The primary purpose of this study is to find out if Afatinib can help treat participants with advanced cSCC.

Inclusion Criteria:

• Age ≥ 18 years at the time of informed consent
• ECOG performance status ≤2
• Adequate bone marrow, organ function and laboratory parameters:
• ANC ≥ 1.0 × 109/L;
• Hemoglobin ≥ 8 g/dL;
• Platelets ≥ 75 × 109/L;
• AST and ALT ≤5 × ULN
• Calculated creatinine clearance > 15mL/min by Cockroft-Gault formula
• Histologic diagnosis of invasive cutaneous squamous cell carcinoma, that is deemed not appropriate for further surgical intervention and/or radiation therapy. Participants may have either locally advanced or metastatic disease.
• At least 1 measurable lesion - either per RECIST 1.1 criteria, or for patients with externally visible cuSCC lesion(s) not measurable on imaging, at least one lesion ≥1 cm in longer diameter, amenable to digital photography with bi-dimensional measurements
• Participants must have received prior immunotherapy with an anti-PD-1/PD-L1 antibody, if participant was deemed eligible (i.e., was not immunosuppressed or a transplant receipt, etc)
• Immunosuppressed participant including those with concurrent autoimmune diseases and solid organ transplant recipients are eligible
• Prior to first dose of study treatment, participant must be at least 2 weeks from any prior systemic therapy, major surgery or radiation
• Able to undergo a pre-treatment and on-treatment tumor biopsy
• Female participants of childbearing potential must have a negative serum or urine β-HCG test result. Female participants of childbearing potential and male participants must agree to use methods of contraception that are highly effective.
• Participants with brain metastases are permitted assuming that the brain metastases have been adequately treated with prior surgery or radiation.

Exclusion Criteria:

• In participants with known liver cirrhosis, those with severe (Child Pugh C) hepatic impairment will be excluded.
• Untreated, uncontrolled or symptomatic brain metastases or leptomeningeal carcinomatosis that are not stable or require corticosteroids,
• Participants with mixed histologies (eg, sarcomatoid, adenosquamous) will generally not be eligible, unless the predominant histology is invasive cuSCC.
• Participants with a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 90 days prior to randomization. Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load prior to randomization.
• Pregnancy or breast feeding.