AK104 and Low-dose Radiation in Recurrent/metastatic HNSCC After Failure of First-line Systemic Therapy

Currently, there is a lack of high-quality clinical evidence for subsequent treatment options for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) after first-line treatment, especially for subsequent treatment after first-line therapy combined with PD-1 inhibitors. Increasing evidence suggests that low-dose radiation (LDRT) can reshape the tumor microenvironment.Cadonilimab is a bispecific antibody that specifically binds to CTLA-4 and PD-1 proteins in the human body.

Considering that low-dose radiotherapy and cadonilimab both have immunomodulatory effects, this study intends to select recurrent metastatic HNSCC patients who have failed first-line and above treatment to explore the safety and efficacy of cadonilimab combined with low-dose radiotherapy.

Currently, there is a lack of high-quality clinical evidence for subsequent treatment options for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) after first-line treatment, especially for subsequent treatment after first-line therapy combined with PD-1 inhibitors. Increasing evidence suggests that low-dose radiation (LDRT) can reshape the tumor microenvironment, polarize macrophages towards M1, and M1 macrophages secrete chemokines to promote the recruitment of effector T cells while inducing vascular normalization.

Cadonilimab is a bispecific antibody that specifically binds to CTLA-4 and PD-1 proteins in the human body. It is the first approved PD-1/CTLA-4 bispecific antibody. In June 2022, cadonilimab was approved by the NMPA for the treatment of recurrent or metastatic cervical cancer patients after platinum-based chemotherapy failure. The drug is currently undergoing clinical trials for other types of cancers, including non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, esophageal cancer, and nasopharyngeal cancer.

In view of the subsequent treatment strategies for recurrent metastatic HNSCC after first-line treatment progress, there is still a lack of high-level evidence-based medical evidence to confirm the best recommendation for subsequent treatment. Considering that low-dose radiotherapy and cadonilimab both have immunomodulatory effects, this study intends to select recurrent metastatic HNSCC patients who have failed first-line and above treatment to explore the safety and efficacy of cadonilimab combined with low-dose radiotherapy.

Eligibility Criteria:
Inclusion Criteria:

1. Patients who signed the informed consent and were willing to complete the study according to the protocol;
2. Aged ≥18 years and ≤75 years;
3. Histologically confirmed head and neck squamous cell carcinoma;
4. Patients with recurrent and metastatic head and neck squamous cell carcinoma, with progression on first-line treatment or above; or locally advanced head and neck squamous cell carcinoma, with recurrence and metastasis within 6 months after radical radiotherapy;
5. For patients with locally recurrent head and neck squamous cell carcinoma, those who are not suitable for local treatment after multidisciplinary evaluation of head and neck tumors;
6. At least one measurable lesion before treatment, that is, meeting the "measurable lesion" requirement in the RECIST 1.1 standard;
7. Expected survival period\>3 months;
8. ECOG score 0-2 points;
9. Good organ function: meet the following requirements:

   1. Absolute neutrophil count (ANC) ≥1.5×109/L;
   2. Platelet count ≥100×109/L;
   3. Hemoglobin ≥9g/dL;
   4. Serum albumin ≥2.8g/dL;
   5. Total bilirubin ≤1.5×ULN, ALT, AST and/or ALP ≤3×ULN;
   6. Serum creatinine ≤1.5×ULN and creatinine clearance ≥60 mL/min (Cockcroft-Gault, see Appendix 3);
   7. Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤1.5× ULN (screening is allowed for patients who are taking 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);
10. 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.
11. Women of childbearing age need to have a negative urine or serum pregnancy test result within ≤7 days before treatment. And 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 cadonilimab, and at least 6 months after the last use of chemotherapy;
12. 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 cadonilimab, and at least 6 months after the last use of chemotherapy.

Exclusion Criteria:

1. Patients who have received anti-CTLA-4 antibodies, or any other antibodies or drugs targeting T cell co-stimulation or checkpoint pathways, or small molecule tyrosine kinase inhibitors, including lenvatinib, anlotinib, apatinib, etc.;
2. Patients with symptoms of spinal cord compression, risk of pathological fracture, or emergency surgery and/or radiotherapy due to other medical needs;
3. Patients with a history of gastrointestinal perforation and/or fistula within 6 months before enrollment (if the gastrointestinal perforation or fistula has been surgically removed, enrollment is allowed);
4. Patients with necrotic lesions within 4 weeks before enrollment, or tumors directly invading the trachea, bronchus, esophagus, or arteries, and who are judged by the investigator to have a risk of major bleeding;
5. Patients with other malignant tumors in the past or at the same time (except for malignant tumors that have been cured and have survived without cancer for more than 3 years, such as basal cell carcinoma of the skin, carcinoma in situ of the cervix, and papillary thyroid carcinoma);
6. Uncontrolled clinical symptoms or diseases of the heart, such as: a. NYHA heart failure of grade II or above; b. Unstable angina pectoris; c. Myocardial infarction within 1 year; d. Patients with clinically significant supraventricular or ventricular arrhythmias requiring clinical intervention;
7. Received any of the following treatments:

   1. Received any research drug within 4 weeks before the first use of the study drug;
   2. Enrolled in another clinical study at the same time, unless it is an observational (non-interventional) clinical study;
   3. Subjects who need to be given corticosteroids (daily prednisone equivalent dose of \>10 mg) 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 adrenocortical hormone replacement at a dose of \>10 mg/day prednisone are allowed;
   4. Patients who have received anti-tumor vaccines or have received vaccines (including live vaccines or inactivated vaccines) within 4 weeks before the first administration of the study drug;
   5. Patients who have undergone major surgery or severe trauma within 4 weeks before the first use of the study drug;
8. The toxicity of previous anti-tumor treatment has not recovered to ≤CTCAE grade 1 (except for sequelae of alopecia and neurotoxicity related to previous platinum treatment) or the level specified by the inclusion/exclusion criteria;
9. Severe infection (CTCAE\>2) occurred within 4 weeks before the first use of the study drug, such as severe pneumonia, bacteremia, infectious complications, etc. requiring hospitalization; baseline chest imaging examinations indicate 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;
10. 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 not including 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/allergies who do not require any intervention as adults;
11. Patients with a history of immunodeficiency, including HIV positive, or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation and allogeneic bone marrow transplantation;
12. Patients with a history of interstitial lung disease (excluding radiation pneumonia without steroid treatment) or non-infectious pneumonia;
13. 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;
14. Subjects with 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);
15. known history of psychotropic drug abuse, alcoholism or drug abuse;
16. pregnant or lactating women;
17. the researcher judges that the subject has other factors that may force him 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.