Phase II Neoadjuvant Study of PD-1 Inhibitor Pembrolizumab in PD-1 Naive Cutaneous Squamous Cell Carcinoma (cSCC)
Phase: PHASE2
Conditions: Squamous Cell Carcinoma
Sponsor: Diwakar Davar

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SPONSOR: Diwakar Davar 
 
TITLE: Phase II neoadjuvant study of PD-1 inhibitor pembrolizumab in PD-1 naive cutaneous 
squamous cell carcinoma (cSCC) 
 
IND NUMBER: IND exempt 
 
NCT NUMBER: NCT04808999 
 
Principal Investigators: 
• Overall PI: Diwakar Davar 
• Surgical co-investigator: Shaum Sridharan 
• Radiation co-investigator: Ravi Patel 
• Dermatologist co-investigator: Melissa Pugliano-Mauro 
 
Statistician: Hong Wang 
 
 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase II neoadjuvant study of PD-1 inhibitor pembrolizumab in PD-1 
naive cutaneous squamous cell carcinoma (cSCC) (Neo-SCC) 
Trial Phase 
Phase II 
Clinical Indication 
High-risk resectable cutaneous squamous cell carcinoma (cSCC) 
Trial Type 
Neoadjuvant 
Type of control 
Non-randomized 
Route of administration 
IV 
Trial Blinding 
N/A 
Treatment Groups  
Single 
Number of trial participants 
30 
Estimated enrollment period 
24 months 
Estimated duration of trial 
84 (24 months enrollment + 60 months followup) months 
Duration of Participation 
12 months 
Estimated average length of 
treatment per patient 
12 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.0 TRIAL DESIGN 
2.1 Trial Design 
This is a phase II single-arm two-stage neoadjuvant study of pembrolizumab in patients with PD-1 naïve 
high-risk resectable cutaneous squamous cell carcinoma (cSCC). Each patient will be treated over a 52-
week period. Patients with high-risk resectable cSCC who have yet to undergo definitive surgery are 
eligible to enroll. Patients with nodal and/or in-transit relapse including those who have received prior 
adjuvant RT are eligible to enroll. However, patients who have received either nivolumab or 
pembrolizumab or other anti-PD-(L)1 therapy are NOT eligible.  
The study schema is outlined in the Figure below (see Figure 2.2-1). Suitable patients will be identified 
pre-operatively. Patients will undergo a 28-day screening evaluation consisting of systemic staging 
scans, tumor biopsy, and blood studies to confirm suitability. Once enrolled, patients will receive 
pembrolizumab peri-operatively for 6 weeks (200mg Q3W; 2 cycles) prior to definitive surgery 
(Neoadjuvant Phase). Following peri-operative therapy, patients will undergo restaging scans and 
surgical evaluation followed by definitive surgical resection (Surgical Phase).  
Post-operatively, patients will receive 15 further cycles of pembrolizumab over a 45-week period 
(200mg Q3W) (Adjuvant Phase). In the post-operative period, if patients are deemed eligible for RT, 
this will be administered concurrently with pembrolizumab. The total duration of pembrolizumab 
therapy is 1 year (52 weeks).  
2.2 Trial Schema 
Figure 2.2-1: Trial Schema
0
4
8
Phase II Study of Pembrolizumab in PD-1 Naïve cSCC
12
16
20
24
…
• High-risk resectable PD-1 naïve cSCC prior to surgery
• Simon optimal 2-stage design: 1st stage (9), 2nd stage (21)
• Endpoints: 
• Primary: pCR by irPRC
• Secondary: safety, landmark RFS (1-/2-/3- year), DMFS and OS
• Duration of therapy: 
• Pre-operative: 6 weeks
• Post-operative: 48 weeks
RESPONSE 
EVALUATION
High-risk cSCC naïve to PD-1 
therapy pre-surgery
• No active CNS disease
• Measurable disease
• I/E criteria as above
Tumor biopsy            Scans
Correlative labs
Pembrolizumab        Post-operative RT 
(if indicated)  
• Inclusion Criteria
• Pathologically confirmed high-risk cSCC
(primary cSCC lesion, cSCC with clinical LN 
involvement, or cSCC LN metastasis within 
draining LN of previously treated cSCC) 
• Exclusion Criteria:
• cSCC associated with transplant
• Immunosuppression as outlined in protocol
• Concurrent other malignancy or other c/i to PD-1

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2.1 
Trial Flow Chart 
 
Trial Period 
Screening 
PhaseA 
Neoadjuvant 
PhaseB 
Surgical PhaseC 
Adjuvant PhaseD 
End of 
TreatmentE 
Post-TreatmentF 
Treatment Cycle/Title: 
1 
2 
Surgical Re-
assessment 
Definitive 
Surgery 
1 
2 
3 
4+ 
30-day Safety 
Follow-up 
Post-Treatment 
Surveillance 
Scheduling Window 
(Days): 
-28 to -1 
± 3 
± 3 
± 7 
± 7 
± 3 
± 7 
± 7 
± 7-14 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Pembrolizumab 
AdministrationG 
 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
Adjuvant 
radiotherapyH 
 
 
 
 
 
X 
X 
 
 
 
 
 
Clinical Procedures/Assessments 
Surgical AssessmentI 
X 
 
 
X 
 
 
 
 
 
 
 
 

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Radiation Oncology 
AssessmentH 
 
 
 
X 
 
 
 
 
 
 
 
 
Full Physical 
ExaminationJ 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures and Assessments 
Pregnancy Test – Urine 
or Serum β-HCGK 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
testsL 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Imaging AssessmentsM 
X 
 
 
X 
 
 
X 
 
 
X (q9) 
 
X 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Pre-treatment 
tumor 
biopsyN 
X 
 
 
 
 
 
 
 
 
 
 
 
Surgical specimenN 
 
 
 
 
X 
 
 
 
 
 
 
 
Correlative labsO 
X 
X 
X 
X 
 
X 
 
X 
X (q6) 
X 
 
 
Stool samplingP 
 
X 
 
X 
 
X 
 
 
X (q12) 
 
 
 
DHQ-3Q 
 
X 
 
 
 
 
 
 
 
 
 
 
Post-progression 
biopsyR 
 
 
 
 
 
 
 
 
 
X 
 
 
Adverse Event Monitoring 
AE monitoring 
Assessed continually from ICF through + 30-day Safety Follow-up 
 
Concomitant 
medications 
 
Assessed continually from C1D1 pembrolizumab through + 30-day Safety Follow-up 
 
 

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Study Calendar Notes: 
AScreening Phase 
• 
Commences upon signing of ICF and lasts 28 days. During this period, patients must undergo all study-specific assessments as delineated above including staging scans, 
biopsy, assessments by Medical Oncology, Surgical Oncology and Radiation Oncology. 
BNeoadjuvant Phase 
• 
Commences following Screening Phase and lasts 6 weeks. During this Phase, patients receive 2 cycles of pembrolizumab. 
CSurgical Phase 
• 
Commences following Neoadjuvant Phase and lasts 2-4 weeks. During this period, patients undergo restaging scans, and other study-specific assessments as delineated 
above including definitive surgical resection. 
DAdjuvant Phase 
• 
Commences following Neoadjuvant Phase and lasts 48 weeks.  
• 
During this period, patients undergo RT (if applicable) and receive further pembrolizumab to complete 45 weeks of therapy. Patients also undergo restaging scans, and 
other study-specific assessments as delineated above including definitive surgical resection. 
EEnd-of-treatment (EOT) assessments. 
• 
EOT will be performed within 7 days following removal of subject from treatment.  
• 
Removal of a subject from treatment is defined as the time in which the Investigator decides to discontinue pembrolizumab treatment for a subject for reasons including 
unacceptable toxicity and/or disease progression. 
• 
Management of patients who develop unacceptable toxicity is defined in Section 5.2.2. and Table 5.2.2-1. 
• 
Patients who progress during this period should undergo a Post-progression biopsy. 
FPost-Treatment follow up including 30-day Safety Follow-up and Post-Treatment Surveillance. 
• 
30-day Safety Follow-up begins +30 days following completion of Cycle 15 Adjuvant Phase. 
o 
Procedures to be followed during this phase are outlined in Section 6.1.5.3.1 and will include a visit, labs (CBC, CMP, LDH, TSH, free T4) and any other studies 
deemed necessary at the discretion of the treating physicians and according to established Standard of Care. 
• 
Post-Treatment Surveillance begins upon completion of 30-day Safety Follow-up. 
o 
Procedures to be followed during this phase are outlined in Section 6.1.5.3.2 and will include imaging (contrast enhanced CT or MRI), labs (CBC, CMP, LDH, 
TSH, free T4) and any other studied deemed necessary at the discretion of the treating physicians and according to established Standard of Care. 
GPembrolizumab is dosed 200mg Q3W during Neoadjuvant and Adjuvant Phases. 
• 
During the Neoadjuvant and Adjuvant Phases of this study, patients will receive 200mg Q3W on D1 of each cycle for a total of 2 cycles (Neoadjuvant Phase) and 15 
cycles (Adjuvant Phase). 
• 
There is a window of +/- 3 days for drug administration. 
• 
Missed cycles during the Neoadjuvant Phase will not be made up. Missed cycles in the Adjuvant Phase will be made up. 
HRadiation therapy guidelines 
• 
Radiation Oncology assessment should be made during Surgical Re-assessment. 
• 
Radiation therapy will commence post-surgery following wound healing per the direction of the treating Radiation Oncologist. Every effort should be made to begin RT 
within 4 weeks of completion of surgery. 
• 
Radiation therapy will follow guidelines as elaborated upon in Section 5.6. 
• 
Radiation therapy may be omitted in patients who attain a pathologic complete response as delineated in n Section 5.6 at the discretion of the treating Investigator, Surgical 
Oncologist, Radiation Oncologist and Principal Investigator. 
ISurgical Assessment 
• 
Assessment of planned resectability must be made during Screening.  

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• 
Planned surgery after Neoadjuvant Phase must be with treating surgeon (Surgical Oncologist; ENT Surgeon; Orthopedic Oncologist; Mohs Surgeon) who initially made 
determination of planned resectability and will follow guidelines as elaborated upon in Sections 5.5.1 to 5.5.3. 
JFull physical exam 
• 
Full physical exams will be conducted at Screening, each treatment visit, EOT, and during Post-Treatment Surveillance. 
• 
Full physical exams should include assessment of ECOG performance status and weight. 
• 
Height will be recorded at Screening only. 
KPregnancy test 
• 
Pregnancy testing should be performed in women of childbearing potential and at Screening only. 
LClinical laboratory tests 
• 
Laboratory tests to be obtained are delineated in Table 6.1.3-1.  
• 
Thyroid function and urinalysis will only obtained at Screening and every 2nd treatment. 
• 
Infectious serology will only be obtained at Screening. 
MImaging assessments to assess tumor status will be obtained at Screening (baseline value should be performed ≤4 weeks prior to first pembrolizumab dose). 
• 
Screening:  
o 
Scans should be performed ≤4 weeks prior to first pembrolizumab dose. 
• 
Neoadjuvant Phase: 
o 
Contrast-enhanced CT scans should be repeated prior to surgery at week 7 as delineated in Section 6.1.2.5.1. 
• 
Adjuvant Phase: 
o 
During Adjuvant Phase, contrast-enhanced CT scans will be repeated every 9 weeks starting with Cycle 2 (or approximately 9 weeks after pre-surgical scan) as 
delineated in Section 6.1.2.5.2. 
o 
Frequency of imaging assessments in patients who complete therapy and transition to Post-Treatment Surveillance is delineated in Section 6.1.5.3.2. 
NTumor biopsy and surgical specimen handling 
• 
Pre-treatment tumor biopsy:  
o 
Pre-treatment tumor biopsy is mandatory. 
o 
Tumor biopsy should be obtained via one of the following techniques: core biopsy (preferred; minimum 6 cores, 16G or 18G), punch biopsy or surgical biopsy. 
• 
Surgical specimen 
o 
Processing of surgical specimen is detailed in Section 6.1.2.5. and Appendix 7. 
OCorrelative blood samples are to be collected at the following times: 
• 
During Screening, prior to administration of C1D1 and C2D1 doses (Neoadjuvant Phase); Surgical re-assessment (Surgical Phase); and every 6 weeks starting with 
C1D1 (Adjuvant Phase) and EOT. 
• 
K2 EDTA sample to be obtained at Screening only. 
PStool sampling will be performed at C1D1 (Neoadjuvant Phase); Surgical re-assessment (Surgical Phase); and every 12 weeks starting with C1D1 (Adjuvant Phase). 
QDietary history questionnaire will be performed concordantly with stool sampling at C1D1 only.  
• 
Dietary questionnaire is detailed in Appendix 6. 
RPost-progression biopsy 
o 
This is optional but preferred in patients in whom progression is confirmed at EOT. Tumor biopsy should be obtained via one of the following techniques: core 
biopsy (preferred; minimum 6 cores, 16G or 18G), punch biopsy or surgical biopsy. 
 
 

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3.0 OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) 
3.1 
Primary Objective(s), Hypothesis(es), and Endpoint(s) 
(1) Objective: To establish the proportion of patients with pathologic complete response [(pCR, 0% 
residual viable tumor (RVT)] of neoadjuvant pembrolizumab in high-risk resectable cSCC. 
Hypothesis: That neoadjuvant pembrolizumab produces pCR in high-risk resectable cSCC. 
Primary Endpoint: pCR proportion as assessed using immune related response criteria.1-3 
3.2 
Secondary Objective(s), Hypothesis(es), and Endpoint(s) 
(1) Objective: To describe spectrum of pathologic response in high-risk resectable cSCC treated 
with neoadjuvant pembrolizumab. 
Hypothesis: That neoadjuvant pembrolizumab produces a spectrum of pathologic response in 
high-risk resectable cSCC. 
Key Secondary Endpoint: Pathologic responses (major pathologic response – <0 to ≤10% 
RVT; partial pathologic response – <10 to ≤50% RVT) as assessed using immune related 
response criteria.1-3 
(2) Objective: To evaluate landmark 1-year recurrence-free survival (RFS) in cSCC patients 
receiving neoadjuvant and adjuvant pembrolizumab. 
Hypothesis: That neoadjuvant and adjuvant pembrolizumab improves landmark 1-year RFS in 
cSCC patients receiving neoadjuvant and adjuvant pembrolizumab. 
Key Secondary Endpoint: Landmark 1-year RFS. 
(3) Objective: To evaluate median RFS, DMFS and OS; landmark 6-month, 2-year and 3-year RFS 
and landmark 1-year and 2-year OS in cSCC patients receiving neoadjuvant and adjuvant 
pembrolizumab. 
Hypothesis: That neoadjuvant and adjuvant pembrolizumab improves median RFS and OS; 
landmark 6-month, 2-year and 3-year RFS and landmark 1-year and 2-year OS in cSCC patients 
receiving neoadjuvant and adjuvant pembrolizumab. 
Secondary Endpoint: Median RFS; median OS; landmark 6-month, 2-year and 3-year RFS; 
landmark 1-year and 2-year OS. 
3.3 
Exploratory Objective(s), Hypothesis(es), and Endpoint(s) 
(1) Objective: To evaluate pre- and on- treatment increases in CD8 T cell density intra-tumorally. 
Hypothesis: That cSCC patients responding to neoadjuvant pembrolizumab demonstrate on- 
treatment increases in CD8 T cell density. 

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Exploratory endpoint: CD8 TIL at post- vs. pre- treatment samples 
(2) Objective: To evaluate immunophenotypic parameters in PBMC and TIL by multi-parameter 
flow cytometry. 
Hypothesis: That cSCC patients responding to neoadjuvant pembrolizumab demonstrate 
evidence of immune activation in tumor tissue, blood, and plasma by multiparameter flow 
cytometry, transcriptomic, genomic and cytokine analyses. 
Exploratory Endpoint: Immune activation in tumor tissue, blood, and plasma by 
multiparameter flow cytometry, transcriptomic, genomic and cytokine analyses. 
(3) Objective: To evaluate the incidence of secondary cutaneous and non-cutaneous cancers in 
cSCC patients treated with neoadjuvant pembrolizumab. 
Hypothesis: That cSCC patients treated with neoadjuvant pembrolizumab demonstrate reduced 
incidence of secondary cutaneous and non-cutaneous cancers. 
Endpoint: Incidence of secondary cutaneous and non-cutaneous cancers. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with 
high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® 
(pembrolizumab) is indicated for the treatment of patients across a number of indications because of its 
mechanism of action to bind the PD-1 receptor on the T cell.  For more details on specific indications 
refer to the Investigator brochure. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades.4 Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various malignancies.  In 
particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-
cells (T-regs) correlates with improved prognosis and long-term survival in solid malignancies, such 
as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and 
renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing 
durable objective tumor responses in cancers such as melanoma.5-7 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related 
to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 
that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2).8,9 
The structure of murine PD-1 has been resolved.10 PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein 
kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade.9,11-13 The mechanism by 
which PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because 
both molecules regulate an overlapping set of signaling proteins.14,15   

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PD-1 binds to PD-L1 (B7-H1)16,17 and PD-L2 (B7-DC).18,19 PD-1 negatively regulates T cell functions 
through the engagement of PD-L1, which is expressed by a wide variety of tissues.20,21 PD-L1 is also 
expressed by human tumors, including melanoma, either constitutively or after treatment with IFN-α. 
In mice, LCMV-specific CD8+ T-cells exhibit a diminished capability to produce cytokines, lyse 
infected cells and proliferate in a progressive and hierarchical fashion.22 These “exhausted” T-cells 
up-regulate PD-1, and PD-1/PD-L1 blockade leads to increased cytokine production and proliferation, 
resulting in a significant reduction of the viral load.22 We have previously shown that the large majority 
of tumor antigen-specific CD8+ T cells upregulate PD-1 expression, which appears to be associated 
with T cell exhaustion/dysfunction in animals and humans.23,24 We observed that PD-1 upregulation 
on spontaneous tumor antigen-specific CD8+ T cells occurs along with T cell activation and is not 
directly associated with an inability to produce cytokines ex vivo upon stimulation with cognate 
antigen.24 Blockade of the PD-1/ programmed death ligand 1 (PD-L1) pathway in combination with 
prolonged antigen stimulation with PD-L1+ antigen-presenting cells or melanoma cells augmented 
the frequencies of cytokine-producing, proliferating and total tumor antigen-specific NY-ESO-1 
CD8+ T cells.24 
PD-1/PD-L1 blockade is associated with improved response and survival rates in the setting of 
advanced cancer in multiple cutaneous malignancies including melanoma,25-29 and cutaneous 
squamous cell carcinoma (cSCC).30-33  
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Population 
cSCC has several hallmarks of a tumor that is potentially sensitive to PD-1/PD-L1 blockade including: 
hallmarks of UV-mediated skin damage as characterized by presence of C>T transitions;34 a very high 
mutation burden (30-60 per Mb; compared to 13 per Mb in melanoma); PD-L1 expression by primary 
and metastatic tumors;35 and presence of CD8+ T cells in both pre-cancerous lesions and invasive 
cSCC.36 
In patients with advanced unresectable or locally advanced (LA) cSCC, PD-1 blockade is efficacious 
with response rates of 44-50% with cemiplimab31,37 and 34-42% with pembrolizumab.32,33 
Specifically, in the CARSKIN trial, an open-label, multicenter phase II study that evaluated 
pembrolizumab in immunocompetent unresectable cSCC, authors reported overall response rate 
(ORR) of 42% in 57 evaluable patients.32 Separately, in KEYNOTE-629, an open-label phase II study 
of immunocompetent unresectable and locally advanced (LA) cSCC, authors reported overall response 
rate (ORR) of 34% in 70 evaluable patients.33 In patients with unresectable LA cSCC, cemiplimab 
produces 44% objective responses with a moderate incidence of grade 3-5 adverse events (50%).37  
These promising results have prompted adjuvant studies of these agents in patients with high-risk 
resected cSCC following definitive surgery and radiation therapy (cemiplimab - NCT03969004; 
pembrolizumab - NCT03833167/MK-3475-630/KEYNOTE-630). In both these studies, eligible 

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patients have locally advanced (LA) cSCC defined as ≥T2 tumors with at ≥1 high-risk clinical and/or 
histologic as defined using the Brigham and Women’s Hospital (BWH) system (Appendix 1B and 
Appendix 1C).38 
Separately, in the setting of high-risk resectable stage III/IV disease, peri-operative cemiplimab was 
well-tolerated and associated with a high rate of pathological response (70%) in a small single-
institution study.39 This study included 20 patients with either stage III disease (T3N0Mx; T1-3N1) or 
stage IV disease (T4N0Mx; T1-3N2Mx; T1-4N3Mx), and the reported data has prompted further evaluation 
of peri-operative anti-PD-1 in cSCC in various schedules as summarized below. 
Study Reference 
Anti-PD-1 
Sample 
Size 
Primary 
Endpoint 
Duration of 
“Neoadjuvant 
Phase” 
Duration of 
“Adjuvant 
Phase” 
Eligibility 
Criteria 
NCT04154943 
Cemiplimab 
76 
Major pathologic 
response 
rate 
(criteria 
unspecified) 
12 weeks 
None 
Stage 
II-IV 
(M1 
excluded) 
NCT04632433 
Cemiplimab 
25 
Major pathologic 
response 
rate 
(criteria 
unspecified) 
6 weeks 
54 weeks (18 
cycles) 
Stage III 
NCT04315701 
Cemiplimab 
34 
Pathologic 
response 
rate 
(criteria 
unspecified) 
9-12 weeks 
None 
Stage 
II-IV 
(M1 
excluded) 
NCT04428671 
Cemiplimab 
20 
Pathologic 
response 
rate 
(criteria 
unspecified) 
9 weeks 
54 weeks (18 
cycles) 
Stage III-IV 
(M1 
excluded) 
 
Of note, these studies vary considerably in design and inclusion exclusion criteria with neoadjuvant 
phases ranging from 6-12 weeks; inconsistent inclusion of adjuvant anti-PD-1 in the post-operative 
phase; variable definition of “high-risk”; and pathologic evaluation criteria. In particular, neoadjuvant 
anti-PD-1 therapy has not been studied in cSCC patients defined as high-risk by BWH criteria.  
This is an important consideration as while both AJCC and BWH criteria have similar monotonicity 
and homogeneity, the BWH staging system is more distinct than AJCC 8, with a higher specificity 
(93%) and positive predictive value (30%) for identifying cases at risk for metastasis and death 
particularly in AJCC T2 and T3 tumors.40 While AJCC 8 T2 and T3 grades have similar risks of nodal 
metastases (10-year cumulative incidence rates of 12% and 14%, respectively); BWH T2a tumors 
have a significantly lower risk of nodal metastases than BWH T2b tumors (5% vs. 24% respectively).  
Hence, there is a pressing need to evaluate the impact of neoadjuvant anti-PD-1 therapy upon 
pathologic complete response (pCR) using validated criteria1-3 in a biologically “high-risk” cSCC 

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patient population, while evaluating the impact of this upon relapse-free survival given the 
observations from studies of neoadjuvant anti-PD-1 therapy in melanoma wherein pathological 
response was associated with improved relapse-free survival (RFS).41-44 
We therefore propose, in this study, to formally evaluate whether both biologically and clinically high-
risk disease benefit from neoadjuvant anti-PD-1 therapy. We also propose to evaluate whether 
response to neoadjuvant anti-PD-1 therapy is associated with improved RFS; while identifying 
pharmacodynamic biomarkers of response to neoadjuvant anti-PD-1 therapy in blood and tumor tissue. 
4.2.2 Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined below, 
this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival at 200 
mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] 
analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). 
All of these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat dose-
exposure-response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as 
the appropriate dose independent of the tumor type. These findings are consistent with the mechanism 
of action of pembrolizumab, which acts by interaction with immune cells, and not via direct binding 
to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation of 
PD-1 in systemic circulation at doses much lower than 200 mg Q3W.45 Second, a PBPK analysis was 
conducted to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 
expression concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood 
and tumor.46 Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing provides 

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similar control of PK variability as weight-based dosing, with considerable overlap in the distribution 
of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.47  
Supported by these PK characteristics and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints: 
• Primary endpoint: Pathologic response rate as assessed using immune related pathologic 
response criteria.1-3 
• Key secondary endpoint: Landmark 1-year RFS. 
• Other secondary endpoints: Median RFS; median OS; landmark 6-month, 2-year and 3-year 
RFS; landmark 1-year and 2-year OS. 
4.2.3.2 Planned Exploratory Biomarker Research 
• Pre-treatment tumor biopsy, post-treatment surgical sample and (if applicable) post-progression 
biopsies 
o Immunohistochemical analyses: CD8+ TIL density, PD-L1 expression and multiplex 
analyses 
o T cell functional studies to assess T cell apoptosis (Annexin V) and T cell proliferation 
(CFSE labelling) 
o Characterization of immune cells in tumor using multiparameter flow cytometry (MFC) 
evaluating immune cell subsets (CD4+ T cells, CD8+ T cells, Foxp3+ Tregs, CD56+ NK 
cells, CD141+ DC), expression of activation markers (Ki67, GZMA, GZMB), expression 
of inhibitory/activating receptors (PD-1, Tim-3, TIGIT, GITR, CD226, CD137, ICOS) 
and expression of ligands (PD-L1, phosphatidylserine, CD112, CD155, GITR-L) 
o Characterization of immune cells in tumor using single cell transcriptomics 
o Transcriptomics and genomic analyses 
• Pre- and on- treatment PBMC 
o Characterization of immune cells in peripheral blood using multiparameter flow 
cytometry (MFC) evaluating immune cell subsets (CD4+ T cells, CD8+ T cells, Foxp3+ 
Tregs, CD56+ NK cells, CD141+ DC), expression of activation markers (Ki67, GZMA, 
GZMB), expression of inhibitory/activating receptors (PD-1, Tim-3, TIGIT, GITR, 

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CD226, CD137, ICOS) and expression of ligands (PD-L1, phosphatidylserine, CD112, 
CD155, GITR-L) 
o Single cell transcriptomics 
• Pre- and on- treatment serum samples 
o Changes in cytokine profiles. 
• Stool sampling pre- and on- treatment: 
o Microbiome analysis using metagenomic and metatranscriptomic sequencing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.0 METHODOLOGY 
5.1 Study Population 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
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. 
a. 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 (see 
Appendix 1B and Appendix 1C). 
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). 

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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 as detailed in Appendix 3 of this protocol 
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 (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 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.  
a. Prior archival tumor tissue sample are not permitted. 
b. 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 as defined in the Table 5.1.1-1 (see Table 5.1.1-1).  Specimens 
must be collected within 10 days prior to the start of study treatment. 
Table 5.1.1-1 Adequate Organ Function Laboratory Values 

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5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
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).  
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 

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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 (see Appendix 3). 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.   
a. 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. 
b. 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).  
a. 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 1 year 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. 
i. Patients with concurrent secondary malignancies may be enrolled at the 
discretion of the treating investigator if the secondary malignancy has been 
adequately treated and/or the management plan is active surveillance. 
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. 

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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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5.1.3 Lifestyle Considerations 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention(s).  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 working 
days if the outcome is a serious adverse experience (e.g. death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  The study Investigator will 
make every effort to obtain permission to follow the outcome of the pregnancy and report the condition 
of the fetus or newborn to Merck.  If a male participant impregnates his female partner, the study 
personnel at the site must be informed immediately and the pregnancy must be reported to Merck and 
followed as described in Section 6.2. 
5.1.5 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breast-feeding are not eligible for enrollment. 
5.2 Trial Intervention(s) 
The intervention(s) to be used in this trial is outlined below in Table  
Table 5.2-1 Trial Intervention 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Neoadjuvant Phase: 
Day 1 of each 3-week 
cycle, 2 cycles 
Experimental 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Adjuvant Phase: 
Day 1 of each 3-week 
cycle, 15 cycles 
Experimental 

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Trial intervention should begin within 28 days of enrollment. 
 
5.2.1 Timing of Dose Administration 
Trial interventions should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial interventions may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial interventions will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given 
the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.2 Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic aetiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last dose 
of pembrolizumab treatment and may affect more than on body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications.  Based on existing 
clinical study data, most irAEs were reversible and could be managed with interruptions of 
pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected irAEs, 
ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests 
such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are 
provided in Table 5.2.2-1 (see Table 5.2.2-1). 

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Table 5.2.2-1 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
 
• 
Monitor participants for signs and symptoms of pneumonitis 
• 
Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid treatment 
 
Grade 3 or 4, or 
recurrent Grade 2  
 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
• 
Monitor participants for signs and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, blood or mucus in stool with or 
without fever) and of bowel perforation (ie, peritoneal signs 
and ileus) 

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Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
• 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
 
• 
Participants with ≥Grade 2 diarrhea suspecting colitis should 
consider GI consultation and performing endoscopy to rule 
out colitis 
• 
Participants with diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake 
is not feasible, fluid and electrolytes should be substituted via 
IV infusion 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 
0.5 - 1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor with liver function tests (consider weekly or more 
frequently until liver enzyme value returned to baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
• 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold d 
• 
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
• 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
 
• 
Monitor participants for hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
• 
Monitor for signs and symptoms of hypophysitis (including 
hypopituitarism and adrenal insufficiency) 

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Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
• 
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated 
Hyperthyroidism  
Grade 2 
Continue 
• 
Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for signs and symptoms of thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
• 
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
• 
Monitor for signs and symptoms of thyroid disorders 
Nephritis and 
renal dysfunction: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) 
followed by taper 
• 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Intolerable/persist
ent Grade 2 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm etiology or exclude 
other causes 
Grade 3 
Withhold or 
discontinue 

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based on the 
event e.  
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 
10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. For participants with 
Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ 
Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM) 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson Syndrome and toxic 
epidermal necrolysis. 
 
 
 
 
 
 
 
 
 
 
 

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Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe hypersensitivity or anaphylaxis. 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 
hours of completion of infusion. Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5.2.2.-2. 
Table 5.2.2.-2 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (e.g. from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and 
the participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug intervention 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
_____ with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
No subsequent dosing 

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recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
intervention. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
 

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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / 
surgical events or logistical reasons not related to study therapy. Participants should be placed back on 
study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the Principal 
Investigator. The reason for interruption should be documented in the patient's study record. 
 
5.3 Randomization or Treatment Allocation 
Not applicable. 
5.4 Stratification 
Not applicable. 
5.5 Surgical Considerations 
The members of the treatment team will make every effort to comply with the surgical procedures within 
the time windows allowed in this study protocol. However, under certain circumstances and as discussed 
between the sub-investigator(s) and the principal investigator, an alteration in the surgical schedule/timing 
is allowed. These include (but are not limited to) the following: 
• A 4-week window between the baseline biopsy and the first dose of pembrolizumab is allowed. 
• The definitive surgery should follow the guidelines in Sections 5.5.1 to 5.5.3 as clinically 
indicated. The definitive surgery may be divided into more than one surgical procedure, scheduled 
at different time points as clinically/surgically indicated. Under certain circumstances, the 
definitive surgery may be done earlier if pembrolizumab was discontinued due to adverse events 
or other reasons. Tissue from any of these surgical procedures may be banked under this protocol 
following the same protocol procedures for tissue handling and banking. The tissue for banking 

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may be digested, frozen or handled in another alternative method as discussed with the 
investigator. 
• If for some reason, the baseline biopsy or definitive surgery could not be completed due to 
unanticipated factors such as patient refusal, this will be documented.  
• NOTE:  
o The surgical guidelines are general and may be followed or modified at the discretion of 
the expert surgical oncologist on the case as clinically indicated and depending on the 
specifics of the individual surgical case. 
o For the baseline biopsy required on this study, patients will undergo a core needle, punch 
biopsy, or other technique at the discretion of the sub-investigator/investigator. The choice 
of biopsy technique will be at the discretion of the surgeon or medical oncologist. 
5.5.1 Primary excision for locally advanced cSCC 
All patients with initial presentation of ≥2 T2 cSCC will be treated by wide excision of the primary. 
Definitive surgery will include wide excision of the primary +/- sentinel lymph node assessment (latter if 
deemed necessary). For patients with known primary cSCC and no history of wide local excision (or Mohs 
surgery) of that primary lesion, an adequate wide excision of the primary lesion (minimum margin 1 cm) 
is recommended. The wide local excision will be done at the time of sentinel lymph node assessment or 
complete lymphadenectomy (latter if deemed necessary). 
The specimen shall be excised to include skin and all subcutaneous tissue down to the muscular fascia. 
Fascia may be included at the discretion of the operating surgeon. Closure of the defect may be via primary 
closure, split thickness skin graft, or rotation-flap at the discretion of the surgeon. At the time of the 
definitive lymphadenectomy, the biopsy site will be included in the operative specimen. 
5.5.2 Regional lymphadenectomy 
Note: For patients undergoing sentinel node mapping and lymphoscintigraphic and dye lymphographic 
identification of regional nodal drainage, the minimum number of nodes may be less than the mandatory 
minimum numbers of: 5/groin, 10/axilla, and 15/cervical node dissection. 
All patients should undergo one of the following staging lymphadenectomies, as found surgically 
applicable by the treating surgical oncologist. At the time of the definitive lymphadenectomy, the biopsy 
site will be included in the operative specimen. 
Head and neck lesions: 
Face, ear and anterior scalp: Modified radical neck or radical neck dissection. Parotidectomy to be 
included if lymphoscintogram indicates flow to the area. 

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Submandibular and anterior neck: Modified radical or radical neck dissection. Posterior scalp, posterior 
neck and uppermost trunk (areas that drain to posterior cervical triangle): Modified posterior triangle neck 
dissection with suboccipital nodes. 
Upper extremity lesions: 
Axillary node dissection to include at least 10 nodes taken from levels I and II. Level III nodes should be 
dissected if they are clinically involved. The pectoralis minor muscle may be divided or sacrificed at the 
surgeon's discretion. 
Lower extremity lesions: 
Superficial inguinal node dissection or deep inguinal node dissection will be performed at the discretion 
of the surgeon. Inguinal node dissection to include at least 5 nodes. 
5.5.3 Lymphadenectomy for local recurrence 
Regional node recurrences will be treated using the appropriate lymphadenectomy procedure for the 
anatomical site as delineated above. Whenever possible, diagnosis of regional node recurrence will be 
made using core biopsy technique. At the time of the definitive lymphadenectomy, the biopsy site will be 
included in the operative specimen. 
5.6 Radiation Therapy Considerations 
Since patients on study have documented high risk features for loco-regional recurrence, radiation 
therapy is recommended for all patients except for patients with pathological complete response to 
neoadjuvant therapy. The necessity of postoperative radiation to the primary site and draining lymph 
node basin should be considered separately. Regimens, treatment fields, and dose constraints should 
follow NCCN and AAPM guidelines and/or institutional standard of care. Radiation therapy is 
recommended to commence within 6 weeks after surgical resection, however delays to ensure wound 
healing prior to RT is allowed. RT will be administered concurrently with anti-PD-1 therapy. Acceptable 
toxicity has been reported in multiple phase I studies of concurrent radiation administered with anti-PD-1 
therapy.48-52 Radiation therapy may be delivered either as external beam photon or electron plans or via 
high dose rate brachytherapy targeted to the skin surface. 
Post-surgery, adjuvant RT is recommended for patients with the following tumors as assessed based on 
pre-operative staging using cSCC-specific AJCC UICC 8th edition staging classification: 
• T2 and Nx and M0 (tumor >2 cm and ≤4 cm in greatest dimension); 
• T3 and Nx and M0 (tumor >4 cm or minor bone erosion or perineural invasion or deep invasion); 
• T4 and Nx and M0 (tumor with gross cortical bone/marrow, skull base invasion and/or skull base 
foramen invasion if deemed surgically resectable); 
• Tx and N1-3 and M0 (if deemed surgically resectable); 

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Primary site 
Recommendations for primary tumors as stated above. 
In patients who achieve pCR, adjuvant RT is not recommended.   
Draining nodal basin  
Adjuvant RT to nodal basin is recommended in patients with node positive disease or if the draining lymph 
node region has not been adequately addressed by LND. For positive cervical or cervical nodes, ipsilateral 
at risk elective nodal irradiation should be considered. Dose painting or simultaneous integrated boost 
techniques could be utilized for positive margins or gross residual disease. 
In patients who achieve pCR, adjuvant RT is not recommended. 
Pretreatment Evaluations 
If the radiation fields include head and neck cervical nodes or the parotid gland, a dental evaluation and 
routine prophylaxis should be performed prior to initiation of adjuvant therapy. 
Dose Specifications  
The prescription volume will be specified with separate primary as well as draining lymph node basin 
volumes, as PTVp and PTVn. Dose will be specified in Gy. Bolus should be utilized to achieve adequate 
skin dose and dose under bolus confirmed at least once during the first 3 fractions of treatment. 
Treatment Planning/Target Volumes 
Pretreatment scans should be fused with treatment planning CT as needed to delineate target volumes. 
5.6.1 RT to the primary site 
The recommended total prescription dose to the primary site should be 24-36 Gy in 5 fractions (5-7.0 Gy 
per fraction) to the planning target volume (PTVp). A minimum of 95% of the planning target volume 
(PTVp) should receive prescription dose. Fractions should be a minimum of 40 hrs apart for any fraction 
size of 5 Gy or greater.  Radiation to the primary site may be delivered via photons, electrons, or HDR 
brachytherapy. BED equivalent BID fractionation may be utilized for HDR regimens. 
While the above short course hypofractionated regimens is strongly recommended, conventionally 
fractionated or moderately hypofractionated RT regimens from 46-66 Gy in 20-33 fractions (2-2.5 Gy per 
fraction) may be administered if deemed necessary to adequately spare normal tissues. 
5.6.2 RT to the draining nodal basin 
The recommended total prescription dose to the nodal basin site should be 24-36 Gy in 5 fractions (5-7.0 
Gy per fraction) to the planning target volume (PTVn). A minimum of 95% of the planning target volume 

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(PTVp) should receive prescription dose.  Radiation to the primary site may be delivered via photons or 
electrons. 
While the above short course hypofractionated regimens is strongly recommended, conventionally 
fractionated or moderately hypofractionated RT regimens from 46-66 Gy in 20-33 fractions (2-2.5 Gy per 
fraction) may be administered if deemed necessary to adequately spare normal tissues. 
5.6.3 Treatment planning and target volumes 
Treatment Planning/Target Volumes 
Pretreatment scans should be fused with treatment planning CT as needed to delineate target volumes.  
Post-neoadjuvant preoperative therapy Gross Tumor Volume (postneo-GTV) will delineated from pre-
operative tumor extent, by use of pre-operative imaging, operative and pathologic reports, and/or sentinel 
lymph node lymphoscintigraphy, when available.  
Primary Site Clinical Target Volume (CTVp)  
The CTVp is defined as the postneo-GTVp and/or surgical scar with a 0.5-2.5 cm margin depending on 
site of primary disease as well as a 1.0-4.0cm expansion deep to the surgical bed to encompass microscopic 
disease. When possible, it is recommended that the margin along the skin surface be delineated with 
radiopaque wire at the time of simulation. The CTVp expansion needs to be trimmed away from the edges 
of anatomic boundaries of microscopic disease spread, including vertebral bodies, osseous structures, and 
organs at risk. The depth should extend to the depth of the subcutaneous fat or 1cm deeper than the distal 
edge of the tumor and be at least 1cm. These constraints would have to be limited anatomically for disease 
surrounding the eyes. The CTVp in certain instances may encompass the immediately adjacent nodal 
regions.  
Draining Nodal Basin Clinical Target Volume (CTVn)  
Head and Neck Nodal Regions  
Radiation treatment field is recommended to include ipsilateral neck nodes down to the clavicle for 
patients at risk of spread. CTVn is to include ipsilateral parotid node for lesions of frontal, preauricular, 
temporal areas, auricle and cheek. CTVn is to include suboccipital nodes for primary lesions located 
behind the mastoid. Elective uninvolved cervical neck levels can be treated at a lower dose than involved 
nodal levels.  
Axillary Nodal Regions  
The target volume includes the full axillary, lateral subpectoral, supraclavicular and low jugular nodes, 
and all the incision and drain sites. All clips marking the dissected region will be included in the treatment 
volume. For primary lesions distal to the epitrochlear region, if SLN or LND demonstrates positive node 
in that region, recommended CTVn should also include the epitrochlear nodal basin with a 2-3cm distal 
and proximal expansion along vessels with 1-2cm radial expansion around vessels. 

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Inguinal/Femoral Nodal Regions  
The target volume should include the inguinal nodes form the superior extent of the pubic ramus to 2 cm 
caudad of the inguino-femoral junction. No more than one-half of the limb volume or two-thirds of the 
limb circumference should be irradiated. For primary lesions distal to the popliteal region, if SLN or LND 
demonstrates positive node in that region, recommended CTVn should also include the popliteal nodal 
echelon with a 2-3cm distal and proximal expansion along vessels with 1-2cm radial expansion around 
vessels. For primary lesions near the ano-genital regions, CTVn may also include the external iliac region. 
Planning Target Volume (PTV)  
Additional margin shall be added to the CTVp and CTVn for set up error and movement. This expansion 
should be 0.3 to 1.0 cm and does not need to be uniform in all dimensions.  
Critical Structures  
Organs at risk to be contoured depends on site of primary and nodal disease. Dose constraints to 
uninvolved normal tissues should follow AAPM/Quantec guidelines using standard dose constraints for 
conventionally fractionated or 5 fraction constraints. 
5.7 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be required.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician. However, the decision to continue the participant on study intervention 
requires the mutual agreement of the investigator, the Sponsor, and the participant. 
5.7.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, over-
the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days prior to the first dose of trial intervention and up 
to 30 days after the last dose of trial intervention should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial intervention should be recorded for SAEs and ECIs 
as defined in Section 7.2 (Safety Monitoring). 
5.7.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 

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• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of study treatment and while participating in 
the study.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 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.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  All treatments that the 
Investigator considers necessary for a participant’s welfare may be administered at the discretion of the 
Investigator in keeping with the community standards of medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study.  If there is a clinical indication for any medication or vaccination specifically prohibited 
during the study, discontinuation from study therapy or vaccination may be required.  The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the participant's primary 
physician.  However, the decision to continue the participant on study treatment requires the mutual 
agreement of the investigator, the Sponsor and the participant. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.7.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined along with the dose modification guidelines in Section 5.2.2 (Table 
5.2.2-1).  
Where appropriate, these guidelines include the use of oral or IV treatment with corticosteroids, as well 
as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased.  For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional supportive care.  
The treatment guidelines are intended to be applied when the Investigator determines the events to be 
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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
5.8 Participant Discontinuation Criteria 
Discontinuation of study intervention does not represent withdrawal from the study. 
Participants may discontinue study treatment at any time for any reason or be dropped from the study 
treatment at the discretion of the investigator should any untoward effect occur.  In addition, a participant 
may be discontinued from study treatment by the investigator or the Sponsor if study treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding procedures to be performed at study treatment discontinuation are provided in Section 7.1.4 – 
Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the study for 
any of the following reasons: 
• The participant or participant’s legally acceptable representative requests to discontinue study 
treatment. 
• Confirmed radiographic disease progression outlined in Section 7.1.2.6. 
• Any progression or recurrence of any malignancy, or any occurrence of another malignancy that 
requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.2. 
• The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test. 
• Noncompliance with study treatment or procedure requirements. 
• Recurrent Grade 2 pneumonitis. 
• The participant is lost to follow-up. 
• Completion of 17 treatments with pembrolizumab. 
• Administrative reasons. 
5.9 Participant withdrawal From Study 
A participant must be withdrawn from the study if the participant or the participant’s legally acceptable 
representative withdraws consent from the study. 

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If a participant withdraws from the study, they will no longer receive study intervention or be followed 
at scheduled protocol visits. 
Specified details regarding procedures to be performed at the time of withdrawal from the study as well 
as specific details regarding withdrawal from future biomedical research are outlined in Sections 7.1.4.1 
and 7.1.4.2. 
5.10 Participant Replacement Strategy 
Subjects who receive at least 1 dose of pembrolizumab in the Neoadjuvant Phase are evaluable for safety. 
Patients who complete Neoadjuvant Phase and receive surgery will be evaluable for pathologic response 
rate and other efficacy endpoints. Patients who did not undergo surgery for reasons of disease progression 
precluding surgery (rapid disease progression) will be deemed pathologic non-responders.  
If in the opinion of the treating investigator and treating surgical oncologist in consultation with Principal 
Investigator, subject’s disease is rapidly progressing to the point that window to intervene surgically is 
narrowing, treatment may be discontinued to permit surgery. These patients are evaluable for pathological 
response rate and other efficacy endpoints. These patients are eligible to receive adjuvant RT and adjuvant 
pembrolizumab during Adjuvant Phase. 
5.11 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to participants 
4. Plans to modify or discontinue the development of the study drug.  
In the event of Merck decision to no longer supply study drug, adequate notification will be provided so 
that appropriate adjustments to participant treatment can be made. 
 

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6.0 TRIAL ASSESSMENTS AND PROCEDURES 
6.1 Trial Procedures 
• Study procedures and their timing are detailed in Section 6.1.2. (Clinical Procedures/Assessments) 
and summarized in Section 2.1 (Trial Flow Chart).   
• Adherence to the study design requirements, including those specified in the Trial Flow Chart 
(Section 2.1) is essential and required for study conduct. 
• The investigator is responsible for ensuring that procedures are conducted by appropriately qualified 
(by education, training, and experience) staff. 
• All screening evaluations must be completed and reviewed to confirm that potential participants meet 
all eligibility criteria. 
• Additional evaluations/testing may be deemed necessary by the investigator, the Sponsor and/or Merck 
for reasons related to participant safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations may require that additional 
informed consent be obtained from the participant. In these cases, such evaluations/testing will be 
performed in accordance with those regulations. 
6.1.1 Administrative and General Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant or each participant’s 
legally acceptable representative prior to participating in a clinical trial. If there are changes to a 
participant’s status during the study (e.g. health requirements) the investigator must ensure appropriate 
consent is in place. 
6.1.1.2 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person conducting 
the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before participation in the 
trial. 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the participant must receive the IRB/ERC’s approval/favorable opinion in advance 
of use.  The participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to continue 
participation in the trial.  The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature. 

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Specifics about a trial and the trial population will be added to the consent form template at the protocol 
level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and Sponsor 
requirements. 
6.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the participant qualifies for the trial.  
6.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history will include 
all active conditions, and any condition diagnosed within the prior 10 years that are considered to be 
clinically significant by the Investigator. Details regarding the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as medical history.   
6.1.1.5 Prior and Concomitant Medications Review 
6.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the participant within 28 days before starting 
the trial. Treatment for the disease for which the participant has enrolled in this study will be recorded 
separately and not listed as a prior medication.  
6.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant during the 
trial. In addition, new medication started during the Second Course should be recorded. All medications 
related to reportable SAEs and ECIs should be recorded as defined in Section 7.2 (). 
6.1.1.6 
Disease Details and Treatments 
6.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
6.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic treatments, 
radiation and surgeries. 
6.1.1.6.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last 
dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 days after the last 

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dose of trial treatment, the 30-day Safety Follow-up visit must occur before the first dose of the new 
therapy.  Once new anti-cancer therapy has been initiated the participant will move into survival follow-
up.  
6.1.1.7 
Assignment of Screening Number 
This will be done upon completion of ICF and patient registration in Hillman Cancer Center’s Clinical 
Trials Management Application (CTMA). 
6.1.1.8 
Assignment of Randomization Number 
Not applicable. 
6.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial. 
6.1.2 Clinical Procedures/Assessments 
6.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  Adverse 
experiences will be graded and recorded throughout the study and during the follow-up period according 
to NCI CTCAE Version 5.0 (see Appendix 2).  Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of AEs.   
6.1.2.2 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during Screening. Clinically 
significant abnormal findings should be recorded as medical history. 
6.1.2.3 
Vital Signs 
The investigator or qualified designee will take vital signs at Screening, prior to the administration of each 
dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 2.1).  
Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure. Height will be 
measured at Screening only. 
6.1.2.4 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1A) at Screening, prior to 
the administration of each dose of trial treatment and discontinuation of trial treatment as specified in the 
Trial Flow Chart (Section 2.1).   
 

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6.1.2.5 
Pathology Sampling and Neoadjuvant Assessment 
Pathology sampling 
In order to achieve accurate and reproducible pathologic assessment in neoadjuvant treated specimens, 
grossing assessment and tissue submission following neoadjuvant treatment should be standardized. These 
recommendations will largely adhere to recommendations made by the International Neoadjuvant 
Melanoma Consortium (see figure below) for the evaluation of melanoma specimens as applied to cSCC 
specimens with certain modifications. 
 
For LN specimens: 
• If the largest grossly positive lymph node measures ≤ 5 cm in greatest dimension, then the entire 
lymph node should be entirely submitted at 2 mm serially sectioned intervals. 
• For any grossly positive lymph node measuring > 5 cm in greatest dimension, representative sections 
of the largest lymph nodes may be utilized to avoid oversampling as indicated below.  
• Following serial sectioning of each lymph node, for those grossly positive nodes > 5 cm, sections 
representing a complete cross section of the entire surface area should be submitted per 1 cm of each 
grossly positive lymph node.  

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• All lymph nodes < 5cm in specimens where the largest node(s) exceeds 5 cm should be submitted 
entirely. 
 
For primary tumor specimens: 
• If the largest primary tumor specimen measures ≤ 5 cm in greatest dimension, then the entire primary 
tumor specimen should be entirely submitted at 2 mm serially sectioned intervals. 
• For any grossly positive primary tumor specimen measuring > 5 cm in greatest dimension, 
representative sections of the primary tumor specimen may be utilized to avoid oversampling as 
indicated below.  
• Following serial sectioning of each lymph node, for those grossly positive nodes > 5 cm, sections 
representing a complete cross section of the entire surface area should be submitted per 1 cm of each 
grossly positive lymph node.  
• All lymph nodes < 5cm in specimens where the largest node(s) exceeds 5 cm should be submitted 
entirely. 
 
Neoadjuvant assessment 
This will follow the guidelines laid out in Appendix 7 (Pathology Sampling and Response Assessment 
Criteria). 
The primary assessment will be the proportion of RVT as defined in Section 7.4 and delineated in 
Appendix 7. 
 
6.1.2.6 
Tumor Imaging and Disease Assessment 
6.1.2.6.1 Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of allocation.  The 
site study team must review screening images to confirm the participant has measurable disease per 
RECIST 1.1.  
The screening images must be submitted to the central imaging vendor for retrospective review. 
Tumor imaging performed as part of routine clinical management is acceptable for use as screening tumor 
imaging if they are of diagnostic quality and performed within 28 days prior to the date of allocation and 
can be assessed by the central imaging vendor.  
Brain imaging is required to rule out radiographically detectable brain metastases at the time of 
enrollment. Magnetic resonance imaging is preferred; however, CT imaging will be acceptable, if MRI is 
medically contraindicated or CT is mandated by local practice. 
Other imaging (MRI neck with contrast etc.) may be obtained in addition (but not in lieu) of definitive 
staging scans if needed either at initial staging and/or following Neoadjuvant Phase to assess resectability 
at the direction of the treating investigator. 

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6.1.2.6.2 Tumor Imaging During the Study 
Following Neoadjuvant Phase, first on-study imaging assessment should be performed at 7 weeks (42 
days ± 7 days) from the date of allocation.  
Post-surgery, during the Adjuvant Phase, first on-study imaging assessment should be performed at Cycle 
2 or approximately 9 weeks (63 days ± 7 days) after pre-surgical scan. Subsequently, all on-study imaging 
assessments should be performed every 9 weeks (63 days ±7 days) starting at week 12. Imaging timing 
should follow calendar days and should not be adjusted for delays in cycle starts.  Imaging should continue 
to be performed until disease progression is identified by the Investigator.  
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to confirm PR 
or CR should be performed at least 4 weeks after the first indication of a response is observed.  Participants 
will then return to regular scheduled imaging every [X] weeks, starting with the next scheduled imaging 
time point.  Participants who receive additional imaging for confirmation do not need to undergo the next 
scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point.   
Per iRECIST (Section 6.1.2.6.6), disease progression should be confirmed 4-8 weeks after first radiologic 
evidence of PD in clinically stable participants. Participants who have unconfirmed disease progression 
may continue on treatment at the discretion of the investigator until progression is confirmed by the site 
provided they have met the conditions detailed in Section 6.1.2.6.6.  
Participants who receive confirmatory imaging and are found not to have PD per iRECIST do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at 
the subsequent scheduled imaging time point, if clinically stable. Participants who have confirmed disease 
progression by iRECIST, as assessed by the site, will discontinue study treatment.  Exceptions are detailed 
in Section 7. 
6.1.2.6.3 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the time of 
treatment discontinuation (±4 week window).  If previous imaging was obtained within 4 weeks prior 
to the date of discontinuation, then imaging at treatment discontinuation is not mandatory.  In 
participants who discontinue study treatment due to documented disease progression and the 
investigator elects not to implement iRECIST, this is the final required tumor imaging. 
For participants who discontinue study treatment without documented disease progression, every effort 
should be made to continue monitoring their disease status by tumor imaging using the same imaging 
schedule used while on treatment as delineated in Section 6.1.5.3.2 and below. This will be done to 
monitor disease status until the start of a new anticancer treatment, disease progression, pregnancy, 
death, withdrawal of consent, or the end of the study, whichever occurs first. 
The first restaging scan during Post-Treatment Surveillance begins 9 weeks (63 ± 7 days) following 
last imaging study during Adjuvant Phase. Subsequent restaging scans will be obtained at the following 
frequency: every 3 months (±2 weeks) if patient is < 2 years from study entry, every 6 months (±4 

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weeks) if patient is 2-5 years from study entry, and every 12 months (±4 weeks) if patient is > 5 years 
from study entry for up to 5 years. 
6.1.2.6.4 Second Course (Retreatment) Tumor Imaging 
Not applicable. 
6.1.2.6.5 RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease 
progression, and as a basis for all protocol guidelines related to disease status (eg, discontinuation of study 
treatment).  Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, the 
Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a 
broader sampling of tumor burden. The first half of the flowchart in Figure 1 illustrates the imaging flow 
involving verification of PD for clinically stable participants. 
6.1.2.6.6 iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen with 
immunotherapeutic drugs.  When clinically stable, participants should not be discontinued until 
progression is confirmed by the Investigator, working with local radiology, according to the rules below.  
This allowance to continue treatment despite initial radiologic PD takes into account the observation that 
some participants can have a transient tumor flare in the first few months after the start of immunotherapy, 
and then experience subsequent disease response. 
A description of the adaptations and iRECIST process is provided in Appendix 4, with additional detail 
in the iRECIST publication.53 iRECIST will be used by the Investigator to assess tumor response and 
progression, and make treatment decisions as delineated in Table 6.1.2.5.6-1 below (see Table 6.1.2.5.6-
1). 
 
 

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Table 6.1.2.5.6-1 Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic evidence of 
PD by RECIST 1.1  
Repeat imaging at 4 to 
8 weeks to confirm PD 
May continue study treatment at 
the Investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion only 
Discontinue treatment 
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per Investigator 
assessment 
No additional imaging 
required 
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor) 
No additional imaging 
required. 
Not applicable 
Repeat tumor imaging shows 
iUPD by iRECIST per 
Investigator assessment 
Repeat imaging at 4 to 
8 weeks to confirm PD.  May 
occur at next regularly 
scheduled imaging visit 
Continue study treatment at the 
Investigator’s discretion 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion only 
Discontinue treatment 
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per Investigator assessment. 
Continue regularly scheduled 
imaging assessments 
Continue study treatment at the 
Investigator’s discretion 
Continue regularly scheduled 
imaging assessments. 
May restart study treatment if 
condition has improved and/or 
clinically stable per Investigator’s 
discretion.  Next tumor imaging 
should occur according to the regular 
imaging schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1.. 

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Figure 1: Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
 
6.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Planned correlative analyses will include but are not limited to flow cytometric analyses of tumor samples, 
TIL and peripheral blood mononuclear cells (PBMC), IHC analyses of pre-/post- treatment tumor samples, 
tumor whole exome/RNA sequencing. Single-cell RNA sequencing will be performed on a subset of 
treated patients. Studies will be performed under the direction of the Principal Investigator along with co-
Investigator Hassane Zarour in Dr. Zarour’s lab. 
Tumor tissue 
Patients must undergo biopsy (e.g. punch or open biopsy) within 28 days of entry to the study (baseline 
biopsy). Definitive surgery will be performed after 2 cycles of pembrolizumab, and any clinically 
indicated variation from this schedule should be discussed between the investigator, treating sub-
investigator and surgical oncologist. Tumor tissue will be processed as described in the lab manual: 
 

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Primary cSCC (if available) 
FFPE tissue block(s) or 10 unstained slides (air dried; 4μm thickness) from all prior resections of primary 
cSCC will be requested as well. 
 
Blood biospecimens 
Blood biospecimens will be collected at baseline, and per the schedule outlined in Trial Flow Chart 
(Section 2.1). 
 
At EACH time point please submit the following: 
• Six (6) 10mL GREEN top sodium heparin tubes 
• Two (2) 5mL YELLOW top SST tube 
• One (1) 8.5mL Streck cf DNA tube 
• One (1) 4mL K2 EDTA tube (Screening only) 
Each tube must be clearly labeled to include:  
• Protocol number: HCC 20-300 
• Patient sequence number  
• Patient initials  
• Originating institution/investigator name  
• Date and time drawn  
• Collection time point 
Stool specimens 
Stool biospecimens will be collected at baseline, and per the schedule in Trial Flow Chart (Section 2.1). 
 
Dietary questionnaire 
DHQ-3 questionnaire may be administered electronically or on paper. Electronic administration is 
preferred. Data will be entered into DHQ-3 online per instructions as outlined in Appendix 6. 
 
6.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below.  
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.1.3 (see 
Table 6.1.3-1).   
 

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Table 6.1.3-1 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Urine (or serum) β-human chorionic 
gonadotropin (β-hCG)† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
Uric Acid 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
$Infectious serology: hepatitis B 
(HepBsAg and HepBsAb); hepatitis C 
(HIV RNA; and if positive, quantitative 
DNA test); and HIV (HIV 1/2 ELISA) 
 
Phosphorus 
 
  
 
Potassium   
 
 Blood for correlative studies 
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
  
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
$ Only at Screening. 
 

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After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. Results 
must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose 
of trial treatment. 
6.1.4 Other Procedures 
6.1.4.1 Discontinuation and withdrawal 
When a participant discontinues prior to trial completion, all applicable activities scheduled for the final 
trial visit should be performed at the time of discontinuation.  Any adverse events which are present at 
the time of discontinuation should be followed in accordance with the safety requirements outlined in 
Section 7.2. - Assessing and Recording Adverse Events. Participants who a) attain a CR or b) complete 
24 months of treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 5.2.3. After discontinuing treatment following 
assessment of CR, these participants should return to the site for a Safety Follow-up Visit (described in 
Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 
7.1.5.3.2). 
Participants who withdraw prior to completion of the trial should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety requirements outlined 
in Section 7.2. 
6.1.4.2 Withdrawal from Future Biomedical Research  
Participants may withdraw their consent for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator. The investigator will inform the Sponsor. It is the 
responsibility of the investigator to subsequently inform the participant of completion of withdrawal. 
Any analyses in progress at the time of request for withdrawal or already performed prior to the request 
for withdrawal being received will continue to be used as part of the overall research study data and 
results. No new analyses should be generated after the request is received. 
In the event that the specimens have been completely anonymized, there will be no link between the 
participant’s personal information and their specimens. In this situation, the request for specimen 
withdrawal cannot be processed. 
6.1.4.3 
Blinding/Unblinding 
6.1.5 Visit Requirements 
Visit requirements and their timing are detailed in Section 6.1.2 Clinical Procedures/Assessments and 
summarized in Trial Flow Chart (Section 2.1). 

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6.1.5.1 
Screening 
Informed consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion prior to enrollment. 
During initial enrollment visit, study investigator (or designee) must discuss the following with patients: 
• Inclusion and exclusion criteria 
• Medical history – pertinently any condition diagnosed within the prior 10 years that are considered 
to be clinically significant by the Investigator. 
• Prior and concomitant medications. All medications related to reportable SAEs and ECIs should 
be recorded as defined in Section 6.2. 
• Disease details and treatments. 
6.1.5.2 
Treatment Periods 
6.1.5.2.1 Neoadjuvant Phase 
Commences following Screening (Weeks 1-6). 
During this phase, patients receive: 
• Pembrolizumab: 200mg I.V. infusion every 3 weeks for 2 cycles. 
6.1.5.2.2 Surgical Phase 
Commences following Neoadjuvant Phase (>6 weeks). 
During this phase, patients undergo restaging scans, surgical and radiation oncology assessment 
followed by definitive surgery. 
6.1.5.2.3 Adjuvant Phase 
Begins following recovering from surgery (Weeks 9 onwards). 
During this phase, patients receive: 
• Adjuvant RT if applicable as delineated in Section 5.6 (Radiation Therapy 
Considerations) 
• Pembrolizumab: 200mg I.V. infusion every 3 weeks for 15 cycles. 

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6.1.5.3 
Post-Treatment Follow-up 
6.1.5.3.1 30-day Safety Follow-up 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of study treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Participants with 
an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-cancer therapy, whichever occurs first. SAEs that occur within 90 days of 
the end of treatment or before initiation of a new anti-cancer treatment should also be followed 
and recorded.  
6.1.5.3.2 Post-Treatment Surveillance 
Participants who complete study therapy or discontinue study treatment for a reason other than 
disease progression will move into the Follow-Up Phase. These patients are evaluated per the 
standard follow-up schedule including imaging (CT vs. CT/PET vs. PET at the discretion of the 
treating physician) at the intervals directed below. 
The first restaging scan during Post-Treatment Surveillance begins 9 weeks (63 ± 7 days) 
following last imaging study during Adjuvant Phase. Subsequent restaging scans will be obtained 
at the following frequency: every 3 months (±2 weeks) if patient is < 2 years from study entry, 
every 6 months (±4 weeks) if patient is 2-5 years from study entry, and every 12 months (±4 weeks) 
if patient is > 5 years from study entry for up to 15 years. From a study perspective, relapse and 
survival information will be collected for up to 5 years. 
Patients who develop recurrent cSCC will be followed for information on survival and for 
information on salvage patterns. During this period, given the field effect that underlies cSCC 
development in this patient population, every effort will be made to distinguish recurrence of the 
original lesion from a new primary lesion. Every effort should be made to collect information 
regarding disease status until the start of new anti-cancer therapy, disease progression, death, end 
of the study as detailed in Section 5.2.3.  
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated. 
6.1.5.3.3 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first. This will 
be done every 3 months. 

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6.2 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing causality 
of AE and SAE and the procedures for completing and transmitting AE, SAE, and other reportable safety 
event reports can be found in Appendix 5 (Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting). 
Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting events that 
meet the definition of an AE or SAE as well as other reportable safety events. Investigators remain 
responsible for following up AEs, SAEs, and other reportable safety events for outcome. 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE or 
SAE as well as other reportable safety events with respect to seriousness, intensity/toxicity and causality. 
6.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but before 
intervention allocation/randomization must be reported by the investigator if the participant is receiving 
placebo run-in or other run-in treatment, if the event cause the participant to be excluded from the study, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure. 
• All AEs from the time of intervention allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator. 
• All AEs meeting serious criteria, from the time of intervention allocation/randomization through 
90 days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. 
• All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through 120 days following cessation of study intervention, or 30 days 
following cessation of study intervention if the participant initiates new anticancer therapy must 
be reported by the investigator. 
• Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately to Merck if the event is considered drug-
related. 
 

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Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in former 
study participants. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify Merck. 
 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and reported 
to Sponsor-Investigator and Merck within the time frames as indicated in Table 6.2.1-1. 
Table 6.2.1-1 Reporting Time Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events 
Type of Event 
Reporting Time Period: 
Consent 
to 
Randomization/ 
Allocation 
Reporting Time Period: 
Randomization/ 
Allocation 
through 
Protocol-specified 
Follow-up Period 
Reporting Time Period: 
After 
the 
Protocol-
specified Follow-up Period 
Time Frame to Report 
Event 
and 
Follow-up 
Information to Merck: 
Serious 
Adverse 
Event 
(SAE) 
including Cancer and 
Overdose 
Report 
if: 
- due to protocol-specified 
intervention 
- 
causes 
exclusion 
- participant is receiving 
placebo run-in or other 
run-in treatment 
Report all 
Report 
if: 
- 
drug/vaccine 
related. 
(Follow 
ongoing 
to 
outcome) 
Within 2 business days but 
no longer than 3 calendar 
days of learning of event 
Pregnancy/Lactation 
Exposure 
Report 
if: 
- 
due 
to 
intervention 
- causes exclusion 
Report all 
Previously 
reported 
– 
Follow 
to 
completion/termination; 
report outcome 
Within 2 business days but 
no longer than 3 calendar 
days of learning of event 
Event 
of 
Clinical 
Interest 
(require 
regulatory reporting) 
Report 
if: 
- 
due 
to 
intervention 
- causes exclusion 
Report 
- potential drug-induced 
liver 
injury 
(DILI) 
- 
require 
regulatory 
reporting 
Not required 
Within 2 business days but 
no longer than 3 calendar 
days of learning of event 
 
6.2.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable safety 
events. Open-ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrence. 

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6.2.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs, SAEs, and other reportable safety events including pregnancy and 
exposure during breastfeeding, events of clinical interest (ECIs), cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost to follow-
up.. In addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given in Appendix 
5 (Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting). 
6.2.4 Sponsor Responsibility for Reporting Adverse Events  
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable country specific regulatory requirements, global laws and regulations.  
6.2.5 Pregnancy and Exposure During Breastfeeding 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any pregnancy or 
infant exposure during breastfeeding in a participant (spontaneously reported to the investigator or their 
designee) that occurs during the study are reportable to Merck. 
All reported pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage, and stillbirth must be reported as serious events (Important Medical 
Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. 
6.2.6 Events of Clinical Interest (ECIs) 
Selected nonserious and SAEs are also known as ECIs and must be reported to Merck.  
Events of clinical interest for this study include:  
1. 
An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results. For purposes of this study, an overdose of pembrolizumab will be defined as 
any dose of 1,000 mg or greater (≥5 times the indicated dose).  No specific information is available 
on the treatment of overdose of pembrolizumab. In the event of overdose, the participant should 
be observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated.  If an adverse event(s) is associated with (“results from”) the overdose of a 
Merck product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 

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2. 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*  
*Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  
 
 
 
 
 
 
 
 
 
 
 
 
7.0 STATISTICAL ANALYSIS PLAN 
7.1 Study Design 
This is a single-arm phase II study of neoadjuvant pembrolizumab using Simon optimal two-stage design. 
Pembrolizumab (I.V.) will be administered for 6 weeks pre-operatively (weeks 1-6) followed by planned 
surgical resection at week 7-10. Following recovery from surgery, pembrolizumab (I.V.) will commence 
and continue for 45 weeks. 

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7.2 Safety Monitoring 
Anti-PD-1 therapy including pembrolizumab has been tested in PD-1 naïve cSCC in multiple studies. The 
safety profile observed thus far suggests that the risk of toxicities is unlikely to be significantly increased 
in the neoadjuvant setting.  
However, in the context of this neoadjuvant trial, we will monitor dose limiting toxicities (DLTs) for 4 
weeks for the 1st 3 patients accrued. At the end of this period, the PI and the study team will review the 
data to assess the safety of the treatment.  
DLT is defined as any adverse event(s) (AEs) considered possibly, probably, or definitely related to 
pembrolizumab, which occur during the first 28 days of therapy in the Neoadjuvant Phase only. During 
DLT monitoring period, no further accrual will be permitted. Any patient who has started the studied 
treatment will be evaluable for safety.  
The following AEs will be considered DLTs if deemed related to study therapy: 
• Hematologic 
o Grade 4 neutropenia 
o Febrile neutropenia, defined as absolute neutrophil count (ANC) ≤1000/mm3 with a 
temperature of ≥ 38.3 degrees °C 
o Grade ≥ 3 neutropenic infection 
o Grade ≥ 3 thrombocytopenia with bleeding 
o Grade 4 thrombocytopenia 
• Non-hematologic 
o Grade ≥ 3 toxicities (non-laboratory) 
o Grade ≥ 3 nausea, vomiting or diarrhea despite maximal medical intervention 
o Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
• Other (non-AST/ALT) non-hematologic Grade ≥ 3 laboratory value if the abnormality leads to 
overnight hospitalization 
An AE believed to be caused by tumor flare or pseudoprogression does not necessarily need to be 
considered a DLT. Any such cases that would otherwise meet DLT criteria must be discussed immediately 
with the Principal Investigator. If the Principal Investigator agrees that tumor flare is a likely explanation 
for the AE, treatment with pembrolizumab may continue so long as the subject is closely monitored by 
the Principal Investigator or study staff while on study. 

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7.3 Statistical Analysis Plan 
We hypothesize that the pre-operative administration of neoadjuvant pembrolizumab in high-risk PD-1 
naive potentially resectable cSCC patients will be associated with anti-tumor effect as determined by 
pathologic response at the time of surgical resection. We also hypothesize that neoadjuvant 
pembrolizumab will be associated with increased CD8+ TIL in responders at surgery and circulating PD-
1+Ki67+ CD8+ T cells in responders on treatment compared to baseline.  
Although the efficacy of neoadjuvant PD-1 blockade is known in melanoma and MCC, neoadjuvant PD-
1 blockade has only been minimally studied in high-risk cSCC as stated in Section 4.2.1 (Rationale for 
the Trial and Selected Population). While there are 4 planned/ongoing studies, only a single study has 
publically reported data.39 In a small single-institution phase II study in patients with either stage III 
(T3N0Mx; T1-3N1) or stage IV (T4N0Mx; T1-3N2Mx; T1-4N3Mx) cSCC, neoadjuvant cemiplimab was well-
tolerated and associated with a high rate of pathological response (70%) in a small single-institution 
study.39 In this study, 11 patients (55%) had pathologic complete responses.39  
Further, the impact upon RFS in cSCC patients who experience pathological response with peri-operative 
anti-PD-1 therapy is unclear. As such, the pathologic response rate of neoadjuvant PD-1 blockade in high 
risk cSCC as defined herein is unknown at this time. In the interests of maximizing safety while 
minimizing exposure to potentially ineffective therapy, we have designed a two-stage phase II study 
using Simon’s optimal design. 
The null hypothesis that the true pathologic complete response (pCR) rate is 5% will be tested versus 
a one-sided alternative of 25% or higher. In the 1st stage, 9 patients will be accrued. If there are 0 pCR, 
the study will be stopped. If ≥1 pCR are observed in 1st stage, 21 additional patients will be enrolled in 
the 2nd stage. Neoadjuvant pembrolizumab will be considered futile if ≤3 pCR are observed across both 
stages; while neoadjuvant pembrolizumab will be regarded as worthy of further study if >4 pCR are 
observed across both stages. 
This design using Simon’s optimal design, and a sample size of 30 patients across both stages, yields a 
type I error rate of 0.05 with power of 0.90 when the true response rate is 0.25. The probability of early 
stopping when the true pathologic response rate is 5% is 0.63. 
7.4 Efficacy Analysis 
Definition of evaluable patient 
See Section 5.10. 
Briefly, subjects who receive at least 1 dose of pembrolizumab in the Neoadjuvant Phase are evaluable 
for safety. Patients who complete Neoadjuvant Phase and receive surgery will be evaluable for pathologic 
response rate and other efficacy endpoints. The primary endpoint of pathological response will be assessed 
using immune related pathologic response criteria.1-3 
Determination of residual volume of tumor (RVT) 

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In the context of melanoma, early neoadjuvant studies in melanoma reported pCR utilizing criteria to 
define the residual volume of tumor (RVT) derived from neoadjuvant studies of chemotherapy in select 
tumors including lung cancer.54 
Neoadjuvant anti-PD-1 immunotherapy results in distinct histopathologic features compared to 
neoadjuvant chemotherapy. Specifically, neoadjuvant PD-1 therapy produces unusual features beyond 
CD8+ T cell infiltrate previously associated with response including features in areas adjacent to the actual 
tumor – a location termed “the regression bed”.55 Histopathologic features associated with response herein 
include neovascularization; proliferative fibrosis; presence of cholesterol clefts; development of tertiary 
lymphoid structures; presence of plasma cells, giant cells, foamy macrophages and granulomas.1,3 
This observations have led investigators to propose new criteria – immune related pathologic response 
criteria (irPRC) – wherein immune related RVT (% irRVT) is defined as the total surface area of RVT 
divided by the total tumor bed area (comprising regression bed area + RVT area + areas of necrosis).1,3 
Compared to standard methods, the use of irPRC in neoadjuvant melanoma trials had lower inter-observer 
variability and better correlated with imaging assessments.  
Multiple studies are evaluable the role of neoadjuvant anti-PD-1 in high-risk resectable cSCC as 
summarized in Section 4.2.1 (Rationale for the Trial and Selected Population), all of which are ongoing 
with no reported data at this time. At this time, a small single-institution study of neoadjuvant cemiplimab 
for 6 weeks in high-risk resectable stage III/IV disease has reported data.39 In 20 high-risk resectable cSCC 
defined as either stage III disease (T3N0Mx; T1-3N1) or stage IV disease (T4N0Mx; T1-3N2Mx; T1-
4N3Mx), peri-operative cemiplimab administered over 6 weeks was well-tolerated and was produced 70% 
pathologic response.39 Pathologic response in this study was assessed using the same criteria as previously 
reported for melanoma.1,3 As such, in this study, the primary endpoint of this study is proportion of patients 
who achieve pCR as defined as 0% residual volume of tumor (RVT) in post-therapy specimen using irPRC 
criteria.1-3 
Residual tumor will be determined in each resection specimen as outlined in Appendix 7. All tumors will 
be macroscopically localized after correlation with radiologic findings. Specimens were sectioned in 5 
mm-thick slices. In patients with multiple metastases, each lesion will be extensively sampled from the 
center to the periphery to include multiple sections of tumor and non-neoplastic parenchyma. Sampling 
of the tumor nodules in the pathology suite will be directed at the most viable section of the tumor nodule. 
More than one section per centimeter will be reviewed from each tumor nodule. The number of 
hematoxylin-eosin slides reviewed per tumor nodule will be at least four (range, 1 to 14 slides). 
Hematoxylin-eosin stained sections will be reviewed by two melanoma pathologists blinded with respect 
to clinical information and treatment regimen.  
Definition of pathologic complete response (pCR) 
pCR is defined as 0% RVT remaining in post-therapy specimen using irPRC criteria.1-3 Other categories 
of response based on %RVT are given below: 
• Major pathologic response (MPR): >0 but ≤10% RVT 
• Partial pathologic response: >10% but ≤50% RVT 

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• Pathologic non-response: >50% RVT 
pCR rate will be calculated by the proportion of patients with a pCR, along with its exact 95% confidence 
interval. Other response rates will be analyzed similarly. 
Definition of other endpoints (RFS, OS, DMFS and landmark survival) 
In the setting of neoadjuvant breast cancer, RFS has typically been calculated from the date of surgery to 
the first evidence of recurrence (any site)56,57. In neoadjuvant studies in melanoma, RFS has variably been 
calculated from either date of surgery or date of treatment initiation to first evidence of recurrence. Given 
the relative novelty of neoadjuvant anti-PD-1 therapy in cSCC, we will endeavor to capture both of these 
as follows.  
RFS1 is defined as the time from initiation of treatment till cSCC relapse or death; while RFS2 is defined 
as the time from date of surgery till cSCC relapse or death. cSCC relapse will be defined as local relapse, 
locoregional relapse and/or distant relapse. Both RFS1 and RFS2 will be captured, and reported at the time 
of final reporting. In this context, patients who are alive and recurrence-free will be censored at the last 
follow-up. Landmark RFS at 6-month, 1-year, 2-year and 3-year timepoints will be collected and reported. 
Given the field effect associated with cSCC carcinogenesis and the expectation that patients may develop 
new primary cSCCs that do not represent l local, locoregional and/or distant relapse, the development of 
new low-grade cSCC lesions (cSCCis, well-differentiated cSCC) or new pre-cancerous lesions 
(keratoacanthomas, actinic keratoses) will not be treated as RFS-defining events, similar to the Guidance 
provided by the FDA in the context of bladder cancer adjuvant therapy.58 
Distant metastasis-free survival (DMFS) is defined as the time interval between the date of surgery in the 
study and the date of the occurrence of distant metastases or death (all causes), whichever occurs first. In 
this context, patients who are alive and event-free will be censored at the last follow-up. 
Overall survival (OS) is defined as initiation of treatment till death from cSCC. Given that cSCC patients 
are typically older, the treating Investigator or Principal Investigator will endeavor to confirm etiology of 
death prior to assuming that death occurred as a result of disease progression. In this context, patients who 
are alive will be censored at the last follow-up. Landmark OS at1-year, and 2-year timepoints will be 
collected and reported. 
All suspected relapse should be biopsied to confirm relapse as stated in Section 2.1 (Study Flow Chart). 
In the event where this is difficult and/or dangerous, imaging may be used as a surrogate. Kaplan-Meier 
estimates of all survival endpoints will be provided. The corresponding median survival time (with 95% 
confidence intervals) will be determined, along with survival estimates at selected time points (e.g. 6 
months, 1 years, and 2 years). 
7.5 Safety Analysis 
As per NCI CTCAE Version 5.0, the term toxicity is defined as adverse events that are classified as either 
possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity 
will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.  

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As pembrolizumab has previously been studied in cSCC, no “dose-escalation” or a formal continuous 
monitoring rule will be used in this study. However, to accurately capture toxicities for the use of this 
agent in this space, we will be monitoring toxicities closely. The detailed data and safety monitoring plan 
is in Section 7.7 (Data Safety and Monitoring Plan). 
7.6 Biomarker Analysis 
To search for potential prognostic biomarkers (and toxicity marker) for the regimen, logistic regression 
will be used to assess the association between each marker and pathological response.  
The Cox proportional hazards model will be used to assess the association of each marker and survival 
endpoints (i.e. RFS and OS). 
7.7 Data Safety and Monitoring Plan 
All enrolled patients will be reviewed weekly to discuss AEs, in particular during DLT period. 
Principal Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, 
clinical research associates, data managers, and clinic staff meet monthly in disease center Data Safety 
Monitoring Boards (DSMB) to review and discuss study data to include, but not limited to, the following:  
• Serious adverse events  
• Subject safety issues  
• Recruitment issues  
• Accrual  
• Protocol deviations  
• Unanticipated problems  
• Breaches of confidentiality 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria version 4.0. All study treatment associated adverse events that are serious, at 
least possibly related and unexpected will be reported to the IRB. Any modifications necessary to ensure 
subject safety and decisions to continue, or close the trial to accrual are also discussed during these 
meetings. If any literature becomes available which changes the risk/benefit ratio or suggests that 
conducting the trial is no longer ethical, the IRB will be notified in the form of an Unanticipated Problem 
submission and the study may be terminated. 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem submission. 
The summaries of these meetings are forwarded to the UPCI DSMC which also meets monthly following 
a designated format. 

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For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC progress 
reports, to include a summary of all serious adverse events and modifications, and approval will be 
submitted to the IRB at the time of renewal. 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed twice a year rather than monthly by the disease center DSMB. 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to suspend accrual 
or further investigate treatment on any trial based on information discussed at these meetings. 
All records related to this research study will be stored in a double locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research records. 
 
 
 
 
 
 
 
 
 
 
 
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
8.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
Pembrolizumab will be provided by Merck as summarized in Table 8.1-1. 
Table 8.1-1 Product Descriptions 

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Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
8.2 Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
8.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
8.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
8.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
or designee, the amount dispensed to and returned by the participants and the amount remaining at the 
conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange 
for disposal of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and procedures, and provided that 
appropriate 
records 
of 
disposal 
are 
kept. 
 
9.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
 
 
 

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Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 
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21 
Loke, P. & Allison, J. P. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc 
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Jin, H. T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral 
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23 
Fourcade, J. et al. PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma 
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25 
Larkin, J. et al. Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF 
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26 
Ribas, A. et al. Association of Pembrolizumab With Tumor Response and Survival Among 
Patients With Advanced Melanoma. JAMA 315, 1600-1609, doi:10.1001/jama.2016.4059 (2016). 
27 
Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J 
Med 372, 320-330, doi:10.1056/NEJMoa1412082 (2015). 
28 
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): 
post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. 
Lancet Oncol 20, 1239-1251, doi:10.1016/S1470-2045(19)30388-2 (2019). 
29 
Robert, C. et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372, 
2521-2532, doi:10.1056/NEJMoa1503093 (2015). 
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Maubec, E. et al. Pembrolizumab as first line therapy in patients with unresectable squamous cell 
carcinoma of the skin: Interim results of the phase 2 CARSKIN trial. Journal of Clinical Oncology 
36, 9534-9534, doi:10.1200/JCO.2018.36.15_suppl.9534 (2018). 
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Migden, M. R. et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell 
Carcinoma. N Engl J Med 379, 341-351, doi:10.1056/NEJMoa1805131 (2018). 
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Maubec, E. et al. Phase II Study of Pembrolizumab As First-Line, Single-Drug Therapy for 
Patients With Unresectable Cutaneous Squamous Cell Carcinomas. J Clin Oncol 38, 3051-3061, 
doi:10.1200/JCO.19.03357 (2020). 
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Grob, J. J. et al. Pembrolizumab Monotherapy for Recurrent or Metastatic Cutaneous Squamous 
Cell Carcinoma: A Single-Arm Phase II Trial (KEYNOTE-629). J Clin Oncol 38, 2916-2925, 
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Amoils, M. et al. PD-L1 Expression and Tumor-Infiltrating Lymphocytes in High-Risk and 
Metastatic Cutaneous Squamous Cell Carcinoma. Otolaryngol Head Neck Surg 160, 93-99, 
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Bauer, C. et al. T-lymphocyte profiles differ between keratoacanthomas and invasive squamous 
cell carcinomas of the human skin. Cancer Immunol Immunother 67, 1147-1157, 
doi:10.1007/s00262-018-2171-7 (2018). 
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from an open-label, phase 2, single-arm trial. Lancet Oncol 21, 294-305, doi:10.1016/S1470-
2045(19)30728-4 (2020). 
38 
Karia, P. S. et al. Evaluation of American Joint Committee on Cancer, International Union Against 
Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell 
carcinoma. J Clin Oncol 32, 327-334, doi:10.1200/JCO.2012.48.5326 (2014). 
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Gross, N. et al. Phase II study of neoadjuvant cemiplimab prior to surgery in patients with stage 
III/IV (M0) cutaneous squamous cell carcinoma of the head and neck (CSCC-HN). Ann Oncol 30, 
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40 
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Committee on Cancer Staging Manual, 8th Edition vs the Brigham and Women's Hospital Tumor 
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41 
Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. 
Nat Med 24, 1649-1654, doi:10.1038/s41591-018-0197-1 (2018). 
42 
Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage 
III melanoma. Nat Med 24, 1655-1661, doi:10.1038/s41591-018-0198-0 (2018). 
43 
Huang, A. C. et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in 
resectable melanoma. Nat Med 25, 454-461, doi:10.1038/s41591-019-0357-y (2019). 
44 
Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant 
ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, 
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56 
Earl, H. et al. Neoadjuvant trials in early breast cancer: pathological response at surgery and 
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11.0  APPENDICES 
Appendix 1A: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 

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Appendix 1B: AJCC UICC 8th Edition Staging for cSCC 
 

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Appendix 1C: Brigham and Womens Hospital (BWH) Risk Factors for cSCC 
BWH Staging High-Risk Features 
• Clinical tumor diameter ≥2 cm  
• Tumor invasion beyond the subcutaneous fat  
• Poorly differentiated histology 
 
• Perineural invasion of nerve(s) ≥0.1 mm in caliber 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
5.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
• A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
o Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
• Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
o A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal range is 
required. 
o Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they agree to 
one of the following during the protocol defined time frame in Section 5.2. 
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long 
term and persistent basis) and agree to remain abstinent. 
● Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year as 
described in Table 9 when having penile-vaginal intercourse with a woman of childbearing potential 
who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration. 
 

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Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table A3-1 during the 
protocol-defined time frame in Section 5.2.  
Table A3-1 Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● 
Combined (estrogen- and progestogen- containing) hormonal contraception b, c 
○ 
Oral  
○ 
Intravaginal  
○ 
Transdermal  
○ 
Injectable 
● 
Progestogen-only hormonal contraception b, c 
○ 
Oral  
○ 
Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● 
Progestogen- only contraceptive implant b, c  
● 
Intrauterine hormone-releasing system (IUS) b  
● 
Intrauterine device (IUD) 
● 
Bilateral tubal occlusion 
● 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used.  
● 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly).  
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable hormonal 
contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when pregnancy 
is otherwise suspected. 
 

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Appendix 4:  Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide whether 
to continue a participant on study treatment until repeat imaging is obtained (using iRECIST for 
participant management (see Section 6.1.2.5.6 and Table 6.1.2.6.1-1). This decision by the Investigator 
should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at site-assessed 
first radiologic evidence of PD and is not required to have repeat tumor imaging for confirmation of PD 
by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study treatment 
and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by iRECIST, per 
Investigator assessment. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and ≥ 5 mm 
from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD 
(confirmed progressive disease).  For purposes of iRECIST assessment, the first visit showing progression 
according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors 
caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual. 

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New lesions will be classified as measurable or non-measurable, using the same size thresholds and rules 
as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 5 lesions total (up 
to 2 per organ), may be selected as New Lesions – Target.  The sum of diameters of these lesions will be 
calculated and kept distinct from the sum of diameters for target lesions at baseline.  All other new lesions 
will be followed qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an overall 
response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), 
or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, compared 
to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared to a 
prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
▪ An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time point  
▪ Visible growth of new non-target lesions  
▪ The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which iUPD is 
seen.  This may correspond to the next visit in the original visit schedule.  The assessment of the 
subsequent confirmation scan proceeds in an identical manner, with possible outcomes of iCPD, iUPD, 
and iSD/iPR/iCR. 
Resolution of iUPD 

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Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR 
if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, whenever it 
occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response 
of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule.  
If PD is confirmed, participants will be discontinued from study treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment may be 
considered.  In this case, if study treatment is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Section 6. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by any of the 
following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) either for 
the first time, or after resolution of previous pseudo-progression.  The nadir is always the 
smallest sum of diameters seen during the entire trial, either before or after an instance of 
pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this progression has not 
resolved, iUPD results from any significant further growth of non-target lesions, taken as a 
whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 

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o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion sum of 
diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation 
process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression must be confirmed 
before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one respect. 
If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the burden of new lesions 
has increased from its smallest value (for new target lesions, their sum of diameters is ≥5 mm increased 
from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the 
new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication.53 
 

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Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting 
11.1.1 Definition of AE 
AE definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a study intervention. 
• NOTE: For purposes of AE definition, study intervention (also referred to as Merck product) 
includes any pharmaceutical product, biological product, vaccine, diagnostic agent, or protocol 
specified procedure whether investigational or marketed (including placebo, active comparator 
product, or run-in intervention), manufactured by, licensed by, provided by, or distributed by 
Merck for human use in this study. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. 
• For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term 
should reflect the clinical symptoms or abnormal test result. An overdose without any associated 
clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect.” 
      

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Events NOT meeting the AE definition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
• Surgery planned prior to informed consent to treat a pre-existing condition that has not worsened. 
 
11.1.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
• The term “life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an 
elective procedure to treat a pre-existing condition that has not worsened is not an SAE. A pre-
existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and 
is documented in the participant’s medical history. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 

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• In offspring of participant taking the product regardless of time to diagnosis. 
f. Other important medical events 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
11.1.3 Additional Events Reported in the Same Manner as SAE 
Additional events that require reporting in the same manner as SAE 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious per ICH 
definition, are reportable to Merck in the same time frame as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose of pembrolizumab 
11.1.4 Recording AE and SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory, and diagnostics reports) related to the event. 
• The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at each 
examination. 
• There may be instances when copies of medical records for certain cases are requested by the Merck. 
In this case, all participant identifiers, with the exception of the participant number, will be blinded 
on the copies of the medical records before submission to the Merck. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 

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Assessment of intensity/toxicity 
• An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, not when it is rated as severe. 
1. 
The investigator will make an assessment of intensity for each AE and SAE (and other reportable 
safety event) according to the NCI Common Terminology for Adverse Events (CTCAE), version 
5. Any AE that changes CTCAE grade over the course of a given episode will have each change 
of grade recorded on the AE CRFs/worksheets. 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
• Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• Grade 4: Life threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
Assessment of causality 
1. 
Did Merck product cause the AE? 
2. 
The determination of the likelihood that Merck product caused the AE will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialed document must be retained for the 
required regulatory time frame. The criteria below are intended as reference guidelines to assist 
the investigator in assessing the likelihood of a relationship between the test product and the AE 
based upon the available information. 
3. 
The following components are to be used to assess the relationship between Merck’s product 
and the AE; the greater the correlation with the components and their respective elements (in 
number and/or intensity), the more likely Merck product caused the AE: 
• Exposure: Is there evidence that the participant was actually exposed to Merck product such 
as: reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
• Time Course: Did the AE follow in a reasonable temporal sequence from administration of 
Merck product? Is the time of onset of the AE compatible with a drug-induced effect (applies 
to studies with investigational medicinal product)? 

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• Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors. 
• Dechallenge: Was Merck product discontinued or dose/exposure/frequency reduced? 
• If yes, did the AE resolve or improve? 
• If yes, this is a positive dechallenge. 
• If no, this is a negative dechallenge. 
• (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the Merck product; (3) the study is a 
single-dose drug study; or (4) Merck product(s) is/are only used 1 time.) 
• Rechallenge: Was the participant re-exposed to Merck product in this study? 
• If yes, did the AE recur or worsen? 
• If yes, this is a positive rechallenge. 
• If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 
or (2) the study is a single-dose drug study; or (3) Merck product(s) is/are used only 1 time.) 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND MAY HAVE 
BEEN CAUSED BY MERCK PRODUCT, OR IF RE-EXPOSURE TO MERCK’S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE INIRB/IEC. 
4. 
Consistency with study intervention profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
5. 
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
6. 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of Merck product relationship). 
• Yes, there is a reasonable possibility of Merck product relationship: 

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• There is evidence of exposure to the Merck product. The temporal sequence of the AE onset 
relative to the administration of Merck product is reasonable. The AE is more likely explained 
by Merck product than by another cause. 
• No, there is not a reasonable possibility of Merck product relationship: 
• Participant did not receive the Merck product OR temporal sequence of the AE onset relative 
to administration of the Merck product is not reasonable OR the AE is more likely explained 
by another cause than the Merck product. (Also entered for a participant with overdose without 
an associated AE.) 
7. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
8. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Merck. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Merck. 
9. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
10. 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
11. 
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent of 
the combination. In general, causality attribution should be assigned to the combination regimen 
(ie, to all agents in the regimen). However, causality attribution may be assigned to a single agent 
if in the investigator’s opinion, there is sufficient data to support full attribution of the AE to the 
single agent. 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.  
• New or updated information will be recorded in the CRF.  
• The investigator will submit any updated SAE data to Merck within 2 business days but no longer 
than 3 calendar days of receipt of the information. 

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11.1.5 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Merck 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European 
Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 
Investigators will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally, 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; 
FAX 215-661-6229) at the time of submission to FDA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 6: Dietary History Questionnaire (DHQ-3) for Microbiome Sampling 
 
Dietary history questionnaire will be administered either on paper or electronically and data entered and 
stored securely electronically. Instrument will be administered by PI or designee. Detailed information for 
study staff:  
• Please obtain patient’s username and password from study PI. 
• Please provide instructions (see below) to patients. 
• Patients are to be instructed to provide detailed dietary information either during visit (preferred) or 
at home.  
• The instrument that will be utilized is the DHQ-3 “past month with portion size” obtained from 
https://epi.grants.cancer.gov/dhq3/ 
 
 
Detailed information for patients: 
• Thank you for participating in this study. We are interested in evaluating your dietary history. To 
do this we are using a validated questionnaire termed the “Diet History Questionnaire (DHQ-3)”. 
• This questionnaire takes approximately 30 minutes to complete. You can do this either while 
receiving your therapy or at home. 
• After completing the questionnaire, you will receive a Respondent Nutrition Report. This report 
shows estimated daily nutrient and food group intakes based on questionnaire responses. 
Recommended values are only available for some nutrients and food groups. 
• Please feel free to discuss this with your study doctor. 
Dietary study login URL: https://epi.grants.cancer.gov/dhq3/ 
Your username (case sensitive): __________ 
Your study password (case sensitive): __________ 

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Appendix 7: Pathology Sampling and Response Assessment Criteria 
In order to achieve accurate and reproducible pathologic assessment in neoadjuvant treated specimens, 
grossing assessment and tissue submission following neoadjuvant treatment should be standardized. These 
recommendations will largely adhere to recommendations made by the International Neoadjuvant 
Melanoma Consortium (see figure below) for the evaluation of melanoma specimens as applied to cSCC 
specimens with certain modifications. 
 
 
 
For LN specimens: 
• If the largest grossly positive lymph node measures ≤ 5 cm in greatest dimension, then the entire 
lymph node should be entirely submitted at 2 mm serially sectioned intervals. 
• For any grossly positive lymph node measuring > 5 cm in greatest dimension, representative 
sections of the largest lymph nodes may be utilized to avoid oversampling as indicated below.  
• Following serial sectioning of each lymph node, for those grossly positive nodes > 5 cm, sections 
representing a complete cross section of the entire surface area should be submitted per 1 cm of 
each grossly positive lymph node.  
• All lymph nodes < 5cm in specimens where the largest node(s) exceeds 5 cm should be 
submitted entirely. 
 
For primary tumor specimens: 
• If the largest primary tumor specimen measures ≤ 5 cm in greatest dimension, then the entire 
primary tumor specimen should be entirely submitted at 2 mm serially sectioned intervals. 
• For any grossly positive primary tumor specimen measuring > 5 cm in greatest dimension, 
representative sections of the primary tumor specimen may be utilized to avoid oversampling as 
indicated below.  

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• Following serial sectioning of each lymph node, for those grossly positive nodes > 5 cm, sections 
representing a complete cross section of the entire surface area should be submitted per 1 cm of 
each grossly positive lymph node.  
• All lymph nodes < 5cm in specimens where the largest node(s) exceeds 5 cm should be 
submitted entirely. 
 
Synoptic 
Background and Demographic Information: 
• 
Sex/Age: 
 
Pre-Treatment Pathology 
• 
Location of tumor 
• 
Nature of tumor: 
• 
Date of initial diagnosis: 
• 
Pre-treatment biopsy: 
o 
Date: 
o 
Nature of biopsy: 
o 
Location/anatomic site: 
o 
Tumor present/absence: 
 
 
Post-Treatment Imaging 
• 
Date:  
• 
Post-treatment imaging findings: 
 
 
Surgical Resection: 
• 
Date: 
• 
Type of surgery: 
• 
Location/anatomic site: 
 
 
Post-Treatment Pathological Response Assessment 
• 
Tissue banked 
o 
Yes 
 
o 
No 
• 
Nature of lesion 
o 
Lymph node  
 
o 
Cutaneous lesion 
 
o 
Both (LN + skin) 
• 
Largest positive LN/nodule size (in mm2): 
• 
Sizes of other lymph nodes/nodules (in mm2): 
• 
Blocks number of positive LN/nodules: 
• 
Treatment response evaluation metrics: 
o 
Size of tumor bed: 
o 
Gross/microscopy: 
▪ 
Percentage of viable tumor: 

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▪ 
Percentage of stromal fibrosis: 
▪ 
Percentage of necrosis: 
o 
For lymph nodes: 
▪ 
Extra-capsular extension 
• 
Y/N 
 
• 
Viable/regressed 
 
• 
Response assessment (based on %RVT): 
o 
Pathologic CR (pCR; %RVT=0%) 
o 
Other 
▪ 
State %RVT                                     ___________