| Eligibility |
Inclusion Criteria:
1. Male/female participants who are at least 18 years of age on the day of signing informed
consent with histologically confirmed diagnosis of high-risk localized or locooregional
cSCC as defined below may be enrolled in this study.
1. NOTE: Patients are eligible for this trial either at initial presentation for cSCC
with locally advanced and/or concurrent regional nodal metastasis; or at the time of
recurrence with locally advanced and/or concurrent regional nodal metastasis assuming
following criteria are met per the cSCC-specific AJCC UICC 8th edition staging
classification
i. T2 and Nx and M0 (tumor >2 cm and =4 cm in greatest dimension) OR;
ii. T3 and Nx and M0 (tumor >4 cm or minor bone erosion or perineural invasion or deep
invasion) OR;
1. Deep invasion is defined as invasion beyond the subcutaneous fat or >6 mm (as measured
from the granular layer of adjacent normal epidermis to the base of the tumor).
2. Perineural invasion is defined as tumor cells within the nerve sheath of a nerve lying
deeper than the dermis or measuring 0.1 mm or larger in caliber, or presenting with
clinical or radiographic involvement of named nerves without skull base invasion or
transgression.
iii. T4 and Nx and M0 (tumor with gross cortical bone/marrow, skull base invasion
and/or skull base foramen invasion if deemed surgically resectable) OR;
iv. Tx and N1-3 and M0 (if deemed surgically resectable) OR;
b. NOTE:
i. If T2, tumors must possess =2 NCCN/BWH clinical or pathologic risk factor(s) as
stated below.
ii. NCCN/BWH clinical risk factors:
1. Tumors =20 mm on trunk or extremities (excluding pretibia, hands, feet, nail units, and
ankles).
2. Tumors =10 mm on cheeks, forehead, scalp, neck, or pretibial areas.
iii. NCCN/BWH pathologic risk factors:
1. Poorly defined borders.
2. Recurrent tumors.
3. Neurologic symptoms to suggest perineural invasion.
4. High-risk histologic subtypes including: poorly differentiated tumor, acantholytic
(adenoid), adenosquamous, desmoplastic, or metaplastic (carcinosarcomatous) subtypes
(as stated in the pathology report or written documentation by Mohs surgeon).
5. Histopathologically documented perineural, lymphatic, or vascular involvement (as
stated in the pathology report or written documentation by Mohs surgeon).
c. NOTE: Tumors of any size on the "mask areas" of the face [central face, eyelids,
eyebrows, periorbital nose, lips (cutaneous and vermilion) are not eligible.
d. NOTE: Tumors of any size on genitalia, hands, and feet may be eligible at the
discretion of the treating surgical oncologist.
e. NOTE: Patients with tumors that arise in the setting of chronic inflammation
(Marjolin's ulcer) such as chronic wounds and/or scars are excluded.
f. NOTE: Determination of surgical resectability must be made before enrollment by the
treating surgical oncologist (or ENT surgeon or equivalent).
2. Male participants: A male participant must agree to use a contraception during the
treatment period and for at least 120 days after the last dose of study treatment and
refrain from donating sperm during this period.
3. 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:
1. Not a woman of childbearing potential (WOCBP)
OR
2. A WOCBP who agrees to follow the contraceptive guidance during the treatment period
and for at least 120 days after the last dose of study treatment.
4. The participant (or legally acceptable representative if applicable) provides
written informed consent for the trial.
5. Have at least a single site of measurable disease based on RECIST 1.1. Lesions
situated in a previously irradiated area are considered measurable if progression has
been demonstrated in such lesions.
6. Willing to undergo pre-treatment biopsies.
1. Prior archival tumor tissue sample are not permitted.
2. Minimum tissue requirements: core (16G or 18G, 6 cores; preferred), punch or
excisional biopsy of a tumor lesion that has not been previously irradiated.
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
a. ECOG evaluation should be performed at Screening and repeated on Cycle 1 Day 1.
8. Have adequate organ function, per protocol criteria
Exclusion Criteria:
1. Diagnosis of immunodeficiency, immunosuppression and/or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of trial treatment.
2. 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 (eg, CTLA-4,
OX 40, CD137).
3. Prior chemotherapy, targeted small molecule therapy within 2 weeks prior to study Day
1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to
a previously administered agent.
4. 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 2-week washout is permitted
for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease.
5. Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study intervention.
6. A WOCBP who has a positive urine pregnancy test at Screening. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
7. Has received a live vaccine within 30 days prior to the first dose of study drug.
1. 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.
2. Seasonal influenza vaccines for injection are generally killed virus vaccines and
are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live
attenuated vaccines and are not allowed.
8. 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 14 days prior to the first dose of study drug.
9. 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).
1. Note: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not
considered a form of systemic treatment and is allowed.
10. Concurrent non-hematologic malignancy other than cSCC within 3 years of data of first
planned dose of therapy except for tumors with a negligible risk of metastasis and/or
death as defined below:
a. Adequately treated non-invasive malignancies including but not limited to melanoma
in situ (MIS), BCC, CIS of cervix, or DCIS of breast may be enrolled.
b. Low-risk early stage prostate adenocarcinoma (T1-T2a N0 M0 and Gleason score =6 and
PSA =10 ng/mL) for which the management plan is active surveillance, or prostate
adenocarcinoma with biochemical-only recurrence with documented PSA doubling time of >
12 months for which the management plan is active surveillance may be enrolled.
c. Indolent hematologic malignancies for which the management plan is active
surveillance including but not limited to CLL/indolent lymphoma may be enrolled.
i. Patients with high-risk hematologic malignancies (CML, ALL, AML, Hodgkin's or non-
Hodgkin's lymphoma) are excluded even if the management plan is active surveillance.
11. Has known active CNS metastases and/or carcinomatous meningitis.
a. Note: 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 Screening), clinically stable and without requirement of steroid treatment for
at least 14 days prior to first dose of study intervention.
12. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients.
13. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
14. Has an active infection requiring systemic therapy.
15. Has a known history of Human Immunodeficiency Virus (HIV) infection.
16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) and/or known active Hepatitis C virus (defined as anti-HCV reactive)
infection.
a. Patients with treated Hepatitis B/C with no evidence of active infection may be
enrolled.
17. Has a known history of active TB (Bacillus Tuberculosis).
18. 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.
19. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
20. 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.
21. Has had an allogenic tissue/solid organ transplant.
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