Trastuzumab and Standard Treatment With Chemo- and Immunotherapy as First Line Treatment for HER2 Positive Esophageal Squamous Cell Carcinoma Patients

Inclusion Criteria:

1. Signed informed consent
2. Age ≥18 years
3. Inoperable locally advanced or metastatic squamous cell carcinoma of the esophagus notamenable for curative intended therapy
4. HER2 positive defined as IHC2+ and FISH amplification ratio ≥2 or IHC3+
5. ECOG PS <2
6. Baseline left ventricular ejection fraction > 50% measured by echocardiography or MUGA
7. Adequate bone marrow function and organ function:
8. Hematopoietic function:
9. Leucocytes > 3.0 x 109/l, neutrocytes > 1.5 x 109/l and thrombocytes > 100 x 109/l
10. Serum bilirubin < 1.5 × upper limit of normal (ULN); and AST/ALT < 2.5 × ULN (or < 5 × ULN in patients with liver metastases).
11. Creatinine clearance > 30 ml/min

Exclusion Criteria:

1. Prior systemic treatment with non-curative intent including HER2-targeting drugs.Prior neoadjuvant and adjuvant therapies as well as palliative radiotherapy areallowed
2. Significant medical illness that in the investigator's opinion cannot be adequatelycontrolled with appropriate therapy or would compromise the patient's ability totolerate study treatment
3. Congestive heart failure (New York Heart Association (NYHA) class 3+4); uncontrolledangina pectoris; poorly controlled hypertension (systolic BP > 180 mmHg or diastolicBP > 100 mmHg); or high-risk uncontrollable arrhythmias.
4. Patients with severe dyspnoea at rest due to complications of advanced malignancy orrequiring supplementary oxygen therapy.
5. Patients with known hypersensitivity to trastuzumab or any of the study drugs, murineproteins, or to any of the excipients
6. Symptomatic brain metastases uncontrolled by corticosteroids or carcinomatousmeningitis
7. Homozygosity or compound heterozygosity for more than one gene variant ofdihydropyrimidine dehydrogenase (DPD) known to cause major reduced metabolism of 5-FUderivates OR plasma uracil > 150 ng/ml are not eligible. Patients with minor DPDinsufficiency are allowed provided that local guidelines for administration of 5-FUare followed.
8. Any other cancer (excluding low risk prostate cancer, carcinoma in situ and radicallyoperated localised squamous skin cancer) with clinical activity within the last 2years
9. Other current cancer treatments except for anti-hormone and anti-resorptive treatmentof bone metastasis.
10. Allopurinol, phenytoin, warfarin treatment is not allowed. Non vitamin K oralanticoagulants (NOAK) and low molecular weight (LMW) heparin is allowed
11. Pregnancy or breast-feeding
12. Positive serum pregnancy test in women of childbearing potential.
13. Subjects with reproductive potential not willing to use an effective method ofcontraception under and 3 months after participation in this study