Safety and clinical activity of pembrolizumab for treatment of
recurrent or metastatic squamous cell carcinoma of the head and
neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
Safety and clinical activity of pembrolizumab for treatmentof
recurrent or metastatic squamous cell carcinoma of thehead and neck
(KEYNOTE-012): an open-label, multicentre,phase 1b trialTanguy 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) 2016Published OnlineMay 27,
2016http://dx.doi.org/10.1016/S1470-2045(16)30066-3
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.
Cont. BackgroundThe 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 mediatePD-L1 expression via interferon-
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.
Cont. BackgroundPembrolizumab 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.
Objectives:The study aims to assess the safety, tolerability,
and anti-tumour activity of pembrolizumab, a
humanizedanti-programmed death receptor 1 (PD-1) antibody, in
patients with PD-L1-positive recurrent or metastatic squamous cell
carcinoma of the head & neck.
Methodology:Study design : An open-label, multicentre, phase 1b
trial of (104) patients with recurrent or metastatic squamous
cellcarcinoma of the head and neck.Centers enrolling patients in
this cohort werelocated throughout the USA and one was located in
Israel.
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
analysisHPV status and biomarker assessment.
Cont. Inclusion criteria :*The no. of previous treatments the
patient had received was not limited for inclusion &
treatment-nave patients were also allowed.
NB.:Patients were allocated to HPV-negative andHPV-positive
subgroups based on investigator HPVdetermination.
Exclusion criteria : *Patients who received previous treatments
especially targeting T-cells co-stimulation or checkpoint-pathways
were excluded.
*Patients with additional progressing malignancies,
CNSmetastases, autoimmune diseases, interstitial lungdisease,
infections requiring systemic therapy, HIV, orhepatitis B or C were
excluded.
Procedure:patients received Pembrolizumab 10 mg/kgintravenously
every 2 weeks until documented diseaseprogression, intolerable
adverse events, intercurrentillness that prevented further
treatment, or completion of 24 months of treatment.
CT scans & MRI were done at baseline & at
8-weeksintervals after treatment initiation to assess response.
patient could continue on treatment if the follow-upscan showed
a reduction in tumour burden comparedwith the initial scan that
showed progressive disease.
Cont. Procedure :Incidence of adverse events was monitored
andgraded using the National Cancer Institute CommonTerminology
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.
Outcomes :The primary outcomes were to assess the safety
ofPembrolizumab and the proportion of patients whoachieved an
overall response.Secondary outcomes included proportion of patients
with an overall responsein HPV-positive patients and in patients
previously treatedwith cetuximab and platinum, and duration of
response, progression-free survival & over-all survival in the
total patient population.
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.
Statistical analysis :All patients who received at least one
dose of Pembrolizumab & had a measurable disease at baseline
either had post-baseline scan or didnt 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 wasassessed using the
full analysis set population.
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.
Results : Safety profile:The overall proportion of patients with
drug-relatedadverse events of any grade was 63% (n=38), with the
mostcommon events being fatigue, pruritus, nausea,
decreasedappetite, and rash (table 2). Ten (17%) of 60 patients
hadgrade 3 drug-related adverse events, which includedincreased
alanine aminotransferase, increased aspartateaminotransferase,
hyponatraemia, fatigue, rash, atrialfi brillation, congestive heart
failure, diarrhoea, lymphopenia,musculoskeletal pain, and neck
abscess
Anti-tumor activity:The proportion of patients with an overall
response was 18%.Severalpatients who were clinically stable or
improving continuedthe study treatment beyond progressive
disease.the proportion of patientswith an overall response was
higher in HPV-positive(fi ve [25%] of 20) than HPV-negative
patients (seven [19%]of 36).
Progression-free survival :
Over-all survival :
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
presentclinical results showing the effectiveness of
immunotherapyfor recurrent or metastatic squamous cellcarcinoma of
the head and neck, paving the way for futurestudies of
immune-modulating drugs in squamous cellcarcinoma of the head and
neck.
Cont.Pembrolizumab monotherapy showed substantial andclinically
significant antitumour activity in patients withheavily pretreated
recurrent or metastatic squamous cellcarcinoma of the head and
neck, with 18% of patientsachieving an overall response by central
review.Overall survival was 13 months (95% CI 5 tonot reached) and
duration of response was approximately53 weeks (122 months).
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 arepresent
to a higher degree in HPV-positive tumours,13 itcould be expected
that HPV-positive and HPV-negativepatients might derive different
benefit frompembrolizumab.
Cont.Pembrolizumab was safe and well tolerated, with38 (63%) of
patients experiencing treatment-relatedadverse events, most
commonly grade 12 pruritus,fatigue, or rash that were transient.
Grade 35 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
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.
Clinical relevance:Given that survival data with pembrolizumab
were onpar with those for first-line combination therapy,
futurestudies to assess the efficacy of pembrolizumab asfirst-line
therapy are warranted. Standard therapies mayalter the immune
environment of squamous cellcarcinoma of the head and neck,
generating conditionsfavouring response to pembrolizumab, and
trials ofpembrolizumab in combination or in sequence
withchemotherapy or radiotherapy are also warranted.
References:Vermorken JB, Mesia R, Rivera F, et al.
Platinum-basedchemotherapy plus cetuximab in head and neck cancer.N
Engl J Med 2008; 359: 111627.
Seiwert TY, Zuo Z, Keck MK, et al. Integrative and
comparativegenomic analysis of HPV-positive and HPV-negative head
and necksquamous cell carcinomas. Clin Cancer Res 2015; 21:
63241.
The Cancer Genome Atlas Network. Comprehensive
genomiccharacterization of head and neck squamous cell
carcinomas.Nature 2015; 517: 57682..
Cont.Keck MK, Zuo Z, Khattri A, et al. Integrative analysis of
head andneck cancer identifi es two biologically distinct HPV
andthree non-HPV subtypes. Clin Cancer Res 2015; 21: 87081.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands
intolerance and immunity. Annu Rev Immunol 2008; 26: 677704.
Carter LL, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory
pathwayaff ects both CD4+ and CD8+ T cells and is overcome by
IL-2.Eur J Immunol 2002; 32: 63443.
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.
Presented by:Dr.Marwa Elsayed MohamedClinical Pharmacy Diploma
2016B.Sc , Faculty of Pharmacy-Tanta university 2006