A Phase II Study of Pembrolizumab in EGFR Mutant, Tyrosine Kinase Inhibitor Naïve Treatment Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Stage IIIA Non-Small Cell Lung Cancer, Stage IIIB Non-Small Cell Lung Cancer, Stage IV Non-Small Cell Lung Cancer
Sponsor: Jonsson Comprehensive Cancer Center

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
TITLE: 
A Phase II Study of Pembrolizumab in EGFR Mutant, Tyrosine Kinase Inhibitor Naïve Treatment 
Patients with Advanced Non-Small Cell Lung Cancer (NSCLC)  
IND NUMBER: 
PRINCIPAL INVESTIGATOR: 
Edward Garon, MD, MS 
Associate Professor of Medicine, Division of Hematology - Oncology 
Jonsson Comprehensive Cancer Center  
David Geffen School of Medicine at UCLA 
EudraCT NUMBER (Studies in Europe only): 
Version 4          01 December 2017 
NCT Number: NCT02879994 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab in Frontline EGFR mutant, TKI-naïve NSCLC 
Trial Phase 
Phase II 
Clinical Indication 
The treatment of subjects with non-small cell lung cancer (NSCLC) 
whose tumors are positive for PD-L1 and harbor an EGFR mutation 
who have not been previously treated with an EGFR TKI 
Trial Type 
Interventional 
Type of control 
Active control without placebo 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded Open-label 
Treatment Groups  
Pembrolizumab 200 mg every three weeks 
Number of trial subjects 
Approximately 25 patients will be enrolled. 
Estimated enrollment period We estimate that the trial will require approximately 16 months 
from the time the first subject signs the informed consent until the 
last subject’s consent. 
Estimated duration of trial 
We estimate that the trial will require approximately 28 months 
from the time the first subject signs the informed consent until the 
subject’s last visit. 
Duration of Participation 
Each subject will participate in the trial from the time the subject 
signs the Informed Consent Form (ICF) through the final protocol-
specified contact. After a screening phase of up to 28 days, eligible 
subjects will receive assigned treatment on Day 1 of the 3-week 
(Q3W) dosing cycle. Treatment with pembrolizumab will continue 
until radiographic progression, documented disease progression, 
unacceptable adverse event(s), intercurrent illness that prevents 
further administration of treatment, investigator’s decision to 
withdraw the subject, subject withdraws consent, pregnancy of the 
subject, noncompliance with trial treatment or procedure 
requirements, or administrative reasons. After progression on 
pembrolizumab, patients will be asked to undergo an additional 
biopsy and blood draw and be followed through periodic follow-up 
visits and calls (every 60 days) for evaluation of duration of 
response with the EGFR TKI as well as survival follow up 
Estimated average length of 
treatment per patient 
6 months 
 
 
 
 

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2.0 TRIAL DESIGN 
2.1 
Trial Design 
Specific procedures to be performed during the trial, as well as their prescribed times and associated 
visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each procedure are provided 
in Section 7.0 – Trial Procedures. 
This is a single-site Phase II trial of intravenous (IV) pembrolizumab in subjects with non-small cell 
lung cancer (NSCLC) with PD-L1 positive (≥1% by immunohistochemistry (IHC) 22C3 pharmDx test) 
and EGFR mutant tumors who have not been previously treated with a tyrosine kinase inhibitor (TKI). 
Approximately 25 subjects will be enrolled in this trial to examine the response to pembrolizumab in 
this TKI-naïve population. Subjects will all receive 200 mg every 3 weeks (Q3W). Assignment to 
pembrolizumab will be unblinded.  
 
Subjects will be evaluated every 9 weeks (63 +/- 7 days) with radiographic imaging to assess response 
to treatment. All imaging obtained on study will be assessed using a modified Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 for determination of objective response rate (ORR) and 
progression-free survival (PFS). Subjects will continue with the assigned study treatment until RECIST 
1.1-defined progression of disease, unacceptable toxicity, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject withdraws consent, 
pregnancy of the subject, noncompliance with trial treatment or procedure requirements, administrative 
reasons, or the subject has received 35 trial treatments of pembrolizumab. Treatment may continue 
despite RECIST 1.1 defined progression if the subject is clinically stable and is considered to be 
deriving clinical benefit by the investigator. Adverse events will be monitored throughout the trial and 
graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. 
 
After the end of treatment, each subject will be followed for a minimum of 30 days for adverse event 
monitoring. After progression on pembrolizumab, patients will be asked to undergo an additional 
biopsy and blood draw and be followed through periodic follow-up visits and calls (every 60 days) for 
evaluation of duration of response with the EGFR TKI as well as survival follow up. Subjects will have 
post-treatment follow-up for disease status until death, withdrawing consent, or becoming lost to 
follow-up.  
 
The primary objective of the trial is objective response rate (ORR) per RECIST 1.1. Safety, as assessed 
by a variety of parameters of adverse events (AEs), will be a secondary objective. Additional secondary 
objectives will be to determine ORR, PFS, and OS of subsequent EGFR TKI therapy in patients with 
EGFR-sensitizing mutation after pembrolizumab and to analyze tumor tissue biomarkers for potential 
correlation with response. 
 
Participation in this trial will be dependent upon supplying tumor tissue from a newly obtained 
formalin-fixed specimen from locations not radiated prior to biopsy; no new systemic antineoplastic 
therapy may be administered between the PD-L1 biopsy and initiating study medication. The qualifying 

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biopsy does not need to be obtained after consent for this trial is signed. The specimen will be evaluated 
at a central laboratory or a CLIA-certified laboratory that uses the 22C3 antibody for expression status 
of PD-L1 in a prospective manner. Only subjects whose tumors demonstrate an EGFR mutation and 
PD-L1 will be eligible for this study. Any CLIA certified test to assess EGFR mutational status is 
acceptable. 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: Determine efficacy [objective response rate (ORR)] of front-line pembrolizumab for 
Stage IIIB or IV metastatic EGFR mutation positive PD-L1+ (> 1% by IHC) NSCLC 
 
Hypothesis: We hypothesize that over 26% of patients with Stage IIIB or IV EGFR mutation 
positive, EGFR TKI-naïve, PD-L1+ NSCLC will show a response with pembrolizumab.  
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective: Determine safety [adverse event tabulation and grading] of front-line pembrolizumab 
for Stage IIIB or IV EGFR mutation positive PD-L1+ [> 1% by immunohistochemistry 
(IHC)]NSCLC 
(2) Objective: Determine efficacy [progression free survival (PFS), overall survival (OS)] of front-
line pembrolizumab for Stage IIIB or IV EGFR mutation positive PD-L1+ (>1% by IHC) NSCLC 
(3) Objective: Determine ORR, PFS and OS of subsequent EGFR TKI therapy in patients with EGFR-
sensitizing mutation after pembrolizumab   
Hypothesis: We hypothesize that the safety, progression free survival, and overall survival among 
EGFR mutant patients who are EGFR TKI naïve and treated with pembrolizumab will be similar 
to what has been generally seen with pembrolizumab in the general population. Further, we 
hypothesize that the clinical outcomes from EGFR TKI treatment in patients with EGFR-
sensitizing mutations after pembrolizumab will be similar to what would be expected in a treatment 
naïve patient population. 
3.3 
Exploratory Objective 
(1) Objective: Analyze tumor tissue biomarkers for potential correlation with response 
Hypothesis: We hypothesize that patients with high level of PD-L1 expression (> 50% by 
immunohistochemistry) are more likely to respond to an anti-PD-1 therapy.  
 

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4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
pembrolizumab. 
 
In the United States, lung cancer is the leading cause of cancer-related deaths in both men and women 
with an estimated 160,340 deaths in 2012, with NSCLC comprising over 85% of all lung cancers (1). 
Approximately 10% of patients in Western countries have mutations in the epidermal growth factor 
receptor (EGFR) gene (2). These tumors are generally responsive to tyrosine kinase inhibitors (TKIs) 
directed against EGFR (2). Unfortunately, TKI benefits are transient, and recurrence inevitably occurs. 
Immunotherapies, specifically inhibitors of programmed cell death 1 (PD-1), are an emerging class of 
drugs that provide durable responses in some lung cancer patients (3).  
 
Epidermal Growth Factor Receptor: Mutations and Targeted Therapies 
Tyrosine kinase receptors play a major role in the tumorigenicity of neoplastic cells, particularly 
NSCLC (4). Up to half of NSCLC patients in Asian populations and approximately 10% in Western 
populations harbor EGFR mutations (5-6).  To stop the proliferative signals of EGFR, TKIs such as 
gefitinib, erlotinib, and afatinib selectively block autophosphorylation of the EGFR intracellular 
tyrosine kinase domain (7). These drugs are approved in multiple countries for the treatment of locally 
advanced or metastatic NSCLC in 2nd or 3rd-line therapy.  
Gefitinib showed superiority as a first line therapy compared to carboplatin-paclitaxel chemotherapy in 
progression-free survival (PFS) in EGFR mutant patients (hazard ratio (HR) for progression, 0.48; 
p<0.001) (8). As a result, EGFR TKIs have become the standard initial therapy in EGFR mutant 
NSCLC. Although there have been meta-analyses and subset analyses that have found improvement in 
survival with an EGFR TKI, individual studies have failed to show improvement in overall survival for 
EGFR TKIs in EGFR mutant patients, presumably based on patients in the chemotherapy arms crossing 
over to EGFR TKIs on progression (9). 
Second generation TKIs including dacomitinib and afatinib have been evaluated (10-11). However, in 
approximately 60% of EGFR mutant patients, resistance is mediated by a secondary T790M mutation 
in EGFR, and 2nd generation agents have not been clinically successful in this setting (12). 
Third generation drugs, including CO-1686 and AZD9291, have been designed to irreversibly inhibit 
the tyrosine kinase activity of mutant EGFR without affecting wild-type EGFR (13-15). Phase I/II trials 
are currently underway (NCT01526928 and NCT01802632), with preliminary data indicating over 
50% objective response rate (ORR) in T790M–positive patients (16-17). However, this accounts for 
only a subset of patients with TKI resistance, leaving a significant proportion of patients without 
favorable options after progression on an EGFR TKI. Moreover, acquired resistance to these new agents 
is anticipated.     
 
PD-1/PD-L1 Play a Role in Tumors Evading Immune Destruction 
PD-1, encoded by the Pdcd1 gene, is an immunoglobulin in the CD28 family. PD-1 is a type I 
transmembrane glycoprotein containing an extracellular Ig variable-type (V-type) domain involved in 

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ligand binding and a cytoplasmic tail involved in intracellular signaling. The cytoplasmic tail contains 
an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based 
switch motif (ITSM) (18). Ligand binding to PD-1 induces recruitment of SHP-1 and SHP-2 to the 
ITSM motif, causing de-phosphorylation of CD3ζ, PKCθ, and ZAP70, which are involved in the CD3 
T cell-signaling cascade (19-20).  
 
One mechanism by which cancer cells evade immune surveillance is up-regulation of the ligand PD-
L1, the binding partner of PD-1. PD-1 is expressed by CD4+ and CD8+ T cells, B cells, Tregs, and NK 
cells (21). In T cells, binding of PD-1 with PD-L1 (or its other ligand, PD-L2) conveys a signal to the 
T cell that down-regulates activation, preventing destruction of the antigen-presenting cell. Under 
healthy conditions, PD-L1 attenuates unwanted immune responses, such as autoimmunity (22).  
 
Cytokines Can Create a Permissive Environment for Tumors 
Cytokines are a group of small proteins released from cells that direct effects through autocrine or 
paracrine signaling mechanisms. Cytokines predominantly modulate the immune system by activating 
or inhibiting immune cells. When investigating the mechanism of PD-1 inhibition in cytotoxic T-
lymphocytes (CTLs), cytokines of interest, such as IL-6 and TGF-β, have been implicated in creating 
a permissive microenvironment, including EGFR mutant NSCLC (23). For L858R tumors in mouse 
models, it was concluded that upregulation of IL-6 and TGF-β assisted in cell proliferation (23). TGF-
β has also been implicated as an inducer of epithelial-mesenchymal transition (EMT), which is 
associated with inhibition of CTL-mediated tumor cell lysis, possibly by overexpression of PD-L1, in 
tumors exhibiting EMT (24-26).  
 
  
Anti PD-1/PD-L1 Immunotherapy Have Led to Durable Responses in NSCLC 
Since T lymphocytes recognize antigens derived from cellular compartments that are presented on the 
surface of tumor cells, T cells are a major focus in cancer immunotherapy (27). Recently, 
immunotherapies have shown promise in the treatment of a variety of cancers including NSCLC (28). 
These treatments act to disrupt immunosuppressive checkpoints, including PD-1/PD-L1, that are 
believed to play important roles in prevention of autoimmune responses but also allow tumors to evade 
destruction by the immune system (29). 
 
Several monoclonal antibodies inhibiting PD-1 are currently in clinical development, including 
nivolumab (BMS936558) and pembrolizumab (MK-3475; lambrolizumab) (3, 30-31). We 
demonstrated safety and efficacy of pembrolizumab in previously treated NSCLC patients, with ORR 
of 20% (3). Similar results were seen with nivolumab (28). Response durations have been ongoing for 
more than 1 year. Recent data from the KEYNOTE 024 study has shown that front line treatment 
with pembrolizumab significantly improved progression free survival as well as overall 
survival in patients with PD-L1 positive (>50%) non-small cell lung cancer as compared to 
platinum based chemotherapy. Patients with EGFR mutations were excluded from this study. 
(37). 
 

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4.1.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades.  Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) 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 seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment 
of patients with unresectable or metastatic melanoma and disease progression following ipilumumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor. KeytrudaTM (pembrolizumab) has also been 
granted accelerated approval by the United States Food and Drug Administration to treat patients with 
metastatic non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments 
and with tumors that express PD-L1 protein.    
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 Subject Population 
Although tyrosine kinases directed against EGFR have revolutionized the care of patients with EGFR 
mutant tumors, progression is generally seen after approximately a year, and the benefit of newer 
inhibitors at the time of progression is generally less than a year. PD-1 inhibition is a promising option 
for NSCLC patients, but an optimal strategy in EGFR mutant patients has been elusive.  The rationale 
for treating TKI naïve patients is corroborated by laboratory studies demonstrating that cell lines treated 
with EGFR TKIs have lower PD-L1 expression levels (33). PD-L1 expression has been positively 
correlated with benefit (34). 
 
This trial could lead us to reevaluate the standard-of-care for non-small cell lung cancer (NSCLC) 
patients with mutations in EGFR. Programmed cell death-1 (PD-1) inhibitors have shown significant 
potential to induce durable responses in NSCLC. To date, responses have been less frequent in patients 
harboring EGFR mutations, although responses are seen (34). Predictors of response in this group are 
unclear. Although studies are being conducted in which EGFR mutant patients are given EGFR tyrosine 
kinase inhibitors (TKIs) and PD-1 inhibitors, the schemas are based on established clinical pathways 
(EGFR TKIs first) rather than objective preclinical and clinical data. It is not clear that the best strategy 
is to treat EGFR mutant patients with an EGFR TKI prior to a PD-1 inhibitor, and in addition, 
approximately 10% of EGFR mutant patients do not have a mutation that is sensitive to available EGFR 
TKIs. In a retrospective analysis in the BRAF-mutant melanoma population (a somewhat similar 

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clinical scenario), prior treatment with immunotherapies did not adversely impact response to BRAF 
inhibitors, while outcomes of immunotherapy following BRAF inhibition were poor (35). 
 
Data from the KEYNOTE-001 trial revealed that prior TKI therapy in NSCLC EGFR mutant patients 
was strongly correlated with a lack of response to PD-1 inhibitor therapy (34).  In contrast, out of the 
29 EGFR mutant patients treated at UCLA, 2 of 3 EGFR TKI naïve patients had a partial response to 
pembrolizumab compared to only 1 of 26 patients who had been previously treated with an EGFR TKI. 
The only patient with a prior EGFR TKI who responded to pembrolizumab had an EGFR mutation that 
is typically not sensitive to available EGFR TKI’s. In addition, based on our data from the clinical 
experience through the KEYNOTE 001 trial, when analyzing response in our EGFR mutant patients 
treated with an anti-PD-1 immunotherapy (N=29) and the subset who received a 9 week scan (N=18), 
response was significantly more favorable in those who did not receive a prior EGFR TKI in both 
subgroups (p<0.001).  
 
Overall EGFR MT Population 
PR SD/PD 
 
 
EGFR MT/9 Week Scan 
PR SD/PD  
No TKI 
2 
1 
3 
 
No TKI 
2 
0 
2 
TKI 
1 
25 
26  
TKI 
1 
15 
16 
Total 
3 
26 
29  
Total 
3 
15 
18 
   
Of the 18 patients with 9 weeks scans, two EGFR mutant patients who were TKI-naïve were enrolled, 
one with a L858R mutation (enrolled prior to an amendment excluding such patients prior to an EGFR 
TKI) and one with an exon 20 insertion (generally EGFR TKI resistant). Both patients achieved a partial 
response (PR) according to RECIST 1.1. Only one of the 16 EGFR mutant patients (the patient had an 
exon 20 insertion) who received prior TKI treatment achieved a PR. A similar correlation was not seen 
when EGFR wild type patients were evaluated based on whether they were treated with an EGFR TKI.  
 
In order to corroborate the results from the clinical trial, we conducted cell line experiments to evaluate 
potential immunomodulatory effects of EGFR TKIs, particularly with respect to the PD-1 pathway 
(Figure 1). Afatinib, an irreversible pan-HER inhibitor is associated with an IC50 < 1µM in H1975, 
HCC827 and Calu-3. Erlotinib, a reversible EGFR inhibitor, inhibits only HCC827 at this level. Neither 
TKI inhibits H460 at this level. The cell lines that were effectively inhibited by the EGFR TKI also saw 
a decrease in PD-L1 levels, confirming results from others (23). When studying TKI-resistant, non-
small cell lung cancer cell lines, PD-L1 expression was not reduced by EGFR TKIs. The results mimic 
what we saw clinically, in which pembrolizumab was not an effective therapy in patients with EGFR 
sensitizing mutations after a prior EGFR TKI. 

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Figure 1: Western blot analysis of 
PD-L1 expression (PD-L1 mAb 
#13684, 
Cell 
Signaling 
Technology) in NSCLC cell lines 
in response to erlotinib and 
afatinib. NSCLC cell lines H1975 
(EGFR L858R/T790M mutation), 
H460 (KRAS Q61H mutation), 
HCC827 
(EGFR 
exon 
19 
deletion), 
and 
Calu-3 
(her2 
amplification) were evaluated at 
baseline and after 24 hours of exposure to 1 μM erlotinib or afatinib. * indicates an IC50 < 1μM for the 
respective drug in that cell line. 
Data from the KEYNOTE 024 trial showed that first-line treatment with pembrolizumab significantly 
improved progression-free and overall survival in patients with PD-L1 positive (>50%) non-small cell 
lung cancer. Pembrolizumab was also associated with a higher overall response rate and a longer 
duration of response than platinum-based chemotherapy. Patients with EGFR mutations were excluded 
from this study (37). 
This study will be the first to our knowledge to evaluate the role of PD-1 inhibitors in EGFR mutant 
patients who have not yet received an EGFR TKI. After progression on pembrolizumab, patients will 
be asked to undergo an additional biopsy and blood draw and be followed through periodic follow-up 
visits and calls (~every 2 months) for evaluation of duration of response with the EGFR TKI as well as 
survival follow up. The goal of this clinical trial is to evaluate a treatment sequence in which EGFR 
mutant NSCLC patients receive pembrolizumab prior to an EGFR TKI. 
 
4.2.2 
Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical activity of 
single agent pembrolizumab (34).  The dose escalation portion of this trial evaluated three dose levels, 
1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid 
tumors (34).  All three dose levels were well tolerated and no dose-limiting toxicities were observed 
(34). This first in human study of pembrolizumab showed evidence of target engagement and objective 
evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No 
maximum tolerated dose (MTD) has been identified to date Recent data from other clinical studies 
within the pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 release 
assay) suggested that peripheral target engagement is durable (>21 days). This early PK and 
pharmacodynamics data provides scientific rationale for using Q3W dosing schedule.   

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A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of 
pembrolizumab were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and 
would support both body weight normalized dosing or a fixed dose across all body weights.  
pembrolizumab has been found to have a wide therapeutic range based on the melanoma indication.  
The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 200 mg Q3W. 
The population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, 
there are no anticipated changes in exposure between different indication settings. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose 
of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained 
with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure 
range established in melanoma as associated with maximal efficacy response and 3) will maintain 
individual patients exposure in the exposure range established in melanoma that are well tolerated and 
safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. 
4.2.3 
Rationale for Endpoints 
4.2.3.1 
Efficacy Endpoints 
The primary endpoint will be objective response rate (ORR), while the secondary endpoints will be 
progression-free survival (PFS) and overall survival (OS). The rationale for using ORR as the primary 
endpoint is that this trial is a single-arm trial; assessing ORR will allow us to attribute the effect of 
treatment directly to pembrolizumab, not to the natural history of NSCLC.  
Since ORR cannot comprehensively measure drug activity, PFS and OS will be used as secondary 
endpoints. This will allow us to account for deaths that are unrelated to cancer and to the effects of 
pembrolizumab. PFS is an acceptable measure of clinical benefit for a Phase 2 trial that demonstrates 
superiority of a new antineoplastic therapy, especially if the magnitude of effect is large and the therapy 
has an acceptable risk-benefit profile. Furthermore, it is an endorsed regulatory endpoint for 1L NSCLC 
trials with recent FDA and EMA approvals including the EGFR inhibitors afatinib and erlotinib. PFS 
will be assessed by RECIST 1.1 by an independent central radiologists’ review. Although PFS assesses 
how long a patient is on trial without progressing, since we have seen that EGFR mutant patients have 

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a high response rate, we will also collect OS data to determine if pembrolizumab is comparable to TKI 
therapy or standard of care chemotherapy. Further, OS is a standard assessment of clinical benefit in 
subjects with advanced or metastatic NSCLC. OS will be assessed by RECIST 1.1 criteria by 
independent central radiology review. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 
Diagnosis/Condition for Entry into the Trial 
Refer to sections 5.1.2 and 5.1.3 of the protocol for more detailed information. 
5.1.2 
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Ability to understand the purpose and risks of the study and provide signed and dated informed 
consent and authorization to use protected health information (PHI). 
 
2. Be ≥18 years of age on day of signing informed consent. 
 
3. Have a life expectancy of at least 3 months. 
 
4. Have a histologically or cytologically confirmed diagnosis of Stage IIIB or IV non-small cell 
lung cancer (NSCLC) and have at least one measurable lesion as defined by modified RECIST 
1.1. The target lesion(s) should also have bi-dimensional measurability for RECIST 1.1 
evaluation on study. 
 
5. Have an EGFR mutation (sensitizing or non-sensitizing) as determined by any CLIA certified 
laboratory. 
 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale.  
 
7. Have adequate organ function 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 

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Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 
X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
aCreatinine clearance should be calculated  using the standard Cockcroft and Gault 
equation. 
 
8. Have provided tissue for PD-L1 biomarker analysis from either a newly obtained or archival 
formalin fixed tumor tissue from a biopsy of a tumor lesion not previously irradiated for 
analysis of PD-L1 expression. The tissue sample must be received and evaluated by the study 
site prior to start of treatment. Fine needle aspirates are not acceptable. Needle or excisional 
biopsies, or resected tissue is required.  
 
9. Have a PD-L1 positive (either strongly or weakly) tumor as determined by the IHC 22C3 
pharmDx test at the study site. If a patient’s initial tumor specimen is not classified as PD-L1 
positive a newly obtained specimen (different from the sample previously submitted) may be 
submitted for testing. If the newer specimen is classified as PD-L1 positive by the study site, 
the patient meets this eligibility criterion. Positivity can either be determined at the central 
laboratory or at any CLIA-certified laboratory using the 22C3 antibody. 
 
10. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less 
(except alopecia). If subject received major surgery or radiation therapy of > 30 Gy, they must 
have recovered from the toxicity and/or complications from the intervention.  
 

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11. Female subject of childbearing potential has a negative urine or serum pregnancy test. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. The serum pregnancy test must be negative for the subject to be eligible.  
 
12. Female subjects may be enrolled in the trial if they are:  
-of non-childbearing potential which is defined as a woman who is postmenarcheal, has 
not reached a postmenopausal state (at least 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  
-of childbearing potential who are willing to use either 2 adequate barrier methods or a 
barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain 
from heterosexual activity throughout the trial, starting with the screening visit (Visit 1) 
through 120 days after the last dose of pembrolizumab.  
13. Male subjects should agree to use an adequate method of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has received prior therapy with an EGFR tyrosine kinase inhibitor (such as erlotinib, gefitinib, 
afatinib, rociletinib, or AZD9291) for NSCLC.  
 
2. Is currently participating or has participated in a study of an investigational agent or using an 
investigational device within 30 days of the first dose of trial treatment. The 30 day window 
should be applied to the last dose of an antineoplastic investigational agent or last use of an 
investigational device with antineoplastic intent.  
 
3. Is receiving systemic steroid therapy within three days prior to the first dose of trial treatment 
or receiving any other form of immunosuppressive medication (corticosteroid use on study for 
management of ECIs is allowed).  
 
4. Is expected to require any other form of systemic or localized antineoplastic therapy while on 
trial (including maintenance therapy with another agent for NSCLC or radiation therapy).  
 
5. Has received prior systemic cytotoxic chemotherapy, antineoplastic biological therapy (e.g., 
cetuximab), major surgery within 3 weeks of the first dose of trial treatment; received thoracic 
radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment. 
 
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 
Has participated in another pembrolizumabclinical trial.  
 

14 
 
Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
7. Has a known history of prior malignancy that in the opinion of the investigator interferes with 
the ability to interpret the radiographic results (e.g. a second active malignancy with some 
lesions being of uncertain origin).  
8. Subjects with central nervous system (CNS) metastases and/or carcinomatous meningitis may 
participate provided they are clinically stable, and are using no steroids for at least seven days 
prior to study medication.  
 
9. Has an active autoimmune disease, or a documented history of autoimmune disease that 
required systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved 
childhood asthma/atopy would be exception to this rule. Subjects that require inhaled steroid 
or local steroid injections will not be excluded from the study. Subjects with hypothyroidism 
who are stable on hormone replacement will not be excluded from the study. 
 
10. Has had an allogeneic tissue/solid organ transplant. 
 
11. Has interstitial lung disease or a history of pneumonitis that required oral or intravenous 
glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not 
exclusionary.  
 
12. Has received or will receive a live vaccine within 30 days prior to the first administration of 
study medication. Seasonal flu vaccines that do not contain live virus are permitted.  
 
13. Has an active infection requiring intravenous systemic therapy.  
 
14. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).  
 
15. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg 
result. Active Hepatitis C is defined by a known positive Hep C Ab result and known 
quantitative HCV RNA results greater than the lower limits of detection of the assay.  
 
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating Investigator.  
 
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial.  
 
18. Is, at the time of signing informed consent, a regular user (including “recreational use”) of any 
illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).  
 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
19. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the screening visit (Visit 1) through 120 days after the last 
dose of pembrolizumab. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg  
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Trial treatment should begin on the day of randomization or as close as possible to the date on which 
treatment is allocated/assigned. 
5.2.1 
Dose Selection/Modification 
5.2.1.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background and 
Rationale.  Details on preparation and administration of pembrolizumab (MK-3475) are provided in 
the Pharmacy Manual.   
5.2.1.2 
Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent 
an immunologic etiology.  These adverse events may occur shortly after the first dose or several months 
after the last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities and severe 
or life-threatening AEs as per Table 3 below. See Section 5.6.1 for supportive care guidelines, including 
use of corticosteroids. 
Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
 
Immune-related AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE 
management 
with 
corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
 
Monitor participants 
for signs and 
symptoms of 
pneumonitis 
 
Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and initiate 
corticosteroid 
treatment 
 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
 
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). 
 
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. 
Grade 4 
Permanently 
discontinue 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
AST / ALT elevation or 
Increased bilirubin 
Grade 2 
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 or 4  
Permanently 
discontinue 
 Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
 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 
 Administer 
corticosteroids 
and initiate 
hormonal 
replacements 
as clinically 
indicated.   
 
 
Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
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 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine 
or 
liothyroinine) 
per standard of 
care 
 
Monitor for signs 
and symptoms of 
thyroid disorders.  
 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
Nephritis and Renal 
dysfunction 
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/ 
persistent Grade 2 
Withhold 
 Based on type 
and severity of 
AE administer 
corticosteroids  
 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude other 
causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.   
NOTE:  
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).   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for interruption should be documented in the patient's study record. 
5.2.2 
Timing of Dose Administration 
Trial treatment 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 treatment may be administered 
up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  The site should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given 

19 
 
Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
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. 
5.2.3 
Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment administered. 
5.3 
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 investigator should discuss any questions regarding this with the Merck Clinical team.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject's primary physician.  
5.3.1 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’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 before the first dose of trial treatment and 30 days 
after the last dose of trial treatment should be recorded.  Concomitant medications administered after 
30 days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined in Section 
7.2. 
5.3.2 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
 
Antineoplastic systemic chemotherapy or biological therapy  
 
Immunotherapy not specified in this protocol 
 
Chemotherapy not specified in this protocol 
 
Investigational agents other than pembrolizumab 
 
Radiation therapy  

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.   
 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
 
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. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use of oral 
or intravenous 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 related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is instructed to 
follow the ECI reporting guidance but does not need to follow the treatment guidance. Refer to Section 
5.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
 
Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience 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.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
 
Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction 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 subject 
is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
Stop Infusion and monitor 
symptoms. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
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 subject 
is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one 
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 subject should be 
premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
of pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
No subsequent dosing 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
5.5.2 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-breast-
feeding women may be enrolled if they are willing to use 2 methods of birth control or are considered 
highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year will 
be considered postmenopausal), or 3) not heterosexually active for the duration of the study.  The two 
birth control methods can be either two barrier methods or a barrier method plus a hormonal method to 
prevent pregnancy. Subjects should start using birth control from study Visit 1 throughout the study 
period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study.  In order to participate in the study they 
must adhere to the contraception requirement (described above) for the duration of the study and during 
the follow-up period defined in section 7.2.2-Reporting of Pregnancy and Lactation to UCLA DSMB.  
If there is any question that a subject will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study. 

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5.5.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The outcome of 
the pregnancy will be reported to the study site’s Data Safety Monitoring Board without delay 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 the UCLA Data Safety Monitoring Board 
(DSMB).   If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the UCLA DSMB and followed as described 
above and in Section 7.2.2. 
5.5.4 
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, subjects 
who are breast-feeding are not eligible for enrollment. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion 
of the investigator should any untoward effect occur.  In addition, a subject may be withdrawn by the 
investigator or the UCLA DSMB if enrollment into the trial is inappropriate, the trial plan is violated, 
or for administrative and/or other safety reasons.  Specific details regarding discontinuation or 
withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 
The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
 
Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may continue on treatment with confirmed radiographic progression if 
clinically stable or clinically improved. Unacceptable adverse experiences as described in 
Section 5.2.1.2 
 
Unacceptable adverse experiences as described in Section 5.2.1.2 
 
Intercurrent illness that prevents further administration of treatment 

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Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
 
Investigator’s decision to withdraw the subject 
 
The subject has a confirmed positive serum pregnancy test 
 
Noncompliance with trial treatment or procedure requirements 
 
The subject is lost to follow-up 
 
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of 
study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects who stop 
pembrolizumab after 24 months may be eligible for up to one year of additional study treatment 
if they progress after stopping study treatment provided they meet the requirements detailed in 
Section 7.1.5.5 
 
Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) and 
Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be followed for 30 
days for adverse event monitoring (serious adverse events will be collected for 90 days after the end of 
treatment as described in Section 7.2.3.1).  Subjects who discontinue for reasons other than progressive 
disease will have post-treatment follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented disease 
progression each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.6.1 
Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that 
have been treated for at least 24 weeks with pembrolizumab and had at least two treatments with 
pembrolizumab beyond the date when the initial CR was declared.  Subjects who then experience 
radiographic disease progression may be eligible for up to one year of additional treatment with 
pembrolizumab via the Second Course Phase at the discretion of the investigator if no cancer treatment 
was administered since the last dose of pembrolizumab, the subject meets the safety parameters listed 
in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at the same dose 
and schedule at the time of initial discontinuation.  Additional details are provided in Section 7.1.5.5. 
5.7 
Subject Replacement Strategy 
A subject that discontinues from the trial will not be replaced. 
5.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 

27 
 
Garon Pembrolizumab IST Protocol Version 4. 01 December 2017 
 
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 subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be provided so 
that appropriate adjustments to subject treatment can be made. 
 

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Protocol/Amendment No.:   
 
 
 
 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
(Visit 1) 
Treatment Cyclesa 
End of 
Treatme
nt 
 
Post-Treatment 
Treatment Cycle/Title: 
 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety Follow-
up Visitsb 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
3 
month
s post 
tx 
6 
months 
post tx 
Approx.Q
2 months 
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status  
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Protocol/Amendment No.:   
 
 
 
 
 
 
Trial Period: 
Screening 
Phase 
(Visit 1) 
Treatment Cyclesa 
End of 
Treatme
nt 
 
Post-Treatment 
Treatment Cycle/Title: 
 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety Follow-
up Visitsb 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
3 
month
s post 
tx 
6 
months 
post tx 
Approx.Q
2 months 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum 
-HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Comprehensive Serum Chemistry 
Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
T3, FT4 and TSH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Efficacy Measurements 

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Protocol/Amendment No.:   
 
 
 
 
 
 
Trial Period: 
Screening 
Phase 
(Visit 1) 
Treatment Cyclesa 
End of 
Treatme
nt 
 
Post-Treatment 
Treatment Cycle/Title: 
 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety Follow-
up Visitsb 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
3 
month
s post 
tx 
6 
months 
post tx 
Approx.Q
2 months 
Tumor Imaging 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Brain Imaging 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection2 
X 
 
 
 
 
 
 
 
 
X3 
 
 
 
Correlative Studies Blood 
Collection 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
1. Brain imaging needed if clinically indicated  
2. If patient has not had a biopsy or if tissue is exhausted, patient must undergo a new biopsy for the trial 
3. Patient has the option of undergoing an additional biopsy at end of treatment.   

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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the UCLA DSMB for reasons 
related to subject safety. In some cases, such evaluation/testing may be potentially sensitive in nature 
(e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional informed consent 
be obtained from the subject.  In these cases, such evaluations/testing will be performed in accordance 
with those regulations. 
7.1.1 
Administrative Procedures 
7.1.1.1 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating in 
a clinical trial. 
7.1.1.1.1  General Informed Consent 
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.  
A copy of the signed and dated consent form should be given to the subject before participation in the 
trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable opinion in 
advance of use.  The subject or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’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 
subject’s dated signature or by the subject’s legally acceptable representative’s dated signature. 
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 
UCLA DSMB requirements. 
 

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7.1.1.2 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the subject qualifies for the trial.  
7.1.1.3 
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 subject has 
enrolled in this study will be recorded separately and not listed as medical history.   
7.1.1.4 
Prior and Concomitant Medications Review 
7.1.1.4.1 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 subject within 28 days before 
starting the trial.  Treatment for the disease for which the subject has enrolled in this study will be 
recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during the 
trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in Section 
7.2. 
7.1.1.5 
Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
7.1.1.5.3 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 subject initiates a new anti-cancer therapy within 30 days after the last 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 subject will move into survival follow-up.  

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Protocol/Amendment No.:   
 
 
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7.1.1.6 
Assignment of Screening Number 
Each subject will be assigned only one screening number. Screening numbers must not be re-used for 
different subjects. Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. 
7.1.1.7 
Assignment of Randomization Number 
Once an allocation number is assigned to a subject, it can never be re-assigned to another subject. A 
single subject cannot be assigned more than 1 allocation number. Note: although this is described as a 
“randomization number,” this study is not randomized. 
 
7.1.1.8 
Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for greater than 18 weeks between 
pembrolizumab doses due to toxicity will require written documentation on subject management. 
7.1.2 
Clinical Procedures/Assessments 
7.1.2.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject 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 4.0 (see Section 11.2).  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.   
7.1.2.2 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period. Clinically significant abnormal findings should be recorded as medical history.   
7.1.2.3 
Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration.   
7.1.2.4 
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 6.0).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 

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7.1.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, prior to 
the administration of each dose of trial treatment and discontinuation of trial treatment as specified in 
the Trial Flow Chart.   
7.1.2.6 
12-Lead ECG 
A standard 12-lead ECG will be performed using local standard procedures once at screening. 
Clinically significant abnormal findings should be recorded as medical history. 
7.1.2.7 
Tumor Imaging and Assessment of Disease 
Subjects will be evaluated every 9 weeks (63 +/- 7 days) with radiographic imaging to assess response 
to treatment. All imaging obtained on study will be assessed using a modified Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 for determination of objective response rate (ORR) and 
progression-free survival (PFS). Subjects will continue with the assigned study treatment until RECIST 
1.1-defined progression of disease, unacceptable toxicity, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject withdraws consent, 
pregnancy of the subject, noncompliance with trial treatment or procedure requirements, administrative 
reasons, or the subject has received 35 trial treatments of pembrolizumab. Treatment may continue 
despite RECIST 1.1 defined progression if the subject is clinically stable and is considered to be 
deriving clinical benefit by the investigator. For further information, see Appendix Section 13.3. 
 
7.1.2.8 
Brain Imaging 
For patients who have prior history of brain metastases, screening brain imaging will need to be 
obtained. MRI is the preferred imaging modality.  
 
7.1.2.9 
Tumor Tissue Collection and Correlative Studies Blood Sampling 
For the first three cycles, prior to treatment, 100 mL of additional blood/serum will be collected for 
correlative research studies. These samples may be collected up to three days prior to treatment. An 
additional sample of 100mL of blood/serum will also be collected at the time of progression. All blood 
drawn must begin processing a maximum of two hours after being drawn. Samples from patients at 
sites close enough to UCLA to allow blood processing within two hours will be couriered for 
processing. Sites that are not near enough to allow blood processing within two hours at UCLA will 
process the correlative blood samples themselves. Sample collection, and storage instructions for serum 
samples will be provided in the lab manual. 
7.1.3 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 

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Protocol/Amendment No.:   
 
 
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Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.  

Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
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Table 5 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum 
β-human 
chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
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 triiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 

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Protocol/Amendment No.:   
 
 
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Hematology 
Chemistry 
Urinalysis 
Other 
† 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. 
 

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Protocol/Amendment No.:   
 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed within 10 
days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted 
up to 72 hours prior to dosing.  Results from the C1D1 tests and C1D1 of Second Course Phase are for 
information only and do not need to be checked prior to therapy. Other results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial treatment.  
7.1.4 
Other Procedures 
7.1.4.1 
Withdrawal/Discontinuation 
When a subject discontinues/withdraws 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/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2 - Assessing and Recording Adverse Events.  Subjects 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 7.1.5.5.  After discontinuing 
treatment following assessment of CR, these subjects 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 7.1.5.4). 
7.1.4.2 
Blinding/Unblinding 
7.1.5 
Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related details 
are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 
Screening 
7.1.5.1.1 Screening Period 
Approximately 28 days prior to start of treatment, potential subjects will be evaluated to determine that 
they fulfill the entry requirements. Screening procedures may be repeated after consultation with the 
UCLA DSMB. 
Written consent must be obtained prior to performing any protocol specific procedure. Results of a test 
performed prior to the subject signing consent as part of routine clinical management are acceptable in 
lieu of a screening test if performed within the specified time frame. Screening procedures are to be 
completed within 28 days prior to the first dose of trial treatment except for the following: 
 
Laboratory tests are to be performed within 10 days prior to the first dose of trial treatment. 
 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours 
prior to first dose of trial treatment. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test, performed by the local study site laboratory, will be required. 
 
Tumor imaging must be performed within 30 days prior to the first dose of trial treatment. 

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Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results from 
assessments performed during the initial screening period are acceptable in lieu of a repeating a 
screening test if performed within the specified time frame and the results meet the inclusion/exclusion 
criteria. 
7.1.5.2 
Treatment Period 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. 
7.1.5.3 
Post-Treatment Visits 
The discontinuation visit should be conducted approximately within 28 +/- 7 days after the last dose of 
trial treatment or before the initiation of a new antineoplastic treatment, whichever comes first. 
7.1.5.4 
Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into the 
Follow-up Phase and should continue to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging 
to monitor disease status. Follow-up Visit 1 should be scheduled 3 months after the last dose of trial 
treatment. Assessment for drug-related immune-related adverse events should occur at Follow-up Visit 
1. Follow-up Visit 2 should occur 6 months after the last dose of trial treatment. After Follow-up Visit 
2 subjects should continue to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging to monitor 
disease status and initiation of new antineoplastic therapy. Unless otherwise noted in the flow chart, 
every effort should be made to collect subject information on the start of new tyrosine kinase inhibitor 
therapy in patients harboring EGFR-sensitizing mutations, disease progression, and death. 
7.1.5.4.1 Survival Follow-up 
Once a subject completes the follow-up visits, the subject moves into the survival follow-up phase and 
should come in for a visit (approximately every 2 months) for survival status and to receive scans until 
death, withdrawal of consent, or the end of the study, whichever occurs first. It is recognized that based 
on variability of post-study management, the frequency of this visit is anticipated to vary significantly. 
In patients for whom follow up is less frequent than every 3 months, we will call patients to evaluation 
vital status, and whether they are currently on an EGFR-TKI.  
7.1.5.5 Second Course Phase 
Subjects may be eligible for up to one year of additional treatment with pembrolizumab via the Second 
Course Phase if the treating investigator believes that the patient will benefit from the Second Course 
Phase. Patients will not need to be re-registered or re-screened in order to participate.  
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 

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relationship with this treatment. An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered adverse events.  Examples of this may include, 
but are not limited to, teething, typical crying in infants and children and onset of menses or menopause 
occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent or 
protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for human 
use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse, and from 
withdrawal. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be excluded 
from the trial, or are the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered to be 
drug related by the investigator. 
From the time of treatment allocation/randomization through 30 days following cessation of treatment, 
all adverse events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets.  The reporting timeframe for adverse 
events meeting any serious criteria is described in section 7.2.3.1. The investigator will make every 
attempt to follow all subjects with non-serious adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified procedure or 
intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first required 
to provide consent to the main study and AEs will be captured according to guidelines for standard AE 
reporting. 
All adverse events will be recorded from the time the consent form is signed through 30 days following 
cessation of treatment and at each examination on the Adverse Event case report forms/worksheets. 
The reporting timeframe for adverse events meeting any serious criteria is described in section 7.2.3.1. 

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7.2.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the UCLA 
DSMB and to Merck 
For purposes of this trial, 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. Appropriate supportive treatment should be provided if clinically indicated. In the 
event of overdose, the subject 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. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse 
effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
UCLA DSMB and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
7.2.2 
Reporting of Pregnancy and Lactation to UCLA DSMB and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported 
to them), that occurs during the trial.  
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be excluded 
from the trial, or are the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization through 120 
days following cessation of Sponsor’s product, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported by the investigator.  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. 
 
Such events must be reported within 24 hours to the UCLA DSMB and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 

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7.2.3 
Immediate Reporting of Adverse Events to UCLA DSMB and Merck 
7.2.3.1 
Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s product 
that: 
 
Results in death; 
 
Is life threatening; 
 
Results in persistent or significant disability/incapacity; 
 
Results in or prolongs an existing inpatient hospitalization; 
 
Is a congenital anomaly/birth defect; 
 
Is a new cancer (that is not a condition of the study); 
 
Is associated with an overdose; 
 
Is another important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any cause 
other than progression of the cancer under study that occurs to any subject from the time the consent is 
signed through 90 days following cessation of treatment, or the initiation of new anti-cancer therapy, 
whichever is earlier, whether or not related to Merck product, must be reported to UCLA DSMB.  
Additionally, any serious adverse event, considered by an investigator who is a qualified physician to 
be related to Merck product that is brought to the attention of the investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the UCLA DSMB. 
7.2.3.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be reported within 24 hours to the UCLA DSMB and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215-993-1220). 
For the time period beginning when the consent form is signed until treatment allocation/randomization, 
any ECI, or follow up to an EVI, that occurs to any subject must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety if it causes the subject to be excluded from 
the trial, or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck product, 
must be reported within 24 hours to the Sponsor and within 24 hours to Merck Global Safety. 
. Events of clinical interest for this trial include: 

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1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for This 
Protocol and Reporting of Overdose, that is not associated with clinical symptoms or abnormal 
laboratory results.  
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 
7.2.3.3 
Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE. 
 
7.2.4 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which changes 
CTCAE grade over the course of a given episode will have each change of grade recorded on the 
adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
7.2.5  Sponsor Responsibility for Reporting Adverse Events 
All Adverse events will be reported to regulatory authorities, IRB/IECs, in accordance with all 
applicable global laws and regulations 

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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it 
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); 
or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or 
 
†Results in or prolongs an existing inpatient 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 thathas not worsened is not a serious adverse event. A pre-existing condition 
is a clinical condition that is diagnosed prior to the use of a pembrolizumab and is documented in the patient’s medical 
history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) (although not serious per ICH definitions, is reportable to the Sponsor 
within 24 hours and to Merck withint 2 working days to meet certain local requirements.); or 

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Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event for collection purposes. An overdose that is not associated with an adverse event is considered a non-serious 
event of clinical interest and must be reported within 24 hours to the Sponsor and to Merck within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action 
taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to Merck 
Product  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse 
event 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 drug and 
the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater 
the correlation with the components and their respective elements (in number and/or intensity), the more likely the Merck 
product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the 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 the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)? 
 
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 
 
Relationship The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 

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(continued)  
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; or (3) the trial is a single-dose drug trial); or (4) 
Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the 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 
trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND 
WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE 
MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS 
PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck 
product or drug class pharmacology or toxicology? 
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. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a 
Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the 
administration of the Merck product is reasonable.  The AE is more likely explained by the Merck product than 
by another cause. 
No, there is not a 
reasonable possibility 
Merck product relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of 
the Merck product is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject 
with overdose without an associated AE.) 

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7.2.5 
Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations.  
8.0 DATA AND SAFETY MONITORING PLAN  
8.1 
JCCC DSMB Oversight 
This trial will be overseen by the JCCC DSMB. The JCCC DSMB meets monthly to review 
all SAE reports for trials overseen by the JCCC DSMB.  All SAE reports, which have been 
filed since the previous meeting, are presented to the committee for review. 
 
For trials overseen by the JCCC DSMB, the DSMB reviews all dose-limiting toxicities 
(DLTs) for dose-escalation studies.  Protocol suspensions and re-opening of accrual to the 
next cohort based on DLT evaluation fall under the purview of the DSMB.     
 
For all JCCC oncology trials and TRIO-US studies where the JCCC DSMB has primary 
oversight, all SAEs shall be reported to the JCCC DSMB in a timely manner [ten days, two 
days for a death] regardless of relationship and expectedness.  The JCCC ORC will review 
all submissions and the ORC staff will enter the information into the JCCC Clinical Trials 
database.  Reports are generated for full JCCC DSMB review.    For trials where the JCCC 
DSMB has primary DSMB review responsibility, the DSMB requires that the PI generate 
cumulative adverse event reports for quarterly, biannual or annual review.  
 
The DSMB reviews each SAE report and determines whether or not protocol modifications 
are warranted to ensure subject safety.  In this review, prior occurrences of similar toxicity 
with the therapy under study are taken into consideration, as well as the severity of the event 
and the likelihood that it was related to a study drug.  The DSMB may recommend no 
changes to the study if the event is expected or related to other causes such as the subject’s 
underlying condition.  The DSMB may request an expert’s advice of another non-Principal 
Investigator with national experience to support their deliberations and decisions.    
 
The JCCC DSMB has the authority to recommend to the UCLA IRB the immediate halt to a 
study (i.e., discontinuation of any further treatment of enrolled subjects and discontinuation 
of enrollment of new subjects) should there be any serious unexpected toxicity that warrants 
further investigation.   
 
Requests for single subject exceptions/waivers from the approved study protocol, including 
out of window procedures and eligibility deviations, must be reviewed and approved by a 
member of the DSMB.  Each trial is assigned a primary and secondary reviewer who is 
responsible for reviewing each exception/waiver request for that trial.  Approvals and 
disapprovals of the request are sent to the Principal Investigator via email and copied to the 
UCLA IRB.  Requests for single subject exceptions/waivers are made by the Principal 
Investigator via email utilizing the “Single Subject Exception Request Form.”  
 

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JCCC DSMB correspondences are addressed to the Principal Investigator and copied to the 
UCLA IRB.   Minutes of the DSMB meetings are maintained in a computer file. 
 
Confidentiality:  Each member of the JCCC DSMB is responsible for maintaining strict 
confidentiality of the study data.  Members will not share any study data or information about 
the study with any individual external to the JCCC DSMB or the statistical working group 
for the study.  The DSMB members may contact the statistical working group directly with 
questions regarding the operational details associated with the data analysis and summary 
presentations.  Communication of deliberations or recommendations of the JCCC DSMB, 
either written or oral, should not be made outside of the Committee or the statistical working 
group.  Outcome results are strictly confidential and must not be divulged to any non-
member of the JCCC DSMB except in those cases where DSMB is required to inform the 
UCLA IRB of its determinations.  Disclosure of outcome results to the IRB must only occur 
with written approval of the DSMB.  A member who believes he or she may have a potential 
intellectual or financial conflict of interest during the course of review of the data must 
inform the chairperson of the DSMB. In such case, the meeting minutes will record the 
disclosure of the potential conflict of interest and that the individual recuse himself from the 
discussions and abstains from voting on the DSMB decision. 
 
8.2 
Assignment of Risk – Level 2  
All interventional clinical trials undergo scientific review by the Internal Scientific Peer 
Review Committee (ISPRC) which requires that a Data and Safety Monitoring Plan is in 
place before a trial can be approved to begin.  For trials overseen by the JCCC DSMB, the 
JCCC DSMB will determine the degree of risk of the study and will ensure that there are 
procedures in place to ensure the safety of the subjects that are enrolled in the trial.  The 
intensity level of study oversight is determined by the risk category.  Some of the factors that 
are considered when assigning the Level of Risk category include: 
 
 A biostatistical design and appropriate procedures for proper data management so that 
the information collected can be properly validated. 
 
 Appropriate Serious Adverse Event reporting procedures must be in place. 
 
 The study duration must be appropriate and must be based on a realistic rate of 
enrollment. 
 
 Data collection and data management must be adequate to verify and ensure subject 
eligibility.  
 
8.2.1 Assignment of Risk  
This protocol is assigned a Level 2 Risk. Assigning risk ensures that the data and safety 
monitoring is based on the level of risk (low, medium, or high) to ensure that the data and 

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safety monitoring activities are appropriate.  Level 2 Risk assignment includes the data and 
safety monitoring activities listed below: 
 
 Compliance Officer meets with PI/Staff prior to study initiation; review regulatory 
requirements and operating system.  Compliance Officer provides real time 
monitoring to determine eligibility prior to enrollment onto the protocol. 
 Real time QA monitoring of the subjects and data collection occurs for all subjects 
entered onto the trial.  
 Comprehensive QA auditing within first year or first 10 subjects enrolled, whichever 
comes first.  Subsequent audit frequency will be annually.  
 Frequency of DSMB Summary Report is typically on a biannual basis or 
approximately every six months. 
 
 
8.3 
Monitoring and Auditing Activities  
The compliance officer of the JCCC Office of Regulatory Compliance [ORC] will monitor 
and audit the clinical records for all human subjects enrolled onto JCCC trials overseen by 
the JCCC DSMB.  The JCCC compliance officer will perform real time review of informed 
consent processes and the meeting of all inclusion and exclusion criteria and screening 
results at study entry.  Active monitoring will offer the JCCC study teams prospective 
information that can be used to enhance the quality of research being performed 
contemporaneously.  Auditing is a review of historic performance of the research effort and 
is performed on case report forms, regulatory files and source documents to measure the 
quality of the research effort in a retrospective manner.  
 
9.0 STATISTICAL ANALYSIS PLAN 
9.1  
Efficacy Endpoints 
Primary 
The primary efficacy analyses will be based on the Full Analysis Set (FAS). Patients with measureable 
disease at baseline who received at least one dose of study treatment will be included in the FAS. The 
primary efficacy endpoint is objective response rate (ORR) and will be determined by blinded central 
review. We will use an exact binomial test to evaluate the response rate to the null hypothesis value of 
0.10.  
Response duration is defined as the time from first documented evidence of response until progression, 
according to RECIST 1.1. Objective response rate is determined as the proportion of patients achieving 
complete response (CR) or partial response (PR) as respectively defined in RECIST 1.1. A 95% 
confidence interval will be provided for the objective response rate of the population. All patients 

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receiving at least one dose of pembrolizumab will be considered evaluable for efficacy and 
toxicity. 
Secondary 
Secondary efficacy endpoints, progression free survival and overall survival, will also be analyzed. Per 
RECIST 1.1, progression free survival (PFS) is defined as time from randomization to first documented 
progression and overall survival (OS) and is defined as time from randomization to death by any cause.  
For patients harboring EGFR-sensitizing mutations, PFS, ORR, OS following TKI therapy will be 
assessed and analyzed against data on treatment-naïve EGFRm NSCLC treated with TKI as control. 
9.2 
 Safety Endpoints 
Safety measurements are described in section 7 
9.3 
 Responsibility for Analyses 
The statistical data obtained from this study will be the responsibility of Dr. Garon and the clinical 
biostatisticians in the UCLA Department of Medicine Medical Statistics Core. 
9.4  
Hypothesis / Estimation 
Objectives and hypotheses of the study are stated in Section 3.0. The study is considered positive and 
to have met its primary efficacy endpoint if anti-tumor response rate of pembrolizumab meets or 
exceeds 26% (see sample size and power explanation below). The null hypothesis is derived from 
subpopulation data describing response rate in EGFR mutation positive NSCLC treated with TKI prior 
to single-agent pembrolizumab on KEYNOTE-001 study which is <8% in this population (36). Our 
study conservatively sets the null hypothesis at 10% objective response rate. 
9.5  
PD-L1 Biomarker  
Pearson correlation will evaluate correlation between PD-L1 expression in tumor samples and percent 
decrease in tumor volume following therapy. When the sample size is 25, the linear regression test for 
the Pearson correlation will have 80% power to detect a correlation of at least 0.51 assuming a two-
side 0.05 level of significance. 
We will evaluate the relationship between PD-L1 expression at baseline with clinical outcomes using 
regression models. For PFS and OS we will use Cox-proportional hazards regression.  
A futility analysis will be conducted after nine patients with ≤50% PD-L1 expression (i.e. 1-
49%) reach their first set of scans. If all nine patients have failed to respond to therapy, we will 
revise the protocol to restrict the study population to patients with PD-L1 staining of >50%. 
Based on data to date, a response rate that low would not be anticipated for patients with >50% 
PD-L1 expression. 

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9.6  
Sample Size and Power Calculations 
With 25 TKI-naïve patients treated at 200mg q3w, an exact binomial test with a nominal 0.10 one-sided 
significance level will have 81% power to detect the difference between the Null hypothesis response 
rate of 10% and the Alternative hypothesis rate of 26%. 
10.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
10.1 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. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
10.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
10.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel 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. 
10.4 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. 

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10.5 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 subjects 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. 
11.0 ADMINISTRATIVE AND REGULATORY DETAILS 
11.1 Confidentiality 
11.1.1 Confidentiality of Data 
The investigator affirms to the Sponsor that information furnished to the investigator by the Sponsor 
will be maintained in confidence, and such information will be divulged to the institutional review 
board, ethics review committee (IRB/ERC) or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or committee, 
affiliated institution and employees. Data generated by this trial will be considered confidential by the 
investigator, except to the extent that it is included in a publication as provided in the Publications 
section of this protocol. 
11.1.2 Confidentiality of Subject Record 
The investigator agrees that the Sponsor (or Sponsor representative), IRB/ERC, or regulatory authority 
representatives may consult and/or copy trial documents in order to verify worksheet/case report form 
data.  By signing the consent form, the subject agrees to this process.  If trial documents will be 
photocopied during the process of verifying worksheet/case report form information, the subject will 
be identified by unique code only; full names/initials will be masked prior to transmission to the 
Sponsor. 
The investigator agrees to treat all subject data used and disclosed in connection with this trial in 
accordance with all applicable privacy laws, rules and regulations. 
11.1.3 Confidentiality of Investigator Information 
The investigator recognizes that certain personal identifying information with respect to the 
investigator, and all subinvestigators and trial site personnel, may be used and disclosed for trial 
management purposes, as part of a regulatory submissions, and as required by law.  This information 
may include: 

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1. Name, address, telephone number and e-mail address; 
2. Hospital or clinic address and telephone number; 
3. Curriculum vitae or other summary of qualifications and credentials; and 
4. Other professional documentation. 
Consistent with the purposes described above, this information may be transmitted to the Sponsor, and 
subsidiaries, affiliates and agents of the Sponsor, in your country and other countries, including 
countries that do not have laws protecting such information.  Additionally, the investigator’s name and 
business contact information may be included when reporting certain serious adverse events to 
regulatory authorities or to other investigators.  The investigator expressly consents to these uses and 
disclosures. 
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor may share 
an investigator’s name and contact information with other participating investigators upon request. 
11.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration Regulations, 
Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the Sponsor's responsibility to 
determine, based on these regulations, whether a request for Financial Disclosure information is 
required. It is the investigator's/subinvestigator's responsibility to comply with any such request.   
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 CFR Part 
54, to provide his/her financial interests in and/or arrangements with the Sponsor to allow for the 
submission 
of 
complete 
and 
accurate 
certification 
and 
disclosure 
statements. 
The 
investigator/subinvestigator(s) further agree to provide this information on a Certification/Disclosure 
Form, commonly known as a financial disclosure form, provided by the Sponsor or through a secure 
password-protected electronic portal provided by the Sponsor.  The investigator/subinvestigator(s) also 
consent to the transmission of this information to the Sponsor in the United States for these purposes.  
This may involve the transmission of information to countries that do not have laws protecting personal 
data. 
11.3 Compliance with Law, Audit and Debarment 
The investigator agrees to conduct the trial in an efficient and diligent manner and in conformance with 
this protocol; generally accepted standards of Good Clinical Practice (e.g., International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Good 
Clinical Practice: Consolidated Guideline and other generally accepted standards of good clinical 
practice); and all applicable federal, state and local laws, rules and regulations relating to the conduct 
of the clinical trial. 

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The Code of Conduct, a collection of goals and considerations that govern the ethical and scientific 
conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 - Merck Code of 
Conduct for Clinical Trials. 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory authority 
inspection of trial-related documents and procedures and provide for direct access to all trial-related 
source data and documents. 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or from 
government programs for procedures included as part of the trial reimbursed to the investigator by the 
Sponsor. 
The investigator shall prepare and maintain complete and accurate trial documentation in compliance 
with Good Clinical Practice standards and applicable federal, state and local laws, rules and regulations; 
and, for each subject participating in the trial, provide all data, and, upon completion or termination of 
the clinical trial, submit any other reports to the Sponsor as required by this protocol or as otherwise 
required pursuant to any agreement with the Sponsor. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator upon 
request and also shall be made available at the trial site upon request for inspection, copying, review 
and audit at reasonable times by representatives of the Sponsor or any regulatory authorities.  The 
investigator agrees to promptly take any reasonable steps that are requested by the Sponsor as a result 
of an audit to cure deficiencies in the trial documentation and worksheets/case report forms. 
The investigator must maintain copies of all documentation and records relating to the conduct of the 
trial in compliance with all applicable legal and regulatory requirements.  This documentation includes, 
but is not limited to, the protocol, worksheets/case report forms, advertising for subject participation, 
adverse event reports, subject source data, correspondence with regulatory authorities and IRBs/ERCs, 
consent forms, investigator’s curricula vitae, monitor visit logs, laboratory reference ranges, laboratory 
certification or quality control procedures and laboratory director curriculum vitae.  The investigator 
agrees that documentation shall be retained until at least 2 years after the last approval of a marketing 
application in an ICH region or until there are no pending or contemplated marketing applications in 
an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  Because the clinical development and marketing 
application process is variable, it is anticipated that the retention period can be up to 15 years or longer 
after protocol database lock. The Sponsor will determine the minimum retention period and notify the 
investigator when documents may be destroyed.  The sponsor also recognizes that documents may need 
to be retained for a longer period if required by local regulatory requirements. All trial documents shall 
be made available if required by relevant regulatory authorities. The investigator must consult with and 
obtain written approval by the Sponsor prior to discarding trial and/or subject files.   
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s primary 
physician about the subject’s participation in the trial if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 

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The investigator will promptly inform the Sponsor of any regulatory authority inspection conducted for 
this trial. 
Persons debarred from conducting or working on clinical trials by any court or regulatory authority will 
not be allowed to conduct or work on this Sponsor’s trials.  The investigator will immediately disclose 
in writing to the Sponsor if any person who is involved in conducting the trial is debarred or if any 
proceeding for debarment is pending or, to the best of the investigator’s knowledge, threatened. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will promptly notify 
that trial site’s IRB/IEC. 
According to European legislation, a Sponsor must designate an overall coordinating investigator for a 
multi-center trial (including multinational).  When more than one trial site is open in an EU country, 
Merck, as the Sponsor, will designate, per country, a national principal coordinator (Protocol CI), 
responsible for coordinating the work of the principal investigators at the different trial sites in that 
Member State, according to national regulations. For a single-center trial, the Protocol CI is the 
principal investigator.  In addition, the Sponsor must designate a principal or coordinating investigator 
to review the trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study Report 
(CSR) CI].  The Sponsor may consider one or more factors in the selection of the individual to serve as 
the Protocol CI and or CSR CI (e.g., availability of the CI during the anticipated review process, 
thorough understanding of clinical trial methods, appropriate enrollment of subject cohort, timely 
achievement of trial milestones). The Protocol CI must be a participating trial investigator. 
11.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the study site for the trial is solely responsible for 
determining whether the trial and its results are subject to the requirements for submission to the 
Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by calling a 
central contact number for further information on appropriate trial locations and trial site contact 
information.     
11.5 Quality Management System 
The investigator agrees to be responsible for implementing and maintaining a quality management 
system with written development procedures and functional area standard operating procedures (SOPs) 
to ensure that trials are conducted and data are generated, documented, and reported in compliance with 
the protocol, accepted standards of Good Clinical Practice, and all applicable federal, state, and local 
laws, rules and regulations relating to the conduct of the clinical trial.  Clinical Research Unit of 
UCLA’s Jonsson Comprehensive Cancer Center already has SOPs. 

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11.6 Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy of subject 
data. The investigator acknowledges that his/her electronic signature is the legally binding equivalent 
of a written signature. By entering his/her electronic signature, the investigator confirms that all 
recorded data have been verified as accurate. Detailed information regarding Data Management 
procedures for this protocol will be provided by the Sponsor. 
11.7 Publications 
This trial is intended for publication, even if terminated prematurely. Publication may include any or 
all of the following: posting of a synopsis online, abstract and/or presentation at a scientific conference, 
or publication of a full manuscript.  The Sponsor will work with the authors to submit a manuscript 
describing trial results within 12 months after the last data become available, which may take up to 
several months after the last subject visit in some cases such as vaccine trials.  However, manuscript 
submission timelines may be extended on OTC trials.  For trials intended for pediatric-related 
regulatory filings, the investigator agrees to delay publication of the trial results until the Sponsor 
notifies the investigator that all relevant regulatory authority decisions on the trial drug have been made 
with regard to pediatric-related regulatory filings. Merck will post a synopsis of trial results for 
approved products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product marketing 
(dispensed, administered, delivered or promoted), whichever is later. 
These timelines may be extended for products that are not yet marketed, if additional time is needed 
for analysis, to protect intellectual property, or to comply with confidentiality agreements with other 
parties.  Authors of the primary results manuscript will be provided the complete results from the 
Clinical Study Report, subject to the confidentiality agreement. When a manuscript is submitted to a 
biomedical journal, the Sponsor's policy is to also include the protocol and statistical analysis plan to 
facilitate the peer and editorial review of the manuscript.  If the manuscript is subsequently accepted 
for publication, the Sponsor will allow the journal, if it so desires, to post on its website the key sections 
of the protocol that are relevant to evaluating the trial, specifically those sections describing the trial 
objectives and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to those 
sections.  The Sponsor reserves the right to redact proprietary information. 
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of the results 
online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an investigator and his/her 
colleagues may publish their data independently.  In most cases, publication of individual trial site data 
does not add value to complete multicenter results, due to statistical concerns. In rare cases, publication 
of single trial site data prior to the main paper may be of value. Limitations of single trial site 
observations in a multicenter trial should always be described in such a manuscript. 
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically 

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for important intellectual content; and 3) final approval of the version to be published. Authors must 
meet conditions 1, 2 and 3.  Significant contributions to trial execution may also be taken into account 
to determine authorship, provided that contributions have also been made to all three of the preceding 
authorship criteria. Although publication planning may begin before conducting the trial, final decisions 
on authorship and the order of authors’ names will be made based on participation and actual 
contributions to the trial and writing, as discussed above. The first author is responsible for defending 
the integrity of the data, method(s) of data analysis and the scientific content of the manuscript. 
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations 
regarding this trial 45 days prior to submission for publication/presentation. Any information identified 
by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include 
efficacy and safety results. Sponsor review can be expedited to meet publication timelines. 
 
 

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12.0  LITERATURE CITED 
1. Howlader NA, Krapcho M, Neyman N, et al.  Cancer Statistics Review, 1975-2009 (Vintage 2009 
Populations). 2012. 
2. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung 
cancer. Nat Rev Cancer 2007;7:169–81. 
3. Garon EB, Leighl NB, Rizvi NA, et al. Safety and clinical activity of MK-3475 in previously treated 
patients (pts) with non-small cell lung cancer (NSCLC). J Clin Oncol 2014; 32:5s (suppl; abstr 
8020). 
4. Kris MG, Johnson BE, Berry LD et al. Using multiplexed assays of oncogenic drivers in lung 
cancers to select targeted drugs. JAMA. 2014 May 21; 311(19):1998-2006. 
5. Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, et al. A Prospective, Molecular 
Epidemiology Study of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung 
Cancer of Adenocarcinoma Histology (PIONEER). J Thorac Oncol 2014; 9: 154–162. 
6. Barlesi F, Blons H, Beau-Faller M, et al. Biomarkers (BM) France: results of routine EGFR, HER2, 
KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 
10,000 non-small cell lung cancer (NSCLC) patients (pts). J Clin Oncol 2013; 31(suppl);abstr8000. 
7. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000; 
19; 6550-6565 
8. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefinitib or carboplatin-
paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361:947–57. 
9. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed 
in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 
20;31(27):3327-34. 
10. Jänne PA, Boss DS, Camidge DR, et al. Phase I dose-escalation study of the pan-HER inhibitor, 
PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011; 17(5):1131-
9. 
11. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, 
metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two 
lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol 2012; 13:528–
538.  
12. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in 
EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M 
mutation. Clin Cancer Res. 2011; 13:1616–1622.  
13. Zhou W, Ercan D, Chen L et al. Novel mutant-selective EGFR kinase inhibitors against EGFR 
T790M. Nature 2009; 462:1070–1074. 
14. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes 
T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Jun 3. pii: 
CD-14-0337. 
15. Sakuma Y, Yamazaki Y, Nakamura Y, et al. WZ4002, a third-generation EGFR inhibitor, can 
overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src 
inhibitors. Lab Invest. 2012; 92:371–83. 

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16. Soria JC, Sequist LV, Gadgeel S, et al. First-in-human evaluation of CO-1686, an irreversible, 
highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). In 
Proceedings of the 15th World Conference on Lung Cancer; Sydney, Australia; 2013. 
17. Ranson M, Pao W, Kim DW, et al. Preliminary results from a Phase I study with AZD9291: An 
irreversible inhibitor of epidermal growth factor receptor (EGFR) activating and resistance 
mutations in non-small-cell lung cancer (NSCLC). European Cancer Congress 2013 Abstract. 
18. Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-mediated 
signaling by recruiting src homology 2-domain containing tyrosine phosphatase 2 to 
phosphotyrosine. PNAS 2001; 98(24). 
19. Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009; 229:114-25. 
20. Sheppard K-A, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3 signalosome and downstream signaling to PKCO. FEBS Lett 2004; 574:37-41. 
21. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan Pathol 
2010; 37(Suppl 1): 48-53 
22. Keir, M.E., Butte, M.J., Freeman, G.J., et al. PD-1 and its ligands in tolerance and immunity. Annu. 
Rev. Immunol 2008; 26, 677–704.  
23. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune 
escape in EGFR-driven lung tumors. Cancer Discovery 2013. 
24. Kudo-Saito C, Shirako H, Takeuchi T,et al. Cancer metastasis is accelerated through 
immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 2009; 15: 195–206.  
25. Akalay I, Janji B, Hasmim M, et al. Epithelial-to-mesenchymal transition and autophagy induction 
in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res 2013; 73:2418–2710. 
26. Cao Y, Zhang L, Kamimura Y, et al. B7–H1 overexpression regulates epithelial-mesenchymal 
transition and accelerates carcinogenesis in skin. Cancer Res. 2011;71(4):1235–1243.  
27. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 
2012; 12:252–64. 
28. Garon EB, Rizvi N, Hui R, et al. Pembrolizumab in Non-Small Cell Lung Cancer. NEJM. 2015.  
29. Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013 Jul 
25; 39(1):61-73. 
30. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (Anti-PD-1) 
in melanoma. N Engl J Med 2013; 369:134–44. 
31. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med. 2012; 366:2443–54. 
32. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma 
treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014 Jun 1;120(11):1695-
701.   
33. Tang Y, Fang W, Zhang Y, et al. The association between PD-L1 and EGFR status and the 
prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-
TKIs. Oncotarget. 2015;6(16):14209-19. 
34. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. 
N Engl J Med. 2015;372(21):2018-28. 
35. Zatloukal P, Heo DS, Park K, Kang J, Butts C, Bradford D, Graziano S, Huang B, Healey D. 
Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive 

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care (BSC)following first-line platinum-based therapy in patients (pts) with advanced non-small 
cell lung cancer (NSCLC). Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology. 2009;27(suppl; abstr 8071). 
36. Hellmann MD, Garon EB, Gandhi L, Hui R, Zhang J, Rangwala R, Lubiniecki GM, 
Rizvi NA. Efficacy of pembrolizumab in key subgroups of patients with advanced non-
small cell lung cancer (aNSCLC). World Conference on Lung Cancer. 2015 September 
6-9. Denver, Colorado. Abstract nr.3057. 
37. Reck M, Rodriguez-Abreu D, Robinson A, et al. KEYNOTE-024: Pembrolizumab (pembro) vs 
platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with PD-L1 
tumour proportion score (TPS) .50%. ESMO. 2016, October 9. Copenhagen, Denmark. Abstract 
nr. LBA8_PR. 
 
13.0  APPENDICES 
13.1 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. 
 
13.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 

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13.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
RECIST v1.1 Tumor Assessment Worksheet Instructions 
 
1.  Refer to the protocol for specific tumor assessment requirements noting: 
a. any protocol specific modifications to RECIST v1.1 criteria – be sure to incorporate 
these into your assessment (i.e., imaging modality) 
b. screening window for tumor assessment 
c. time-points/windows/frequency of tumor assessments during treatment and follow-up 
when applicable 
 determine time-point that first assessment is to be done, i.e.,: 6 weeks from 
randomization date or 6 weeks from C1D1 (+/- 7days) 
2. Standard method of assessment for RECIST v1.1 remains grounded in the anatomical 
assessment of disease by contrast CT of Chest, Abdomen, and Pelvis, and CT or MRI of brain 
when clinically indicated.  If contrast CT is contraindicated, then a non-contrast CT of Chest 
and MRI of Abdomen and Pelvis should be done.  Functional imaging or FDG-PET is not an 
acceptable method of tumor assessment per RECIST v1.1 criteria; rather it is used as an adjunct 
to determination of disease progression.  Bone scan or plain films are not considered adequate 
imaging techniques to measure bone lesions; however these techniques can be used to confirm 
the presence or disappearance of bone lesions.  Imaging based evaluation should always be 
done rather than clinical exam unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
3. Radiologist should provide a thorough baseline assessment of all sites of disease, non-nodal 
and nodal, along with the longest diameter in mm of non-nodal disease and the short axis 
measurement in mm of nodal disease.  Non-disease findings should also be documented in the 
radiology report and noted in the investigator’s note (i.e.: simple cyst, fatty tissue).  
4. Using the radiologist’s assessment, the investigator should select a total of ten (10) target 
lesions (TL) with a maximum of five (5) lesions per organ on the basis of their size, be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  All other sites of disease should be identified as non-
target lesions (NTL).  The investigator should document his/her choice and rationale for 
selection of lesions for baseline assessment of overall tumor burden to be assessed for response.   
Note:  You may record multiple non-target lesions involving the same organ as a single NTL 
on the form, i.e.:  multiple bone mets, multiple liver mets; multiple enlarged pelvic lymph 
nodes.   
a. Target Lesions (TLs) are defined as non-nodal lesions with a minimum longest 
diameter (LD) of≥10mm by CT/MRI; 10mm caliper measurement by clinical exam 
(documented with photo and ruler); ≥20mm by chest X-ray (For the purpose of this 
study, CT is preferred); and lymph nodes >15mm in the short axis (SA). Note: 
Measure the longest diameter of the node first.  Then determine the longest dimension 
perpendicular to the longest diameter and report that measurement as the short axis. 
(For example: a cervical lymph node is reported as being 17mm x 22mm.  The SA 

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measurement would be 17mm).  Note: Lytic or mixed lytic-blastic bone lesions with 
identifiable soft tissue components that can be evaluated by CT/MRI and meet the 
definition of measurability can be considered as measurable lesions 
b. Non-Target Lesions (NTLs) are defined as non-measurable and include:  any 
measurable lesions that were not selected as target lesions; non-nodal lesions <10mm 
in longest diameter; lymph nodes that have a short axis >10mm and <15mm Note:  
SA nodal non-target lesion must have a reduction in SA to <10mm to be considered a 
CR; therefore, documenting nodal non-target lesions SA is recommended.   ; blastic 
bone lesions, lytic or mixed lytic-blastic lesions without an identifiable soft tissue 
component that meets the definition of measurable, and lesions considered truly non-
measurable which include:  leptomeningeal disease, ascites, pleural/pericardial 
effusions, inflammatory breast disease, lymphangitic involvement of skin/lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.  Note:  lesions situated in a previously 
irradiated area are considered non-measurable lesions (non-target) unless there has 
been demonstrated progression in the lesion and then it may be considered a target 
lesion. 
c. Non-Pathological Lesions include nodes that have a short axis of <10mm and simple 
cysts.  These should not be recorded as target or non-target lesions.   
5. List each selected baseline target lesion under the column “Lesion Description” and record the 
LD/SA (Largest Diameter(non-nodal)/Short Axis(nodal)) for each lesion in the corresponding 
Baseline LD/SA mm column.  Baseline assessment of overall tumor burden is calculated by 
adding the longest diameter measurement of non-nodal target lesions and the short axis 
measurement for target nodal lesions in mm and reporting this as the baseline Sum of the   
Diameters (SOD).  Add the baseline measurements and record the SOD in the corresponding 
space.  
6. List all non-target sites of disease under the column “Lesion Description” and record as present 
in the corresponding Baseline Present/Absent column. Measurements are not required and 
should be followed as “present”, “absent”, or in rare cases “unequivocal progression” (write 
this in space when applicable).  Note:  There are not a maximum number of non-target lesions; 
therefore, you may need to use an additional assessment form to document all non-target 
lesions.  However, keep in mind that multiple non-target lesions involving the same organ may 
be recorded as a single item, i.e., multiple liver mets     
7. Document the time-point response of Target Lesions in the row labeled “TL Response” that 
corresponds to the specific assessment time-point.  Target lesion response is determined by the 
SOD of subsequent tumor assessments.  Note:  All Target Lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small.  If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as “0”mm.  If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5mm should be recorded. 
a. Complete Response (CR):  Disappearance of all target lesions (each pathological 
lymph nodes must have a reduction in short axis to <10mm) 

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b. Partial Response (PR):  >30% decrease in the baseline SOD.  To find the PR 
threshold, at baseline, multiple the baseline SOD x 0.7 and record this in the 
corresponding spaces for each tumor assessment time-point. Note: This calculation 
only needs to be calculated at baseline.  For example:  Baseline SOD = 32mm x 0.7 = 
22.4mm; therefore, on subsequent assessments, the SOD would have to be <22.4mm 
to be documented and recorded as a PR. 
c. Progressive Disease (PD):  >20% increase in the Nadir SOD (this includes the 
Baseline SD if it is the smallest on study) + an absolute increase of 5mm over the 
nadir SOD.  The appearance of one or more new lesions representing disease is also 
considered PD.   To find the PD threshold, determine the smallest SD recorded and 
multiple it by 1.20 and record this calculation in the corresponding space for each 
tumor assessment time-point.  Note:  This calculation must be done at each assessment.  
Example:  Baseline SOD = 43mm PD threshold = 43 x 1.20 = 51.6mm.  Assessment 
#2 SOD = 35mm, = 1.2 x 35 = new PD threshold = 42mm Assessment #3 SOD = 
37mm. PD threshold = 42mm (Nadir SOD of 35mm).  Assessment #4 SOD = 43mm 
= >20% ↑ over nadir SOD (Assessment #2) and the SOD of 43mm is an absolute 
increase of 8mm over the nadir SOD of 35mm. 
d. Stable Disease (SD):  There is neither sufficient shrinkage (compared to baseline) to 
qualify for PR nor sufficient increase (taking as reference the smallest SOD while on 
study) to qualify for PD. 
e. Not All Evaluated (NE):  When no imaging/measurement is done at all at a particular 
assessment time point or only a subset of lesion measurements are made at an 
assessment (unless documentation is made that the contribution of the individual 
missing lesion(s) measurements would not change the assigned time point response. 
This would most likely happen in the case of PD).   Note:  Make all attempts at 
obtaining/clarifying measurements for all baseline sites of disease at each subsequent 
assessment time-point. 
8. Document the time-point response of Non-Target Lesions in the row labeled “NTL Response” 
that corresponds to the specific assessment time-point. Non Target Lesion response is defined 
as: 
a. Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10mm 
short axis) 
b. Non CR/Non PD:  Persistence of one or more non-target lesions and/or maintenance 
of tumor marker level above normal limits 
c. Progressive Disease (PD):  Unequivocal progression of existing non-target lesions.  
The appearance of one or more new lesions is also considered progression.  Note:  
When there is measurable disease, to achieve unequivocal progression, there must be 
an overall level of substantial worsening in non-target disease, such that even in 
presence of SD or PR of target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  When there is only non-measurable 
disease, there needs to be an increase in tumor burden representing an additional 73% 
increase in volume (example:  increase in pleural effusion from trace to large) 

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d. Not All Evaluated (NE):  When none or only some imaging is done at a particular 
assessment time point. 
9. Document the presence or absence of any new lesion (Target or Non-Target) in the row labeled 
“NEW LESION” at each assessment time point after baseline.  This represents disease 
progression; however, this finding should be unequivocal and not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor (Example: a new bone lesion may represent healing or flare of pre-existing 
lesions).   
a. A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease progression 
b. If a new lesion is equivocal (i.e. because of small size), continued therapy and follow 
up evaluation may clarify if it truly represents new disease.  Discuss and obtain 
approval from medical monitor to continue treatment and re-evaluate.  If re-eval 
confirms it as a new lesion, then PD should be recorded as the date of initial scan. 
10. Document the overall response in the row labeled “OVERALL RESPONSE” at each 
assessment time point after baseline.  Refer to Table 1 (for subjects with Target +/- Non Target 
Disease) and Table 2 (for subjects with Non Target Disease only). 
11. Document the review and confirmation date of the Clinical Investigator in the row labeled 
“Investigator Signature/Date” at baseline and each subsequent assessment time point.  
Important:  This is source documentation that disease burden and response have been 
confirmed by the investigator prior to continued study treatment after each assessment time 
point.  In addition, the investigator’s documentation should reflect any clarifications related to 
imaging/treatment discussed with radiologist and/or study monitor.  
 
Additional RECIST v1.1 Guidance: 
 
1. Special Notes on Response Assessment: 
Complete Response: 
 
When nodal disease is included in the Sum of Largest Diameter of target lesions and 
the nodes decrease to “normal” size (<10mm), measurements may still be reported on 
scans.  The measurements should be recorded even though the nodes are normal to 
prevent the overstatement of progression should progression be based on increase in 
the size of the nodes.  This means that responses with CR may not have a total sum of 
“zero”. 
 
When it is difficult to distinguish residual disease from normal tissue and the 
evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (FNA/Biopsy) before assigning a status of CR.  FDG-PET may 
be used to upgrade a response to CR in cases where a residual radiographic abnormality 
is thought to represent fibrosis or scarring.  Note:  both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Progression: 
 
For equivocal findings of progression (i.e., very small and uncertain new lesions, cystic 
changes or necrosis in existing lesions), treatment may continue until the next 

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scheduled assessment.  If at the next scheduled assessment, progression is confirmed, 
the date of progression should be the earlier date when progression was suspected.  
Note:  The investigator’s documentation should reflect the equivocal findings with 
decision to continue to treat until the next scheduled assessment. 
 
Patients with global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”.  Every effort should be made to document 
objective progression even after discontinuation of treatment.  Symptomatic 
deterioration is a reason for discontinuing study therapy, not an objective response 
which is determined by evaluation of target and non-target disease. 
Target Lesions that Split or Coalesce: 
 
When non-nodal lesions split, the longest diameters of the split portions should be 
added together to calculate the target lesion sum 
 
When a non-nodal lesion has coalesced (no longer separable), the vector of the longest 
diameter should be the maximal longest diameter for the coalesced lesion 
Target Lesions that become “too small to measure”: 
o Actual measurements of all baseline nodal and non-nodal lesions should be recorded 
at each subsequent assessment, even when very small (i.e., 2mm).  If the radiologist is 
not comfortable with assigning an exact measurement and the radiologist feels 
o that the lesion has likely disappeared, the measurement should be recorded as 
“0”mm 
o that the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of “5”mm should be recorded 
2. Confirmatory Measurement of Response 
a. In non-randomized trials where response is the primary endpoint, confirmation of CR 
and PR is required to ensure responses identified are not due to measurement error. 
b. In randomized (phase II or III) trials where SD or PD are the primary endpoints, 
confirmation of response is not required 
c. Stable Disease measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general > 6-8 weeks) that is defined in the study 
protocol. 
Modified RECIST Definitions: 
 Definition for SD, PR, and CR are the same as RECIST 1.1. 
 PD by modified RECIST:  Although the same rules for progression apply for modified 
RECIST, if the subject is clinically stable, at the discretion of the PI, they may continue 
treatment until the next imaging time points ≥4 weeks later.   If PD is confirmed, the 
date of PD is the same as the initial date of PD by RECIST.  If PD is not confirmed, 
the date of PD is based on the second event for PD by imaging.    
 
o The following scenarios defined confirmation of PD or lack thereof at the repeat 
imaging time point.  Note that if PD is not confirmed, imaging should resume the 
regular interval per the schedule.  Also, if a second PD event occurs, no further 

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confirmation of PD is required.  Note; if PD is confirmed and the subject is achieving 
a clinically meaningful benefit, the site should speak with DSMB to discuss the 
potential to continue on treatment.    
 
PD IS CONFIRMED:   
 
1. If initial PD is due to increase in tumor burden ≥ 20% compared to nadir, PD is Confirmed if 
ANY of the following are met: 
o    At follow-up scan tumor burden remains ≥ 20% compared to nadir + 5mm absolute 
increase if tumor burden is small  
o   New  unequivocal PD of non-target lesion (NTL) qualitative)  
o   One or more new lesion(s) 
o   Clinical instability 
 
2. If initial PD is due to unequivocal PD of NTL, PD is CONFIRMED at follow up if ANY of the 
following conditions are met: 
o NT disease resulting in initial PD is worse (qualitative)   
o New additional unequivocal PD of NTL   
o ( qualitatively assessed)  
o Additional new lesion (s)  
o New PD due to tumor burden  (SOD) ≥ 20% compared to nadir+ 5 mm absolute  
increase if tumor burden is small 
 
3. If PD is due to New Lesion, PD is CONFIRMED at follow up time point if ANY of the 
following conditions are met: 
o New lesion resulting in initial PD is worse (qualitative)  
o Additional new lesion (s ) 
o New unequivocal PD of non target  (qualitative)  
o New PD due to tumor burden (SOD)  ≥ 20% compared to nadir + 5 mm absolute  
increase if tumor burden is small   
      
PD IS NOT CONFIRMED AT  FOLLOW UP IMAGING FOR THE FOLLOWING 
SCENARIOS :    
 
4. If PD is due to increase in tumor burden by 20% compared to nadir,  PD is NOT CONFIRMED 
at follow up if ALL of the following conditions are met 
o Tumor burden is <20% compared to nadir  
o No unequivocal PD of non target lesion (qualitative)  
o No new lesion(s) 
o Continued clinical stability 
 
5.  If PD is due to New Lesion(s), PD is NOT CONFIRMED at follow up time point if ALL of 
the following conditions are met: 

Product:  Pembrolizumab 
67 
Protocol/Amendment No.:   
 
 
  
 
 
 
o Previous new lesion (that was initially called PD) is not worse (qualitative)   
o No additional new lesion(s)  
o No unequivocal PD of non target  (qualitative)  
o No new PD due to tumor burden (SOD)  ≥ 20% compared to nadir  
o Continued clinical stability 
 
6. If PD is due to unequivocal PD of non target, PD is NOT CONFIRMED at follow up if ALL 
of the following conditions are met: 
o Initial PD  of  non target disease is not worse (qualitative)  
o No additional new unequivocal PD of non target  qualitative)  
o No new lesion(s ) 
o No new PD due to tumor burden (SOD)  ≥ 20% compared to nadir   
o Continued clinical stability 
 
 
Time point response of Measurable Disease (Target Lesions) with or without Non-Measurable 
Disease (Non Target Lesions) 
 
Target Lesion Response 
 
Non Target Lesion 
 
New Lesions 
 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=Complete Response,  PR=Partial Response,  SD=Stable Disease, PD=Progressive 
Disease, and NE=Not All Evaluated 
 
Time point response of Non-Measurable Disease Only (Non Target Lesions) 
 
Non Target Lesion Response 
 
New Lesions 
 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Con-PD 
NE 
No 
NE 

Product:  Pembrolizumab 
68 
Protocol/Amendment No.:   
 
 
  
 
 
 
Unequivocal Progression 
Yes or No 
PD 
Any 
Yes 
PD 
CR=Complete Response, PD=Progressive Disease, and NE=Not All Evaluated 
Non-CR/Non-PD is preferred over “Stable Disease” for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Note:  If a CR is truly met at a time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that time point since disease must have 
reappeared after CR.