• For Oncologists
  • For Pathologists
 
Biomarker Testing
and KEYTRUDA

INFORMATION ON PD-L1 EXPRESSION AND TESTING
FOR ONCOLOGISTS

TEST
Test Patients for PD-L1 Expression at Diagnosis of Gastric or GEJ Cancer
Test all patients for PD-L1 expression at diagnosis of gastric or GEJ cancer
EVALUATE
Evaluate PD-L1 Expression to Help Inform Treatment Options
Evaluate PD-L1 expression to inform treatment options
TREAT
Treat Appropriate Patients With KEYTRUDA® (pembrolizumab) for Advanced Gastric or GEJ Cancer
Treat appropriate patients with KEYTRUDA

GEJ = gastroesophageal junction; PD-L1 = programmed death ligand 1.


START INFORMED: TEST
ALL PATIENTS FOR PD-L1 EXPRESSION AT DIAGNOSIS OF GASTRIC OR GEJ CANCER

  • PD-L1 is an immune-related biomarker.
  • Evaluating PD-L1 expression level at diagnosis of gastric or GEJ cancer contributes to a better understanding of your patient’s tumor and helps inform treatment decisions.
Request PD-L1 Testing for All Patients at Diagnosis of Gastric or GEJ Cancer
NCCN Guidelines recommend PD-L1 testing in metastatic gastric or
gastroesophageal junction adenocarcinoma.1,2

National Comprehensive Cancer Network® (NCCN®) makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.


PD-L1 EXPRESSION LEVEL HELPS INFORM TREATMENT DECISIONS WITH KEYTRUDA

Identify PD-L1–positive patients with CPS3,a
PD-L1 expression level CPS <1 CPS ≥1
PD-L1 expression status No expression Expression

aPD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit from Agilent Technologies.

CPS = combined positive score; IHC = immunohistochemistry.

Select patients for treatment of metastatic gastric cancer with KEYTRUDA as a single agent based on the presence of positive PD-L1 expression. If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining a tumor biopsy for PD-L1 testing.


PREVALENCE OF PD‑L1 EXPRESSION BASED ON PATIENTS WITH GASTRIC OR GEJ CANCER SCREENED FOR PD‑L1 IN A CLINICAL TRIAL FOR KEYTRUDA

PD-L1 expression (CPS ≥1)
Clinical Trials for KEYTRUDA® (pembrolizumab) Screened for PD-L1 in Patients With Gastric or GEJ Cancer

55% (n=143/259) of patients with advanced gastric or GEJ cancer had PD-L1 expression in the KEYNOTE-059 study.

  • Patients had MSS tumor status or undetermined MSI or MMR status.

MSS = microsatellite stable; MSI = microsatellite instability; MMR = mismatch repair.

Request PD-L1 Testing for All Patients at Diagnosis of Gastric or GEJ Cancer
Request PD-L1 testing for all patients at diagnosis of gastric or GEJ cancer to
help identify patients most likely to benefit from treatment with KEYTRUDA.

INFORMATION ON PD-L1 EXPRESSION AND TESTING
FOR PATHOLOGISTS

TEST
For Pathologists: Test Patients for PD-L1 Expression at Diagnosis of Gastric or GEJ Cancer
Test all patients for PD-L1 expression at diagnosis of gastric or GEJ cancer
IDENTIFY
Identify Combined Positive Score (CPS) and PD-L1 Expression Level in Gastric or GEJ Cancer
Identify CPS and PD-L1 expression level in gastric or GEJ cancer
INFORM
Help Inform Treatment Decisions With a Report That Includes CPS and Expression Levels
Inform treatment decisions with a report that includes CPS and expression level

GEJ = gastroesophageal junction; PD-L1 = programmed death ligand 1; CPS = combined positive score.

Request PD-L1 Testing for All Patients at Diagnosis of Gastric or GEJ Cancer
NCCN Guidelines recommend PD-L1 testing in metastatic gastric or gastroesophageal junction adenocarcinoma.1,2

National Comprehensive Cancer Network® (NCCN®) makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.


UNDERSTANDING THE ROLE OF PD-L1 EXPRESSION IN ADVANCED GASTRIC OR GEJ CANCER

PD-L1 expression is measured differently depending on the type of cancer3

  • Assessment of PD-L1 in advanced gastric or GEJ cancer is determined by the CPS.
  • Assessment of PD-L1 in mNSCLC is determined by the TPS.
Gastric or GEJ Cancer: CPS3
Evaluate the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells.3
PD-L1 Expression in Metastatic NSCLC: Determined by Tumor Proportion Score (TPS)CPS =iconx 100
NSCLC: TPS3,4
Evaluate the percentage of viable tumor cells showing partial or complete membrane staining at any intensity.3
PD-L1 Expression in Advanced Gastric or GEJ Cancer: Determined by Combined Positive Score (CPS)TPS =iconx 100

mNSCLC = metastatic NSCLC; NSCLC = non–small cell lung cancer; TPS = tumor proportion score.


PD-L1 EXPRESSION LEVEL HELPS INFORM TREATMENT DECISIONS WITH KEYTRUDA

Identify PD-L1–positive patients with CPS3,a
PD-L1 expression level CPS <1 CPS ≥1
PD-L1 expression status No expression Expression
Specimens should be considered to have PD-L1 expression if CPS ≥1

aPD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit from Agilent Technologies.

IHC = immunohistochemistry.

  • If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining a tumor biopsy for PD-L1 testing.

The PD-L1 IHC 22C3 pharmDx is a qualitative immunohistochemical assay that was used in both the advanced gastric or GEJ cancer and metastatic NSCLC clinical trials with KEYTRUDA3

  • Intended for use in the detection of PD-L1 protein in formalin-fixed, paraffin-embedded specimens.
  • Requires a minimum of 100 viable tumor cells in the PD-L1–stained slide for the specimen to be considered adequate for PD-L1 evaluation.

PREVALENCE OF PD-L1 EXPRESSION BASED ON PATIENTS WITH GASTRIC OR GEJ CANCER SCREENED FOR PD-L1 IN A CLINICAL TRIAL FOR KEYTRUDA

PD-L1 expression (CPS ≥1)
Clinical Trials for KEYTRUDA® (pembrolizumab) Screened for PD-L1 in Patients With Gastric or GEJ Cancer

55% (n=143/259) of patients with advanced gastric or GEJ cancer had PD-L1 expression in the KEYNOTE-059 study.

  • Patients had MSS tumor status or undetermined MSI or MMR status.

MSS = microsatellite stable; MSI = microsatellite instability; MMR = mismatch repair.

Interpreting CPS and TPS With the Dako Instructions for Use and the Dako Interpretation Manual
To learn more about scoring and interpreting CPS and TPS, please refer
to the Dako Instructions for Use and the Dako Interpretation Manual.

ALL INDICATIONS

  • ADVANCED MELANOMA:KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
  • ADJUVANT THERAPY:KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.
  • FIRST-LINE COMBINATION THERAPY IN NONSQUAMOUS mNSCLC:KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non‒small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
  • FIRST-LINE COMBINATION THERAPY IN SQUAMOUS mNSCLC:KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein‑bound, is indicated for the first‑line treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC)NSCLC.
  • FIRST-LINE MONOTHERAPY IN NONSQUAMOUS AND SQUAMOUS ADVANCED NSCLC:KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
  • SECOND-LINE OR GREATER MONOTHERAPY IN NONSQUAMOUS AND SQUAMOUS mNSCLC:KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
  • RECURRENT OR METASTATIC HEAD AND NECK SQUAMOUS CELL CARCINOMA ON OR AFTER PLATINUM-CONTAINING CHEMOTHERAPY:KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • REFRACTORY OR RELAPSED cHL:KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • REFRACTORY OR RELAPSED PMBCL:KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
  • FIRST-LINE MONOTHERAPY—CISPLATIN (PD-L1 EXPRESSION [COMBINED POSITIVE SCORE (CPS) ≥10]) AND PLATINUM CHEMOTHERAPY INELIGIBLE:KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • SECOND-LINE MONOTHERAPY—POST–PLATINUM FAILURE:KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
  • ADVANCED MSI-H/dMMR CANCERS:KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
    • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
    • colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
    This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.
  • ADVANCED GASTRIC OR GEJ CANCER:KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • ADVANCED CERVICAL CANCER:KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • HEPATOCELLULAR CARCINOMA:KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • ADVANCED MERKEL CELL CARCINOMA:KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • ADVANCED RENAL CELL CARCINOMA:KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
EGFR = epidermal growth factor receptor; PD-L1 = programmed death ligand 1; HER2/neu = human epidermal growth factor receptor 2. mNSCLC = metastatic NSCLC;
EGFR = epidermal growth factor receptor;
ALK = anaplastic lymphoma kinase;
PD-L1 = programmed death ligand 1.
PD-L1 = programmed death ligand 1;
HER2/neu = human epidermal growth factor receptor 2.
SELECTED SAFETY INFORMATION for KEYTRUDA® (pembrolizumab)
  • Immune-Mediated Pneumonitis
    • KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%).
    • Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
  • Immune-Mediated Colitis
    • KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
  • Immune-Mediated Hepatitis, or Hepatotoxicity (in Combination With Axitinib)

    Immune-Mediated Hepatitis

    • KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

    Hepatotoxicity (in Combination With Axitinib)

    • KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. Grades 3 and 4 increased ALT and AST were seen in 20% and 13% of patients, respectively. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used in monotherapy. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.
  • Immune-Mediated Endocrinopathies
    • KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 15% (28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.
    • Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.
  • Immune-Mediated Nephritis and Renal Dysfunction
    • KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.
  • Immune-Mediated Skin Reactions
    • Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
  • Other Immune-Mediated Adverse Reactions
    • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
    • The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.
    • Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.
  • Infusion-Related Reactions
    • KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.
  • Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
    • Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions.
    • In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.
  • Increased Mortality in Patients With Multiple Myeloma
    • In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.
  • Embryofetal Toxicity
    • Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.
  • Adverse Reactions
    • In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
    • In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%).
    • In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).
    • In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein‑bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.
    • In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).
    • In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).
    • In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.
    • In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
    • In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).
    • In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).
    • In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).
    • Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
    • In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).
    • Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).
    • Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).
    • In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients; the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).
  • Lactation
    • Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.
  • Pediatric Use
    • There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with various cancers, including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%), and hyponatremia (18%).
ALT = alanine aminotransferase; AST = aspartate aminotransferase; cHL = classical Hodgkin lymphoma; HCC = hepatocellular carcinoma; HNSCC = head and neck squamous cell carcinoma; MCC = Merkel cell carcinoma; NSCLC = non–small cell lung cancer; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PMBCL = primary mediastinal large B-cell lymphoma; RCC = renal cell carcinoma. Before prescribing KEYTRUDA, please read the accompanying Prescribing Information. The Medication Guide also is available.

Reference:
  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.5.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed October 19, 2017. To view the most recent and complete version of the guidelines, go online to NCCN.org.
  2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Esophageal and Esophagogastric Junction Cancers V.4.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed October 30, 2017. To view the most recent and complete version of the guidelines, go online to NCCN.org.
  3. Agilent Technologies, Inc. Instructions for Use: PD‑L1 IHC 22C3 pharmDx.
References:
  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.5.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed October 19, 2017. To view the most recent and complete version of the guidelines, go online to NCCN.org.
  2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Esophageal and Esophagogastric Junction Cancers V.4.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed October 30, 2017. To view the most recent and complete version of the guidelines, go online to NCCN.org.
  3. Agilent Technologies, Inc. Instructions for Use: PD‑L1 IHC 22C3 pharmDx.
  4. Agilent Technologies, Inc. PD‑L1 IHC 22C3 pharmDx Interpretation Manual.


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