This is a phase II study to evaluate the effectiveness and safety of Afininib compared to irinotecan in the 3-gene RNA sequencing (ALTRK) negative advanced esophageal squamous squamous carcinoma.

Participants were assigned to either group A or group B at 2:1 randomization (block randomization). Group A received afatinib (40 mg orally/day) every 6 weeks; Group B received irinotecan (140-180mg/m2 intravenous) every 2 weeks.

Inclusion Criteria:

1. Agree to participate and sign the informed consent form in writing;
2. Age: 18-75 years old;
3. No gender limit;
4. Esophageal squamous cell carcinoma diagnosed by pathology;
5. The results of 3-gene RNA sequencing (ALTRK) in tumor tissue were negative;
6. Imagingly confirmed unresectable advanced esophageal squamous cell carcinoma;
7. Failure of previous platinum-containing regimens and immunotherapy regimens (PD-1/PD-L1 monoclonal antibody);
8. At least one measurable lesion (according to RECIST1.1 criteria) or non-measurable lesion that can be evaluated, with imaging diagnosis ≤ 21 days from enrollment;
9. Estimated survival≥ 3 months;
10. General Physical Condition (ECOG) 0-1;
11. Sufficient bone marrow hematopoietic function (within 7 days): hemoglobin ≥ 9 g/dL, white blood cell ≥ 3.0×10^9/L, neutrophil ≥1.5×10^9/L, platelet ≥ 100×10^9/L; Normal liver and kidney function (within 14 days): TBIL ≤ 1.5 times the upper limit of normal; ALT and AST ≤ 2.5 times the upper limit of normal, and if liver metastases are present, ≤ 5 times the upper limit of normal; Creatinine ≤ 1.5 times the upper limit of normal;

Exclusion Criteria:

1. Those who are currently receiving other effective programs;
2. Patients who have participated in other clinical trials within 4 weeks before enrollment;
3. There is no measurable tumor foci, such as fluid accumulation in the body cavity or diffuse infiltration of organs;
4. Those who have received radiotherapy for measurable lesions;
5. Previous anti-EGFR monoclonal antibody or EGFR-TKI treatment;
6. Patients with other primary malignant tumors other than esophageal cancer at the same time, except for cured skin basal cell carcinoma and cervical carcinoma in situ;
7. Clinically significant cardiovascular diseases, such as heart failure (NYHA GRADE III-IV), uncontrolled coronary heart disease, cardiomyopathy, arrhythmia, uncontrolled hypertension or history of myocardial infarction within the past 1 year;
8. Neurological or psychiatric abnormalities affecting cognitive ability, including central nervous system metastases;
9. Active severe clinical infection (grade >2 NCI-CTCAE version 5.0) within 14 days prior to enrollment, including active TB;
10. Known or reported HIV infection or active hepatitis B or C;
11. Uncontrolled systemic diseases, such as poorly controlled diabetes;
12. History of interstitial lung disease, such as interstitial pneumonia, pulmonary fibrosis, or evidence of interstitial lung disease on baseline chest x-ray/CT;
13. Keratitis, ulcerative keratitis or severe dry eye;
14. Known hypersensitivity or anaphylaxis to any component of the investigational drug;
15. Pregnancy (determined by serum β-chorionic gonadotropin test) or breastfeeding;
16. The investigator determines that there are abnormal heart or lung or kidney or liver function that is not suitable for the treatment of this study;