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