2. METASTATIC MELANOMA
• 10-year survival rate less than 10%
• Single-agent chemotherapy:
• Well-tolerated, but response rates of only 5-20%
• Dacarbazine and Temozolomide:
• Equally effective; primarily for palliation
• Phase II randomized trial studying dacarbazine vs temozolomide PFS 2.1
& 2.3 months; OS 9.3 & 9.1 months, respectively
• Combination chemotherapy does not extend survival and is
associated with greater toxicity
• BRAF inhibitors for BRAF V600 mutation (+) melanoma:
• Vemurafenib in previously treated patients: 53% response rate, mean
duration of response 6.7 months
(Bhatia S., 2009); (NCI, 2014)
3. METASTATIC MELANOMA
• Interleukin-2
• In 270 patients, ORR was 16% and 60% of complete responders had
durable responses ranging from 42(+) to 122(+) months
• Risk of multi-organ complications limits IL-2 to younger patients
with excellent performance status and organ function
• Ipilimumab:
• Anti-CTLA4 antibody that potentiates immune responses against
cancer cells
• Phase 3 study, ipilimumab (10mg/kg) + dacarbazine (850mg/m2) vs
dacarbazine + placebo
• OS 11.2 vs 9.1 months, respectively, with higher survival rates in
ipilimumab-dacarbazine at 1 year (47.3% vs 36.3%)
(Bhatia S., 2009); (Robert C., 2011)
4. WHAT IS PEMBROLIZUMAB?
• A monoclonal IgG4 antibody that binds to programmed
death receptor-1 (PD-1) receptors and blocks its interaction
with PD-L1 and PD-L2 ligands
• Also known as MK-3475, KEYTRUDA
• Previously known as Lambrolizumab
(FDA, 2014); (Merck & Co., Inc., 2014)
5. CLINICAL PHARMACOLOGY
• Binding of PD-L1 and PD-L2 to PD-1 receptors on T cells
inhibits T cell proliferation and cytokine production
• PD-L1 and/or PD-L2 expression by APCs or tumor cells down-
regulates the activity of PD-1–expressing T cells and other cells
• Interruption of PD-1:PD-L1 and PD-1:PD-L2 binding by
pembrolizumab prevents PD-1 pathway-mediated T-cell
functional inhibition
(FDA, 2014); (Merck & Co., Inc., 2014); (Langer C., 2014)
6. Tre
patients
endocrin
in 5% of
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treatmen
Tw
docetaxe
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(Fig. 2).
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shown p
and evid
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weeks. R
B
FIGURE 1. Antibody blockade of the CTLA-4 and PD-1 immune
checkpoint pathways. Immune checkpoint blockade can restore
antitumor T-cell responses. A, Anti–CTLA-4 antibodies prevent
(Langer C., 2014)
Many cancers suppress cytotoxic T cell activity by expressing PD-L1/PD-L2 on
cell surfaces
7. FDA APPROVAL
• FDA approved pembrolizumab under the Accelerated
Approval Program based on tumor response rate and
durability of response
• Based on the results of a multi-centre, open-label,
randomized (1:1), expansion cohort of phase 1
KEYNOTE-001 study
(FDA, 2014); (Robert C., et al., 2014)
8. KEYNOTE-001
• Ongoing multi-centre, single arm, open-label study
evaluating pembrolizumab monotherapy in more than 1000
patients with diverse late-stage cancers, predominantly
melanoma and lung
• 3 dosing regimens evaluated: 10mg/kg every 2 weeks,
10mg/kg every 3 weeks, 2mg/kg every 3 weeks
• Tumour response assessed every 12 weeks by independent,
central, blinded radiographic review per RECIST1.1
(ClinicalTrials.gov, 2014)
9. KEYNOTE-001
Part A: Safety,
tolerability, PK,
PD, maximum
tolerated doses
Part B: Safety,
tolerability, efficacy
in metastatic
melanoma
Expansion
cohort
Part D: Low
and high doses
(2 mg/kg or 10
mg/kg every 3
weeks) in
metastatic
melanoma
Part F: Low and
high doses in
NSCLC
(ClinicalTrials.gov, 2014)
10. FDA APPROVAL
• Eligibility Criteria:
• Age 18 years or older
• Progressive, measurable, unresectable melanoma previously treated
with at least 2 doses of ipilimumab 3mg/kg or higher every 3 weeks
• Confirmed disease progression using immune-related response
criteria within 24 weeks of last dose of ipilimumab
• Adequate performance status and organ function
• Resolution of all ipilimumab-related adverse effects to grade 0 or 1
• Previous treatment with BRAF inhibitor required if BRAF-
mutant melanoma
(FDA, 2014); (Robert C., et al., 2014)
11. FDA APPROVAL
• Exclusion Criteria:
• Previous treatment with PD-1 or PD-L1 blocking agent
• Current systemic immunosuppressive therapy
• Active infection or autoimmune disease
• History of severe immune-mediated adverse events from ipilimumab
• Defined as any grade 4 toxicity requiring treatment with corticosteroids,
or
• Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/
day prednisone or equivalent) for more than 12 weeks
(FDA, 2014); (Robert C., et al., 2014)
12. FDA APROVAL
• Open-label study
• 178 patients were randomly assigned to receive one of 2
dosing regimens: 2 mg/kg every 3 weeks or 10 mg/kg every
3 weeks administered by IV over 30 minutes
• First 60 patients randomly assigned in 2:1 ratio to 2mg/kg every 3
weeks or 10mg/kg every 3 weeks
• Sample size was later increased by 100 patients, randomized in a 2:3
ratio
• Median age 61
• 40% female; 97% White
• BRAF V600 mutation (+) 17%
• Brain metastases 9%
• 2 or more prior treatments for advanced/metastatic disease 73%
(FDA, 2014); (Robert C., et al., 2014)
13. FDA APPROVAL
• Primary endpoint:
• Overall response rate according to RECIST v.1.1 as assessed by
independent central review
• Secondary endpoint:
• Response duration, progression-free survival, & overall survival
• Tumor response assessed every 12 weeks
(FDA, 2014); (Robert C., et al., 2014)
14. FDA APPROVAL
• 178 patients randomized; 173
received treatment
• Overall response rate 26% in
both arms
• 2 mg/kg arm:
• 1 complete and 20 partial
responses
• Among 21 with objective
response, 3 had disease
progression at 2.8, 2.9, 8.2
months after initial response
• Remaining 18 had ongoing
responses ranging 1.4(+) to
8.5(+) months
• Similar ORR results observed
in 10 mg/kg arm
• Progression free survival: 22 and
14 weeks with 2mg/kg and
10mg/kg, respectively
Articles
RECIST, independent central review
Pembrolizumab
2 mg/kg
Pembrolizumab
10 mg/kg
Estimated diff
(95% CI)
Bestoverall response* n=81 n=76
Complete response 1 (1%) 1 (1%) ··
Partial response 20 (25%) 19 (25%) ··
Stabledisease 20 (25%) 18 (24%) ··
Progressivedisease 27 (33%) 31 (41%) ··
Not evaluable† 13 (16%) 7 (9%) ··
No assessment‡ ·· ·· ··
Overall response rate (95%CI) 26% (17to 37) 26% (17to 38) 0%§ (–14to 13
Disease control rate (95%CI) 51% (39to 62) 50% (38to 62) 1%§ (–15to 16
Patientswith response n=21 n=20 ··
Timeto response
(weeks; median, range)
12 (11to 36) 12 (7to 17) ··
Responseduration
(weeks; median, range)
NR (6–37¶) NR (8–37¶) ··
Progression-free survival n=89 n=84 ··
Median (weeks; 95%CI) 22 (12to 36) 14 (12to 24) 0·84|| (0·57–1
At 24weeks (95%CI) 45% (34to 55) 37% (27to 48) ··
RECIST=Response Evaluation Criteria In SolidTumors (version 1.1). NR=not reached. *Eight p
independent central review at baseline and were excluded from the analysis of best overall re
for response assessment or who had radiological images of non-diagnostic quality. ‡Patients
investigator. §Difference. ¶Non-progressive disease or ongoing response at the last assessme
(FDA, 2014); (Robert C., et al., 2014)
16. least 6 months of follow-up. Median number of days
from first to last pembrolizumab dose was 188·0 days
in the pembrolizumab 2 mg/kg group and 185·5 days
in the pembrolizumab 10 mg/kg group (appendix). At
patients; p=0·96; table 2). 59 (73%) patients in the
pembrolizumab 2 mg/kg group and 52 (68%) in the
10 mg/kg group had a reduction from baseline in target
lesion size (figure 2A). Change from baseline in index
Figure 2: Efficacy of pembrolizumab at 2 mg/kg and 10 mg/kg
(A)Waterfall plot of maximum percentage change from baseline in the sum of the longest diameter of each target lesion as assessed per RECIST by independent
central review for patients with measurable disease by independent central review at baseline who had at least one post-baseline tumour assessment. (B)Time to and
duration of response in responders as assessed per RECIST by independent central review. RECIST=Response Evaluation Criteria In SolidTumors (version 1.1).
–100
–80
B
C
Individual patients
0 10 20 30 40 50
IndividualpatientswhohadresponseperRECIST
Time (weeks)
Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Complete response
Partial response
Progression
On treatment
Analysis of time to response: although most responses occurred by week 12, responses
might also occur late in the course of treatment, some as late as 36 weeks
(FDA, 2014); (Robert C., et al., 2014)
17. FDA APPROVAL
• Adverse effects identified in 89 patients who received
pembrolizumab 2mg/kg every 3 weeks
• Pembrolizumab was discontinued for adverse reactions in
7% of 89 patients
• Most common adverse reactions (reported in at least 20%
of patients) were:
• Fatigue, cough, nausea, pruritus, rash, decreased appetite,
constipation, arthralgia, and diarrhea
• Most frequent (>20%) serious adverse reactions included:
• Renal failure, dyspnea, pneumonia, and cellulitis
(FDA, 2014); (Robert C., et al., 2014)
18. Discussion
The anti-PD-1 antibody pembrolizumab at doses of
2 mg/kg and 10 mg/kg every 3 weeks had similar and
substantial anticancer activity and an acceptable safety
profile in patients with advanced melanoma whose
disease had progressed on ipilimumab, and in those with
BRAF-mutant disease, who were previously treated with
BRAF or MEK inhibitors, or both. This study is the
largest reported of anti-PD-1 therapy in patients with
melanoma and the first reported randomised comparison
of an anti-PD-1 agent (panel).
Similar to other immunotherapies,14,28
the clinical
benefit provided by pembrolizumab is long lasting.
With a median follow-up of 8 months (minimum of
6 months), 88% of responses were ongoing at the time
of analysis. This response duration is consistent with
data previously reported for patients with
pembrolizumab-treated melanoma, whereby after a
median follow-up of 15 months, 88% of responses were
ongoing and the median duration of response was not
reached.16
A high percentage of patients were
progression free at 24 weeks. The finding that 19% of
patients with progressive disease as per RECIST were
progression free at 6 months as per immune-related
response criteria suggests that conventional use of
RECIST might underestimate the therapeutic benefit of
pembrolizumab. The finding of delayed response also
suggests that additional objective responses will occur
with longer follow-up. According to previously reported
data for a mixed population of ipilimumab-treated and
ipilimumab-naive patients, initial responses occurred
as late as 11 months after initiation of pembrolizumab,
with complete responses occurring as late as
16 months.16
This prolonged time to complete response
might partly explain why the percentage of patients
with complete response in this study after a median
follow-up of 8 months was only 1%. With additional
follow-up, it is possible that there will be more complete
responses. Overall, and as was previously suggested for
ipilimumab,21,29
these data suggest that traditional
response criteria might need to be revised for the
overall therapeutic benefits of pembrolizumab to be
Pembrolizumab
2 mg/kg (n=89)
Pembrolizumab
10 mg/kg (n=84)
Total (n=173)
Drug-related adverse events
Total 73 (82%) 69 (82%) 142 (82%)
Grade 3 or 4 13 (15%) 7 (8%) 20 (12%)
Serious 7 (8%) 1 (1%) 8 (5%)
Immune-related adverse events
Grade 3 or 4 1 (1%) 2 (2%) 3 (2%)
Serious 3 (3%) 1 (1%) 4 (2%)
Adverse events of special interest
Grade 3 or 4 4 (4%) 7 (8%) 11 (6%)
Drug-related, grade 3 or 4 3 (3%) 4 (5%) 7 (4%)
Serious 4 (4%) 4 (5%) 8 (5%)
Adverse events leading to discontinuation of drug*
Total 6 (7%) 9 (11%) 15 (9%)
Drug-related, any grade 5 (6%) 1 (1%) 6 (3%)
Drug-related, grade 3 or 4 2 (2%) 1 (1%) 3 (2%)
Immune-related 3 (3%) 1 (1%) 4 (2%)
Of special interest 3 (3%) 1 (1%) 4 (2%)
Grade 3 or 4 drug-related adverse events occurring in one or more patients
Fatigue 5 (6%) 0 5 (3%)
Amylase increased 1 (1%) 0 1 (<1%)
Anaemia 1 (1%) 0 1 (<1%)
Autoimmune hepatitis 1 (1%) 0 1 (<1%)
Confusion 1 (1%) 0 1 (<1%)
Diarrhoea 0 1 (1%) 1 (<1%)
Dyspnoea 0 1 (1%) 1 (<1%)
Encephalopathy 1 (1%) 0 1 (<1%)
Hypophysitis 1 (1%) 0 1 (<1%)
Hypoxia 0 1 (1%) 1 (<1%)
Muscular weakness 1 (1%) 0 1 (<1%)
Muscoloskeletal pain 0 1 (1%) 1 (<1%)
Pancreatitis 0 1 (1%) 1 (<1%)
Peripheral motor neuropathy 1 (1%) 0 1 (<1%)
Pneumonitis 1 (1%) 0 1 (<1%)
Rash 0 1 (1%) 1 (<1%)
Rash maculopapular 0 1 (1%) 1 (<1%)
Data are number (%), unless otherwise indicated. *Medical Dictionary for Regulatory Activities preferred terms
“progressive disease” and “malignant neoplasm progression” not related to study drug are excluded.
Table 3: Summary of adverse events in the pembrolizumab 2mg/kg and 10 mg/kg groups
• Adverse events in 73 & 69 patients
• 8 patients had drug-related serious
AE
• 7% & 11% patients discontinued
treatment in 2mg/kg and 10mg/kg
arms, respectively
• No drug-related deaths were reported
• Grade 3 or 4 AE occurred in 20
patients
• Only fatigue occurred in more than 1
patient (5)
• Grade 3 or 4 AE of special interest
occurred in 11 patients, 7 classified as
drug-related:
• Autoimmune hepatitis, diarrhea, hypo-
physitis, maculopapular rash,
pancreatitis, pneumonitis
• Immune-mediated AE manageable
with treatment interruptions and
corticosteroids
(FDA, 2014); (Robert C., et al., 2014)
19. FDA APPROVAL
• Doses of 2mg/kg and 10mg/kg every 3 weeks had similar and substantial
anticancer activity and acceptable safety profiles
• Estimated progression-free survival at 24 weeks was 45% in 2mg/kg group
and 37% in 10mg/kg group
• Estimated 1 year overall survival was 58% and 63%, respectively
• 88% of responders were alive and progression-free at time of analysis, with
at least 6 months of follow-up
• Finding of delayed response suggests additional objective responses will
occur with longer follow-up
• As late as 11 months for initial responses and 16 months for complete responses
• Trend towards a lower response in BRAF-mutant population (ORR 19%)
• Small number of patients with BRAF mutation and BRAF inhibitor pretreatment
makes it difficult to identify factors contributing to the response
(Bhatia S., 2014); (FDA, 2014); (Robert C., et al., 2014)
20. WHY WAS IT GRANTED ACCELERATED
APPROVAL?
• 10 year survival for patients with metastatic melanoma is
less than 10%
• Recent successes with ipilimumab and inhibitors of BRAF
(vemurafenib, dabrafenib, trametinib)
• Ipilimumab is current standard of therapy, but patients who do not
respond or progress while receiving ipilimumab have very few
options remaining
• Pembrolizumab confirmed to be an active agent against
melanoma in patients having previously received
ipilimumab and/or BRAF inhibitors
(Bhatia S., 2014); (FDA, 2014); (Robert C., et al., 2014)
21. HOW DO WE GET IT IN CANADA?
• Pembrolizumab is available via Special Access Program in
Canada
• Supplier: Idis pharma
• Patient’s health care providers must fill out the Health
Canada Special Access Form A
• Patient’s medical history, severity of condition, prognosis
• Treatments failed/considered/unsuitable
• Why the patient is a candidate for pembrolizumab therapy
• Why pembrolizumab is the best choice for the patient
• Specific data/references with respect to safety and efficacy of
pembrolizumab that supports practitioner’s decision
(Health Canada, 2014)
22. NSCLC
• Pembrolizumab studied in phase 1 study as initial therapy
in previously untreated patients with PD-L1 positive, Stage
IV NSCLC
• Preliminary data presented at ASCO 2014 annual meeting:
• Objective response rate was 47% by irRC
• 80% demonstrated tumor shrinkage
• Interim progression-free survival was 37 weeks
• Most common AE: fatigue, pruritus, hypothyroidism, rash, diarrhea,
dyspnea
• AE resulting in discontinuation: pneumonitis (1 grade 3) and acute
kidney injury (1 grade 2)
(Johnson D. et al., 2014)
23. BLADDER CANCER
• Studied as monotherapy in patients with PD- L1 positive,
advanced urothelial cancer
• Ongoing KEYNOTE-012 trial
• Results from early findings presented at ESMO 2014
Congress:
• Confirmed overall response rate 24% (n = 7/29)
• Pembrolizumab used as monotherapy measured by RECIST1.1, central
review
• Complete response rate 10% (n = 3/29)
• Response durations spanned 16(+) to 40(+) weeks
(Halse, K., 2014)
24. GASTRIC CANCER
• Phase 1b study assessing safety, tolerability, and antitumor
activity in patients with recurrent/metastatic
adenocarcinoma of stomach or gastroesophageal junction
• Treated with pembrolizumab 10 mg/kg every 2 weeks up to
24 months
• Overall response rate 31%
• Responses were ongoing, ranging 8(+) to 20(+) weeks
• Common AE treatment-related: hypothyroidism & fatigue
• Grade 3 or greater AE deemed treatment-related occurred in 3
patients
• 1 hypoxia, 1 peripheral neuropathy, 1 pneumonitis
(ESMO, 2014)
25. KEYNOTE-
028 (PMH)
Patients with PD-L1 (+) advanced
solid tumors who failed standard
therapy, for which no standard therapy
exists, or standard therapy is not
appropriate
20 advanced solid tumors: colon/
rectal, pancreas, esophageal, ovarian,
fallopian tube, cervical …
Phase 1B Pembrolizumab 10
mg/kg every 2 week
KEYNOTE-
023 (PMH)
Patients with multiple myeloma who
have failed at least 2 lines of prior
therapy
Phase 1 Pembrolizumab +
lenalidomide +
dexamethasone
ONGOING STUDIES
(ClinicalTrials.gov, 2014)
26. KEYNOTE-
013 (PMH)
Hematologic malignancies:
Hodgkin’s lymphoma,
mediastinal large B cell
lymphoma, non-Hodgkin’s
lymphoma, myelodysplastic
syndrome
Phase 1B Pembrolizumab:10 mg/kg
every 2 weeks for 24 months
KEYNOTE-
031
Renal cell cancer in 36
patients
Phase 1 Pembrolizumab: up to 3 doses
of 200 mg every 3 weeks +
Surgical Resection
vs.
Surgical Resection (Standard
of care)
ONGOING STUDIES
(ClinicalTrials.gov, 2014)
27. KEYNOTE-010
(PMH)
NSCLC PD-L1(+)
tumors who have
disease progression
after platinum-
containing therapy
Phase 2/3 Pembrolizumab: 2 mg/kg every 3
weeks or 10 mg/kg every 3 weeks
vs.
Docetaxel 75 mg/m2 every 3
weeks
KEYNOTE-006
(PMH)
Advanced
melanoma
Phase 3 Pembrolizumab: 10 mg/kg every
2 weeks or 10 mg/kg every 3
weeks
vs.
Ipilimumab 3 mg/kg every 3
weeks for 4 doses
ONGOING STUDIES
(ClinicalTrials.gov, 2014)
28. CONCERNS
• Improvement in survival or disease-related symptoms was
not established with the expansion cohort
• Conditions for approval:
• MERCK is required to conduct a multi-centre, randomized trial
establishing superiority of pembrolizumab against standard therapy
to verify and describe clinical benefit
• Very expensive: $150,000 per year in US
(Bhatia S., 2014); (FDA, 2014); (Robert C., et al., 2014)
29. PRESCRIBING INFORMATION
• Indication:
• Treatment of patients with unresectable or metastatic melanoma and
disease progression following ipilimumab, and if BRAF V600
mutation positive, a BRAF inhibitor
• Dosage and Administration:
• 2 mg/kg as IV infusion over 30 minutes every 3 weeks until disease
progression or unacceptable toxicity
(Merck & Co., Inc., 2014)
30. PREPARATION
• Dosage form: 50 mg, lyophilized powder in single-use vial
for reconstitution
• Preparation:
• Add 2.3 mL Sterile Water for Injection by injecting water along walls
of vial and not directly into powder
• Swirl vial slowly. Allow 5 minutes for bubbles to clear
• Visually inspect reconstituted solution for particulate matter and
discoloration
• Reconstituted pembrolizumab is clear to slightly opalescent, colourless to
slightly yellow solution
• Withdraw required volume and inject into 50mL 0.9% Sodium
Chloride IV bag and mix by gentle inversion
(Merck & Co., Inc., 2014)
31. STORAGE AND ADMINISTRATION
• Product does not contain preservative
• Store reconstituted solutions either:
• Room temperature for no more than 4 hours from time of
reconstitution
• Includes: room temperature storage of reconstituted vials, storage of
infusion solution in IV bag, and duration of infusion
• At 2-8oC for no more than 24 hours
• Administer IV over 30 minutes through IV line containing a
sterile, non-pyrogenic, low-protein binding 0.2-5 micron in-
line or add-on filter
(Merck & Co., Inc., 2014)
32. PHARMACOKINETICS
• Studied in 479 patients receiving doses of 1-10 mg/kg every
2 weeks or 2-10 mg/kg every 3 weeks
• Mean clearance: 0.22 L/day
• Mean elimination half-life: 26 days
• Clearance increased with increasing body weight
• Adequately addressed by administration of weight-based dosing
• No important effect on clearance: age, gender, renal impairment,
mild hepatic impairment, tumor burden
• Steady-state concentration reached by 18 weeks of repeated
dosing with an every 3-week regimen
(Merck & Co., Inc., 2014)
33. ADVERSE REACTIONS
Immune-
Mediated
Pneumonitis
- Evaluate patients with radiographic imagining and
administer corticosteroids for grade 2 or greater pneumonitis
- Withhold for grade 2 pneumonitis and permanently
discontinue for grade 3-4 pneumonitis
Immune-
Mediated
Colitis
- Administer corticosteroids for grade 2 or greater
- Withhold for grade 2 or severe colitis, permanently
discontinue for life-threatening (grade 4) colitis.
Immune-
Mediated
Hepatitis
- Monitor for changes in liver function. Administer
corticosteroids for grade 2 or greater hepatitis
- Withhold: AST/ALT 3-5 times ULN
- Discontinue: AST/ALT >5 times ULN or total bilirubin >3
times ULN
(Merck & Co., Inc., 2014)
34. ADVERSE REACTIONS
Renal Failure &
Immune-
Mediated
Nephritis
- Including: autoimmune nephritis & interstitial nephritis
- Monitor changes in renal function. Administer corticosteroids
for grade 2 or greater nephritis
- Withhold for grade 2 and discontinue for grade 3-4
Immune-
Mediated Adverse
Reactions
- Exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis,
hemolytic anemia, partial seizures, adrenal insufficiency
- Withhold for grade 3; discontinue for persistent grade 2 or 3
adverse reactions that do not recover to grade 0-1 within 12
weeks
Immune-
Mediated
Hyperthyroidism
&
Hypothyroidism
- Monitor for changes in thyroid function. Administer
corticosteroids for grade 3 or greater hyperthyroidism
- Withhold for grade 3 hyperthyroidism, discontinue for grade 4.
Isolated hypothyroidism may be managed with replacement
therapy without interruptions
(Merck & Co., Inc., 2014)
35. REFERENCES
Bhatia S., Tykodi S., Thompson J. Treatment of Metastatic Melanoma: An Overview. Oncology
(Williston Park). 2009 May;23(6):488-496.
Bhatia S. & Thompson J. Melanoma: immune checkpoint blockade story gets better. Lancet. 2014
Sep 20;384(9948):1078-9. doi: 10.1016/S0140-6736(14)61140-5.
ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Obtained from: http://
clinicaltrials.gov/ct2/results?term=pembrolizumab&Search=Search
European Society for Medical Oncology. ESMO 2014: Pembrolizumab shows promise in several
solid tumours. 2014 Sept 30. Obtained from: http://www.esmo.org/Conferences/ESMO-2014-
Congress/News-Articles/Pembrolizumab-Shows-Promise-in-Several-Solid-Tumours
Halse K. Merck drug shows promise in bladder cancer. Daily Digest News 2014 Sept 29. Obtained
from: http://dailydigestnews.com/2014/09/merck-drug-shows-promise-in-bladder-cancer/
Health Canada. Special Access to Drugs & Health Products. 2013 Dec 20. Obtained from: http://
www.hc-sc.gc.ca/dhp-mps/acces/drugs-drogues/index-eng.php
Johnson D., Rioth M., Horn L. Immune Checkpoint Inhibitors in NSCLC. Current Treatment
Options Oncology. 2014 Aug 6. doi: 10.1007/s11864-014-0305-5.
36. REFERENCES
Langer C. Emerging Immunotherapies in the Treatment of Non-Small Cell Lung Cancer
(NSCLC). Am J Clin Oncol 2014 March 28:00:000-0000. doi: 10.1097/COC. 0000000000000059.
National Cancer Institute. Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment.
2014 Sept 19. Obtained from: http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/
HealthProfessional/page9
Merck & Co. Inc. Highlights of Prescribing Information KEYTRUDA. 2014 September. Obtained
from: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
Robert C. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-
refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet
2014;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2
Robert C. et al. Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. N
Engl J Med 2011;364:2517-2526. doi: 10.1056/NEJMoa1104621
U.S. Food and Drug Administration. Pembrolizumab. 2014 September 5. Obtained from: http://
www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm412861.htm
