![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).](https://image.slidesharecdn.com/8100d4d3-2c73-4de3-bec5-07ccbe55a07c-170108225825/85/Safety-and-clinical-activity-of-pembrolizumab-for-treatment-17-320.jpg)
Safety and clinical activity of pembrolizumab for treatment
- 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).
- 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