The European Commission ( EC ) has approved Keytruda , an anti-PD-1 therapy, as monotherapy or in combination with Platinum and 5-Fluorouracil ( 5-FU ) chemotherapy, for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma ( HNSCC ) whose tumors express PD-L1 ( combined positive score [ CPS ] greater than or equal to 1 ).
This approval is based on findings from the pivotal phase 3 Other treatments, in which Pembrolizumab compared with standard treatment ( Cetuximab with Carboplatin or Cisplatin plus 5-FU ), has demonstrated a significant improvement in overall survival ( OS ) as monotherapy ( hazard ratio, HR = 0.74 [ 95% CI, ( 0.61-0.90 ); p=0.00133 ] and in combination with chemotherapy ( HR=0.65 [ 95% CI, 0.53-0.80 ]; p=0.00002 ), in patients whose tumors expressed PD-L1 ( CPS greater than or equal to 1 ).
The approval is based on data from the phase 3 KEYNOTE-048 trial, a multi-center, randomized, open-label, active-controlled trial conducted in 882 patients with histologically confirmed metastatic or recurrent HNSCC of the oral cavity, pharynx or larynx, who had not previously received systemic therapy for recurrent or metastatic disease and who were considered incurable by local therapies.
Randomization was stratified by tumor PD-L1 expression ( Tumor Proportion Score [ TPS ] greater than or equal to 50% or less than 50% ), HPV status ( positive or negative ), and ECOG Performance Status ( PS ) ( 0 versus 1 ).
The dual primary endpoints were overall survival and progression-free survival ( PFS ). Patients were randomized 1:1:1 to one of the following treatment arms:
a) Pembrolizumab 200 mg intravenously every three weeks;
b) Pembrolizumab 200 mg intravenously every three weeks; Carboplatin AUC 5 mg/mL/min intravenously every three weeks or Cisplatin 100 mg/m2 intravenously every three weeks and 5-FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every three weeks ( maximum of six cycles of platinum and 5-FU );
c) Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, Carboplatin AUC 5 mg/mL/min intravenously every three weeks or Cisplatin 100 mg/m2 intravenously every three weeks and 5-FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every three weeks ( maximum of six cycles of Platinum and 5-FU ).
Treatment with Pembrolizumab continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity or a maximum of 24 months.
At the second interim analysis, Pembrolizumab alone improved overall survival versus Cetuximab with chemotherapy in the CPS of 20 or more population ( median 14.9 months vs 10.7 months, HR=0.61 [ 95% CI 0.45–0.83 ], p=0·0007 ) and CPS of 1 or more population ( 12.3 vs 10.3, 0.78 [ 0.64–0.96 ], p=0.0086 ) and was non-inferior in the total population ( 11.6 vs 10.7, 0.85 [ 0.71–1.03 ] ).
Pembrolizumab with chemotherapy improved overall survival versus Cetuximab with chemotherapy in the total population ( 13.0 months vs 10.7 months, HR=0.77 [ 95% CI 0.63–0.93 ], p=0.0034 ) at the second interim analysis and in the CPS of 20 or more population ( 14.7 vs 11.0, 0.60 [ 0.45–0.82 ], p=0.0004 ) and CPS of 1 or more population ( 13.6 vs 10.4, 0.65 [ 0.53–0.80], p less than 0.0001 ) at final analysis.
Neither Pembrolizumab alone nor Pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis.
The safety of Pembrolizumab as monotherapy has been evaluated in 5,884 patients with advanced melanoma, resected stage III melanoma ( adjuvant therapy ), non-small cell lung cancer ( NSCLC ), classical Hodgkin lymphoma, urothelial carcinoma, or HNSCC across four doses ( 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks ) in clinical studies.
In this patient population, the median observation time was 7.3 months ( range: 1 day to 31 months ) and the most frequent adverse reactions with Pembrolizumab were fatigue ( 32% ), nausea ( 20% ), and diarrhea ( 20% ).
The majority of adverse reactions reported for monotherapy were of grades 1 or 2 severity.
The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.
The safety of KEYTRUDA in combination with chemotherapy has been evaluated in 1,067 patients with NSCLC or HNSCC receiving 200 mg, 2 mg/kg or 10 mg/kg Pembrolizumab every 3 weeks, in clinical studies.
In this patient population, the most frequent adverse reactions were anemia ( 50% ), nausea ( 50% ), fatigue ( 37% ), constipation ( 35% ), diarrhea ( 30% ), neutropenia ( 30% ), decreased appetite ( 28% ) and vomiting ( 25% ).
Incidences of grades 3-5 adverse reactions in patients with NSCLC were 67% for Pembrolizumab combination therapy and 66% for chemotherapy alone and in patients with HNSCC were 85% for Pembrolizumab combination therapy and 84% for chemotherapy plus Cetuximab.
Pembrolizumab is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells.
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth.
Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck.
Two substances that greatly increase the risk of developing head and neck cancer are tobacco and alcohol. It is estimated that there were more than 705,000 new cases of head and neck cancer diagnosed and over 358,000 deaths from the disease worldwide in 2018.
In Europe, it is estimated that there were more than 146,000 newly diagnosed cases of head and neck cancer and around 66,000 deaths from the disease in 2018. ( Xagena )
Source: Merck, 2019