TPS is calculated by dividing the number of tumour cells showing partial or complete PD-L1 membrane staining by the total number of all viable tumour cells present in the sample and multiplying the quotient by 100%.
CPS scoring – Definition of positive immune cells in contrast to positive tumour cells:
Positivity of immune cells:
Any membrane and/or cytoplasmic staining (at any intensity) of lymphocytes and macrophages (mononuclear inflammatory cells ; MICs) within tumour nests and/or adjacent supporting stroma is considered PD-L1 staining and should be included in scoring. Only MICs directly associated with the response against the tumour are scored.
Positivity of tumour cells:
Any convincing partial or complete linear membrane staining (at any intensity) of viable tumour cells that is perceived as distinct from cytoplasmic staining is considered PD-L1 staining and should be included in scoring.
Tumour cell
Tumour-associated immune cells
PD-L1–positive cell
Combined Positive Score (CPS)1
CPS =
of PD-L1 positive cells
Total # of viable tumour cells
x 100
CPS is reported as a numeric value.
CPS is calculated by dividing the number of PD-L1–positive tumour cells and tumour-associated immune cells
included:
lymphocytes
macrophages
excluded:
neutrophils
eosinophils
plasma cells
by the total number of all viable tumour cells in the sample and multiplying the quotient by 100. The maximum score is defined as CPS 100.
CPS scoring – Definition of tumour-associated immune cells:
Adjacent MICs are defined as being within the same 20x field as the tumour. However, MICs that are NOT directly associated with the response to the tumour should be excluded.
This is an example of an NSCLC specimen from the Agilent NSCLC manual for the PD-L1 IHC 22C3 pharmDx test, and is not meant to be representative of all patients and tissue stains. Furthermore, these images should not be used as a means to diagnose and prescribe KEYTRUDA®.
Please consult the KEYTRUDA® product monograph when determining whether PD-L1 testing is required for a particular KEYTRUDA® NSCLC indication.
This is an example of a TNBC specimen from the Agilent TNBC manual for the PD-L1 IHC 22C3 pharmDx test, and is not meant to be representative of all patients and tissue stains. Furthermore, these images should not be used as a means to diagnose and prescribe KEYTRUDA®.
Please consult the KEYTRUDA® product monograph when determining whether PD-L1 testing is required for a particular KEYTRUDA® TNBC indication.
KEYTRUDA® has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. Patients should be advised of the nature of the authorization. KEYTRUDA® is indicated for the treatment of:
cHL (classical Hodgkin Lymphoma)
As monotherapy, for the treatment of adult and pediatric patients with refractory or relapsed cHL who have failed ASCT (autologous stem cell transplant), or who are not candidates for multi-agent salvage chemotherapy and ASCT; an improvement in overall survival has not yet been established
PMBCL (primary mediastinal B-cell lymphoma)
As monotherapy, for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more lines of therapy; an improvement in survival or disease-related symptoms has not been established
UC (urothelial carcinoma)
As monotherapy, for the treatment of adult patients with locally advanced unresectable or metastatic UC who are not eligible for any platinum-containing chemotherapy
For the treatment of adult patients with BCG (Bacillus Calmette-Guerin) unresponsive, high-risk, NMIBC (non-muscle invasive bladder cancer) with CIS (carcinoma in-situ) with or without papillary tumours who are ineligible for or have elected not to undergo cystectomy
KEYTRUDA® has been issued marketing authorization without conditions for:
HNSCC (head and neck squamous cell carcinoma)
For the first-line treatment of metastatic or unresectable recurrent HNSCC as monotherapy, in adult patients whose tumours have PD-L1 expression (CPS ≥ 1) as determined by a validated test.
For the first-line treatment of metastatic or unresectable recurrent HNSCC in combination with platinum and FU (fluorouracil) chemotherapy, in adult patients.
TNBC (triple-negative breast cancer)
In combination with chemotherapy, for the treatment of adult patients with locally recurrent unresectable or metastatic TNBC, who have not received prior chemotherapy for metastatic disease and whose tumours express PD-L1 (CPS ≥ 10) as determined by a validated test. Consult the description of the study for the chemotherapy (paclitaxel, nab-paclitaxel or gemcitabine/carboplatin) and dosing regimens used. Marketing authorization with conditions is based on PFS.
For the treatment of adult patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery. Consult the description of the study for the chemotherapy regimen (carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide) used.
NSCLC (non-small cell lung carcinoma)
For the first-line treatment, as monotherapy, of adult patients with metastatic NSCLC or stage III disease where patients are not candidates for surgical resection or definitive chemoradiation, expressing PD-L1 (TPS ≥ 1%) as determined by a validated test, with no EGFR or ALK genomic tumour aberrations. A positive association was observed between the level of PD-L1 expression and the magnitude of the treatment benefit.
In combination with pemetrexed and platinum chemotherapy, for the treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumour aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC.
In combination with carboplatin and either paclitaxel or nab-paclitaxel, for the treatment of adult patients with metastatic squamous NSCLC with no prior systemic chemotherapy treatment for metastatic NSCLC.
As monotherapy, for the treatment of adult patients with metastatic NSCLC whose tumours express PD-L1 (TPS ≥ 1%) as determined by a validated test and who have disease progression on or after platinum-containing chemotherapy; patients with EGFR or ALK genomic tumour aberrations should have received an authorized therapy for these aberrations prior to receiving KEYTRUDA®.
KEYTRUDA® as monotherapy is indicated for the adjuvant treatment of adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC who have undergone complete resection and platinum-based chemotherapy.
UC (urothelial carcinoma)
For the treatment of adult patients with locally advanced or metastatic UC as monotherapy who have disease progression during or following platinum-containing chemotherapy or within 12 months of completing neoadjuvant or adjuvant platinum-containing chemotherapy.
Cervical cancer
In combination with chemotherapy with or without bevacizumab, for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumours express PD-L1 (CPS ≥ 1) as determined by a validated test.
Melanoma
For the treatment of adult patients with unresectable or metastatic melanoma who have not received prior treatment with ipilimumab; subjects with BRAF V600 mutant melanoma may have received prior BRAF inhibitor therapy.
For the treatment of adult patients with unresectable or metastatic melanoma and disease progression following ipilimumab therapy and, if BRAF V600 mutation positive, following a BRAF or MEK inhibitor.
For the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB or IIC melanoma following complete resection.
For the adjuvant treatment of adult patients with Stage III melanoma with lymph node involvement who have undergone complete resection.
RCC (renal cell carcinoma)
In combination with axitinib, for the treatment of adult patients with advanced or metastatic RCC with no prior systemic therapy for metastatic RCC.
In combination with lenvatinib, for the treatment of adult patients with advanced (not amenable to curative surgery or radiation) or metastatic RCC with no prior systemic therapy for metastatic RCC.
As monotherapy, for the adjuvant treatment of adult patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
CRC (colorectal cancer)
As monotherapy, for the first-line treatment of adult patients with metastatic MSI-H (microsatellite instability-high cancer) or dMMR (mismatch repair deficient) CRC as determined by a validated test.
Endometrial carcinoma
In combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior platinum-based systemic therapy, and are not candidates for curative surgery or radiation.
Esophageal Cancer
In combination with platinum and fluoropyrimidine based chemotherapy, for the first-line treatment of adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus.
Gastric Cancer or Gastroesophageal junction (GEJ) Adenocarcinoma
In combination with trastuzumab, fluoropyrimidine- and platinum- containing chemotherapy, for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumours express PD-L1 (CPS ≥ 1) as determined by a validated test.
in combination with fluoropyrimidine- and platinum-containing chemotherapy,for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.
MSI-H (microsatellite instability-high cancer)
As monotherapy, for the treatment of adult patients with unresectable or metastatic MSI-H or dMMR (as determined by a validated test) for:
Colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; or
Endometrial cancer that has progressed following prior therapy and who have no satisfactory alternative treatment options
Biliary Tract Cancer
For the treatment of adult patients with locally advanced unresectable or metastatic biliary tract carcinoma (BTC), in combination with gemcitabine-based chemotherapy
Clinical use:
Pediatrics
The safety and efficacy of KEYTRUDA® has not been established for pediatric patients with conditions other than relapsed or refractory cHL, relapsed or refractory PMBCL, or melanoma (Stage IIB or IIC).
Geriatrics (≥65 years of age)
No overall differences in safety or efficacy were reported between elderly patients (65 years and over) and younger patients (less than 65 years) for pembrolizumab monotherapy. No overall differences in efficacy were reported between elderly patients (65 years and over) and younger patients (less than 65 years) for pembrolizumab combination therapy. Limited safety and efficacy information is available for Keytruda in cHL ≥ 65 years of age (n=20).
Relevant warnings and precautions:
Immune-mediated adverse reactions, including severe and fatal cases:
Pneumonitis
Colitis
Hepatitis
Nephritis and renal dysfunction
Endocrinopathies including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus and thyroid disorders
Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis
Other immune-mediated adverse events including uveitis, arthritis, myositis, encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis, vasculitis, Guillain-Barré syndrome, hemolytic anemia, pancreatitis, myelitis, myocarditis, hypoparathyroidism, sclerosing cholangitis, aplastic anemia, and gastritis
Solid organ transplant rejection
Use in combination with axitinib for RCC
Use with thalidomide analogue and dexamethasone in multiple myeloma
Allogeneic stem cell transplant after and before treatment
Severe infusion-related reactions
Teratogenic toxicity
Women should avoid pregnancy and breastfeeding during treatment and for at least 4 months after it
Patients with hepatic or renal impairment
Driving and operating machinery
Monitoring requirements
Pediatrics
Geriatrics
For more information:
Please consult the Product Monograph at www.merck.ca/static/pdf/KEYTRUDA-PM_E.pdf for important information regarding adverse reactions, drug interactions, and dosing information which have not been discussed in this piece. The Product Monograph is also available by calling us at 1-800-567-2594 or by email at medinfocanada@merck.com.
