Pembrolizumab is a humanized monoclonal antibody that targets the PD-1 receptor. This study evaluated the safety and efficacy of pembrolizumab in 104 patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The results showed that pembrolizumab had a manageable safety profile, with 63% of patients experiencing drug-related adverse events mostly grade 1-2. Pembrolizumab also demonstrated promising anti-tumor activity with an 18% overall response rate. Progression-free survival was 13 months. This study provides evidence that pembrolizumab is a potential new treatment option for this patient population.

1. Tanguy Y Seiwert, Barbara Burtness, Ranee Mehra, Jared Weiss, Raanan Berger, Joseph Paul
Eder, Karl Heath, Terrill McClanahan, Jared Lunceford,
Christine gause, Jonathan D Cheng, Laura Q Chow
Lancet Oncol , IF (26.509) 2016
Published Online
May 27, 2016
http://dx.doi.org/10.1016/
S1470-2045(16)30066-3

2. Background :
Squamous cell carcinoma of the head & neck is the seventh
most common cancer worldwide. Patients with recurrent or
metastatic disease have poor prognosis & fewer treatment
options.
One of the risk factors for this type of cancer is the infection with
Human Papilloma Virus (HPV ).
The combination of Cetuximab, platinum& fluorouracil is
commonly used as first-line chemotherapy treatment for
recurrent or metastatic head & neck squamous cell carcinoma,
although taxanes& methotrexate are used in later lines of
treatment.
However, a more effective and less toxic treatment is needed in this
palliative setting.

3. Cont. Background
The programmed death 1 (PD-1) receptor is expressed
on activated T-cells and interact s with its ligands ,
PD-L1 , PD-L2 to protect healthy cells from excessive
inflammatory or auto-immune response.
Host tumour-infiltrating T lymphocytes6,13,14 mediate
PD-L1 expression via interferon-γ secretion.
Tumor associated regulation of PD-1 pathway might lead
to escape from immune serveillance. Tumor cells
express PD-L1 can reduce T-cell effector activity and
terminate immune responses.

4. Cont. Background
Pembrolizumab is a high affinity , humanized , IgG4-k
monoclonal PD-1 anti-body has shown efficacy in
patients with various advanced solid tumors and is
approved for the treatment of melanoma.
Additionally,
PD-L1 expression has been correlated with a higher
treatment response to anti-PD-1 antibodies in many
cancer types. However, patients with negative PD-L1
staining also benefit from treatment with PD-1
inhibitors but at a lower frequency than those with
positive PD-L1 expression.

5. Objectives:
The study aims to assess the safety,
tolerability, and anti-tumour activity of
pembrolizumab, a humanized
anti-programmed death receptor 1 (PD-1)
antibody, in patients with PD-L1-positive
recurrent or metastatic squamous cell
carcinoma of the head & neck.

6. Methodology:
Study design : An open-label, multicentre, phase 1b trial
of (104) patients with recurrent or metastatic
squamous cell
carcinoma of the head and neck.
Centers enrolling patients in this cohort were
located throughout the USA and one was located in
Israel.

7. Inclusion criteria :
*Patients aged 18 years or older & had a confirmed
diagnosis of metastatic or recurrent squamous cell
carcinoma of the head & neck with at least 1 %
expression of PD-L1 as determined by immuno-histo-
chemical assay.
*Adequate organ function determined by tests done
within 10 days of treatment initiation
*Provision of tumor tissue for PD-L1 expression analysis
HPV status and biomarker assessment.

8. Cont. Inclusion criteria :
*The no. of previous treatments the patient had received
was not limited for inclusion & treatment-naïve
patients were also allowed.
NB.:
Patients were allocated to HPV-negative and
HPV-positive subgroups based on investigator HPV
determination.

9. Exclusion criteria :
*Patients who received previous treatments especially
targeting T-cells co-stimulation or checkpoint-
pathways were excluded.
*Patients with additional progressing malignancies, CNS
metastases, autoimmune diseases, interstitial lung
disease, infections requiring systemic therapy, HIV, or
hepatitis B or C were excluded.

10. Procedure:
patients received Pembrolizumab 10 mg/kg
intravenously every 2 weeks until documented disease
progression, intolerable adverse events, intercurrent
illness that prevented further treatment, or completion of 24
months of treatment.
CT scans & MRI were done at baseline & at 8-weeks
intervals after treatment initiation to assess response.
patient could continue on treatment if the follow-up
scan showed a reduction in tumour burden compared
with the initial scan that showed progressive disease.

11. Cont. Procedure :
Incidence of adverse events was monitored and
graded using the National Cancer Institute Common
Terminology Criteria for Adverse Events.
For patients who experienced grade 3 or worse drug related
adverse events , Pembrolizumab treatment was withheld
until toxicity resolved to grade 0-1.
Patients could discontinue treatment if the drug-related
toxicity
Had not resolved within 12-weeks of the last infusion.

12. Outcomes :
The primary outcomes were to assess the safety of
Pembrolizumab and the proportion of patients who
achieved an overall response.
Secondary outcomes included proportion
of patients with an overall response
in HPV-positive patients and in patients previously
treated
with cetuximab and platinum, and duration of response,
progression-free survival & over-all survival in the
total patient population.

13. Clinical question:
Is Pembrolizumab safe & effective in treatment of
patients with metastatic squamous cell carcinoma of
the head & neck?
Patient : Recurrent or metastatic squamous cell carcinoma
of the head & neck.
Intervention : Pembrolizumab, a humanized monoclonal
antibody.
Comparison : The combination of Cetuximab, Platinum &
Fluorouracil as a first-line therapy.
Outcome: To assess the safety of Pembrolizumab & the
proportion of patients who achieved an over-all response.

14. Statistical analysis :
All patients who received at least one dose of Pembrolizumab
& had a measurable disease at baseline either had post-
baseline scan or didn’t have a baseline scan and discontinue
therapy beacause of disease progression or intolerable
adverse events were included in the efficacy analysis.
All patients who received at least one dose of
pembrolizumab were included in the safety analysis.
Overall survival was assessed using the intention to-
treat population, and progression-free survival was
assessed using the full analysis set population.

15. Cont. Statistical analysis :
For the proportion of patients with overall response, the
95% CI & P-value were provided using exact binomial
distribution.
Ptients without response were defined as non-
responders.
HPV-negative & HPV-positive patients were assessed
separately.

16. Results :
Safety profile:
The overall proportion of patients
with drug-related
adverse events of any grade was
63% (n=38), with the most
common events being fatigue,
pruritus, nausea, decreased
appetite, and rash (table 2). Ten
(17%) of 60 patients had
grade 3 drug-related adverse
events, which included
increased alanine
aminotransferase, increased
aspartate
aminotransferase, hyponatraemia,
fatigue, rash, atrial
fi brillation, congestive heart
failure, diarrhoea, lymphopenia,
musculoskeletal pain, and neck
abscess

17. Anti-tumor activity:
The proportion of patients
with an overall response
was 18%.
Several
patients who were clinically
stable or improving
continued
the study treatment
beyond progressive disease.
the proportion of patients
with an overall response
was higher in HPV-positive
(fi ve [25%] of 20) than
HPV-negative patients
(seven [19%]
of 36).

18. Progression-free survival :

19. Over-all survival :

20. Discussion :
Pembrolizumab showed a manageable safety profile &
promising anti-tumor activity in patients with PD-L1
positive recurrent or metastatic squamous cell carcinoma
of the head & neck.
Present treatment options for advanced squamous cell
carcinoma of the head & neck are limited.
This is the first study to present
clinical results showing the effectiveness of immunotherapy
for recurrent or metastatic squamous cell
carcinoma of the head and neck, paving the way for future
studies of immune-modulating drugs in squamous cell
carcinoma of the head and neck.

21. Cont.
Pembrolizumab monotherapy showed substantial and
clinically significant antitumour activity in patients with
heavily pretreated recurrent or metastatic squamous cell
carcinoma of the head and neck, with 18% of patients
achieving an overall response by central review.
Overall survival was 13 months (95% CI 5 to
not reached) and duration of response was
approximately
53 weeks (12・2 months).

22. Cont.
This level of anti-tumor activity & the duration of
response compares with single-drug
cetuximab(Proportion of patients with an over-all
response,13%; duration of response , 4 months).
Because tumor inflammation and PD-L1 expression are
present to a higher degree in HPV-positive tumours,13 it
could be expected that HPV-positive and HPV-negative
patients might derive different benefit from
pembrolizumab.

23. Cont.
Pembrolizumab was safe and well tolerated, with
38 (63%) of patients experiencing treatment-related
adverse events, most commonly grade 1–2 pruritus,
fatigue, or rash that were transient. Grade 3–5 treatmant
related adverse events occurred in 17% of patients.
The degree of PD-L1 expression assessed by immuno-
histochemical assay was found to be predictive of best
overall response & improved progression free survival

24. Limitations :
Small no. of patients restricts the ability of complete
identification & determination of the clinical
usefulness of the intervention .
It was an open-label study & funded by Merck so, there
may be a degree of bias in the results.

25. Clinical relevance:
Given that survival data with pembrolizumab were on
par with those for first-line combination therapy, future
studies to assess the efficacy of pembrolizumab as
first-line therapy are warranted. Standard therapies may
alter the immune environment of squamous cell
carcinoma of the head and neck, generating conditions
favouring response to pembrolizumab, and trials of
pembrolizumab in combination or in sequence with
chemotherapy or radiotherapy are also warranted.

26. References:
Vermorken JB, Mesia R, Rivera F, et al. Platinum-based
chemotherapy plus cetuximab in head and neck cancer.
N Engl J Med 2008; 359: 1116–27.
Seiwert TY, Zuo Z, Keck MK, et al. Integrative and comparative
genomic analysis of HPV-positive and HPV-negative head and neck
squamous cell carcinomas. Clin Cancer Res 2015; 21: 632–41.
The Cancer Genome Atlas Network. Comprehensive genomic
characterization of head and neck squamous cell carcinomas.
Nature 2015; 517: 576–82..

27. Cont.
Keck MK, Zuo Z, Khattri A, et al. Integrative analysis of head and
neck cancer identifi es two biologically distinct HPV and
three non-HPV subtypes. Clin Cancer Res 2015; 21: 870–81.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its
ligands in
tolerance and immunity. Annu Rev Immunol 2008; 26: 677–704.
Carter LL, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory
pathway
aff ects both CD4+ and CD8+ T cells and is overcome by IL-2.
Eur J Immunol 2002; 32: 634–43.

28. Acknowledgement:
Special thanks for Fadic team who was the reason for my
success in completing this great program & helping me
to be a good drug information specialist.

29. Presented by:
Dr.Marwa Elsayed Mohamed
Clinical Pharmacy Diploma 2016
B.Sc , Faculty of Pharmacy-Tanta university 2006