enrollment, or patients with a history of active pulmonary tuberculosis infection more than 1 year ago but without formal treatment.
9. Subjects have active hepatitis B ( HBV DNA ≥ 500 IU/mL or 2500 copies/mL ), hepatitis C (positive hepatitis C antibody, and HCV-RNA is higher than the detection limit of the analytical method).
10. Underwent major surgery or severe trauma in the past 30 days.
11. The researcher assesses that the patient has a high risk of bleeding (such as a history of severe bleeding tendency or abnormal coagulation function, such as the tumor enveloping the carotid artery >180 degrees, the tumor invading the trachea, etc.).
12. Known history of psychotropic substance abuse, alcoholism or drug abuse.
13. Pregnant or breastfeeding women.
14. The researcher judges that the subject has other factors that may force him/her to terminate the study midway, such as other serious diseases (including mental illness) requiring combined treatment, serious abnormal laboratory test values, family or social factors that may affect the safety of the subject or the collection of trial data.