Inclusion Criteria:
* Male/female participants who are at least 18 years of age on the day of signing informed consent.
* Histologically confirmed diagnosis of locally advanced or diffuse or recurrent orbital or periorbital cutaneous squamous cell carcinoma.
* Female participants:
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
* Not a woman of childbearing potential (WOCBP) as defined.
* A WOCBP who agrees to follow the contraception guidance during the treatment period and for at least 120 days after the last dose of study treatment.
* The participant provides written informed consent for the trial.
* Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
* Absolute neutrophil count (ANC) ≥ 1500/uL.
* Platelets ≥ 100000/uL.
* Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L.
* Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
* Creatinine ≤ 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) ≥ 30 mL/min for participant with creatinine levels \> 1.5 x institutional ULN.
* Creatinine clearance (CrCl) should be calculated per institutional standard.
* Total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels \> 1.5 x ULN.
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 x ULN (≤ 5 x ULN for participants with liver metastases).
* International normalized ratio (INR) OR prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
* Have recovered from toxicities and/or complications from any prior major surgery before starting study treatment.
* Have a life expectancy of at least 12 weeks.
* Patients with human immunodeficiency virus (HIV) adequately controlled on antiretroviral therapy.
* Patients with known hepatitis B infection (defined as hepatitis B surface antigen \[HbsAg\] reactive) should be on suppressive anti hepatitis B virus (HBV) therapy, and patients with history of hepatitis C infection (defined as hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] detected) must complete curative antiviral treatment with HCV viral load below limit of quantification. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
Exclusion Criteria:
* Has any other histologic type of skin cancer other than invasive squamous cell carcinoma as the primary disease under study.
* A WOCBP who has a positive pregnancy test within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a negative serum pregnancy test will be required.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
* Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to enrollment. Participants must have recovered from all adverse events (AEs) due to previous therapies to ≤ grade 1 or baseline. Participants with ≤ grade 2 neuropathy may be eligible.
* Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
* Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist \[registered trademark\]) are live attenuated vaccines and are not allowed.
* Is currently participating in or has participated in a study of an investigational agent or has used an interventional investigational device within 4 weeks prior to the first dose of study intervention. Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers like ocular surface squamous cell neoplasia.
* Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
* Has severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients.
* Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
* Has an active infection requiring systemic therapy.
* Has a known history of active tuberculosis (TB) (bacillus tuberculosis).
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
* Has had an allogenic tissue (e.g., hematopoietic stem cell transplant \[HSCT\])/solid organ transplant.
* Has a history of any of the following cardiovascular conditions:
* Myocardial infarction within 6 months of enrollment.
* Active unstable angina.
* Congestive heart failure (≥ New York Heart Association Classification Class II)
* Cerebral vascular accident/stroke within 6 months of enrollment.
* Serious cardiac arrhythmia requiring medication. The classification of "serious" is at the discretion of the investigator.
