Prescribing Information Medication Guide

Explore the site to learn more from your colleagues about treatment with KEYTRUDA in combination with enfortumab vedotin (EV) in patients with locally advanced or metastatic urothelial cancer (LA/mUC)

Dr Aragon-Ching headshot

Jeanny Aragon-Ching, MD, FACP, FASCO

Fairfax County, VA

Dr Lattanzi headshot

Mike Lattanzi, MD

Austin, TX

Dr Ravilla headshot

Rahul Ravilla, MD, MS

Albany, NY

Dr Bupathi headshot

Manojkumar Bupathi, MD

Littleton, CO

KEYTRUDA + EV: A 1L treatment option for adult patients with LA/mUC, regardless of cisplatin eligibility1

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KEYNOTE-A39
Efficacy and Safety

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KEYTRUDA Dosing
and Administration

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Select NCCN Guideline® Recommendations

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KEYNOTE-A39a: A Pivotal Phase 3 Trial for KEYTRUDA + EV in Patients With LA/mUC1

An open-label, randomized, multicenter study of KEYTRUDA + EV vs gemcitabine + cisplatin or carboplatin in patients with previously untreated LA/mUC (N=886)

clinical practice guidelines icon

At trial initiation, maintenance therapy was not an approved treatment option. Once it was approved, a protocol amendment occurred.

Maintenance therapy was then allowed, at the discretion of the investigator and where available, to be used following completion and/or discontinuation of platinum-containing therapy.1,2

KEYNOTE-A39 is also known as EV-302.2

IV infusion over 30 minutes. When administered on the same day, KEYTRUDA was given approximately 30 minutes after EV.

As assessed by BICR according to RECIST v1.1.

As assessed by BICR.

AUC = area under the curve; BICR = blinded independent central review; CNS = central nervous system; IV = intravenous; PD-L1 = programmed death ligand 1; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1.

Dr Aragon-Ching headshot
When determining a treatment option for my appropriate patients with locally advanced or metastatic urothelial cancer, I consider the patient population studied in the clinical trials. In my practice, I see patients who fit within the indicated patient population studied in KEYNOTE-A39, which helps factor into my decision-making.

Jeanny Aragon-Ching, MD, FACP, FASCO

Fairfax County, VA

Baseline Patient Characteristics

Baseline patient characteristics table

Treatments received in the chemotherapy control arm at first cycle:

  • Of the 234 cisplatin-eligible patients, 220 (94.0%) received cisplatin at first cycle, 8 received carboplatin at first cycle, and 6 were never treated.
  • Of the 210 cisplatin-ineligible patients, 205 (97.6%) received carboplatin at first cycle; 5 were never treated.

3 patients had an unknown primary site of disease origin.

ECOG PS = Eastern Cooperative Oncology Group performance status.

KEYNOTE-A39a: For the 1L Treatment of Adult Patients With LA/mUC2

Superior OS With KEYTRUDA + EV vs gemcitabine + cisplatin or carboplatin

KEYNOTE-A39 OS graph KEYNOTE-A39 OS graph

KEYNOTE-A39 is also known as EV-302.2

Calculated using stratified Cox proportional hazard regression model.

Two-sided P value based on stratified log-rank test.

CI = confidence interval; gem/plat = gemcitabine with cisplatin or carboplatin; HR = hazard ratio; NR = not reached; OS = overall survival.

Dr Lattanzi headshot
When considering treatment options for my appropriate patients with locally advanced or metastatic urothelial cancer, I review the clinical findings for available treatments. I encourage you to review the efficacy and safety results from KEYNOTE-A39 to learn more about KEYTRUDA in combination with enfortumab vedotin.

Mike Lattanzi, MD

Austin, TX

KEYNOTE-A39: Exploratory Analysis of Prespecified Subgroups2,3

OS in Cisplatin-Eligible and Cisplatin-Ineligible Patients3

LIMITATIONS: In KEYNOTE-A39, formal statistical testing for OS based on cisplatin eligibility was not conducted. The study was not powered to detect differences in the treatment effect based on cisplatin eligibility. Therefore, results should be interpreted with caution and no conclusions should be drawn.

KEYNOTE-A39 Kaplan-Meier

From: N Engl J Med; Powles T, Valderrama BP, Gupta S, et al. Supplementary appendix to: Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. Vol 390(10), Page 10. Copyright © 2024 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

KEYNOTE-A39: Exploratory Analysis of Prespecified Subgroups1,3

OS Across Prespecified Subgroups2

LIMITATIONS: In KEYNOTE-A39, formal statistical testing for these subgroups was not conducted. The study was not powered to detect differences in the treatment effect in these subgroups. Therefore, results should be interpreted with caution and no conclusions should be drawn.

OS Across Prespecified Subgroups

From: N Engl J Med; Powles T, Valderrama BP, Gupta S, et al. Supplementary appendix to: Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. Vol 390(10), Page 884. Copyright © 2024 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

KEYNOTE-A39: For the 1L Treatment of Adult Patients With LA or mUC2

Superior PFS With KEYTRUDA + EV vs gemcitabine + cisplatin or carboplatin

Kaplan-Meier Estimates of PFS

PFS Graph PFS Graph

Calculated using stratified Cox proportional hazard regression model.

Two-sided P value based on stratified log-rank test.

Dr Bupathi headshot
I consider KEYTRUDA in combination with enfortumab vedotin as a potential first-line treatment option for appropriate patients with locally advanced or metastatic urothelial cancer, regardless of their cisplatin eligibility, after reviewing the efficacy and safety data from the KEYNOTE-A39 study.

Manojkumar Bupathi, MD

Littleton, CO

KEYNOTE-A39: For the 1L Treatment of Adult Patients With LA or mUC2

Superior ORR With KEYTRUDA + EV vs gemcitabine + cisplatin or carboplatin

68% of patients responded to KEYTRUDA + EV vs 44% with gem/plat

ORR pie graphic
  • ORR results were consistent across all stratified patient subgroups:
    • Cisplatin eligibility
    • PD-L1 expression
    • Presence of liver metastases

Includes only patients with measurable disease at baseline (n=437 for KEYTRUDA + EV, n=441 for gem/plat) and is based on patients with a best overall response as confirmed complete or partial response.

Two-sided P value based on Cochran-Mantel-Haenszel test stratified by PD-L1 expression, cisplatin eligibility, and liver metastases.

CR = complete response; PR = partial response.

Dr Ravilla headshot
I encourage careful review of the results from KEYNOTE-A39, in which KEYTRUDA was evaluated in combination with enfortumab vedotin and demonstrated a statistically significant and superior objective response rate of 68% in the first-line treatment of patients with locally advanced or metastatic urothelial cancer, compared with 44% of patients treated with gemcitabine with cisplatin or carboplatin.

Rahul Ravilla, MD, MS

Albany, NY

KEYNOTE-A39: Selected Safety Profile

The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial cancer. A total of 440 patients received KEYTRUDA 200 mg on day 1 and enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle compared with 433 patients who received gemcitabine on days 1 and 8 and investigator’s choice of cisplatin or carboplatin on day 1 of each 21-day cycle.

Median duration of exposure Median duration of exposure

Fatal adverse reactions
Fatal adverse reactions occurred in 3.9% of patients treated with KEYTRUDA in combination with enfortumab vedotin including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).

Serious adverse reactions
Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).

Permanent discontinuation
Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%).

Dose interruptions
Dose interruptions of KEYTRUDA occurred in 61% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), alanine aminotransferase increased (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%).

Selected Abnormalities Worsened From Baseline Occurring in ⩾ 20% of Patients in KEYNOTE-A39

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available KEYTRUDA (range: 407 to 439 patients).

Graded per NCI CTCAE v4.03.

ILD = interstitial lung disease; COVID-19 = Coronavirus Disease 2019; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.

Adverse Reactions ⩾20% (All Grades) in Patients Treated With KEYTRUDA in Combination With Enfortumab Vedotin in KEYNOTE-A39

Clinically relevant adverse reactions (<20%) include pyrexia (18%), dry skin (17%), vomiting (12%), pneumonitis/ILD (10%), hypothyroidism (10%), blurred vision (6%), infusion site extravasation (2%), and myositis (0.5%).

Graded per NCI CTCAE v4.03.

Includes multiple terms.

KEYNOTE-A39 Dosing Schedule

Dosing schedule

Patients received enfortumab vedotin 1.25 mg/kg as an IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle followed by KEYTRUDA 200 mg as an IV infusion on Day 1 of a 21-day cycle approximately 30 minutes after enfortumab vedotin. Patients were treated until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, KEYTRUDA was continued for up to 2 years.

IV = intravenous; Q3W = every 3 weeks.

References: 1. Powles T, Valderrama BP, Gupta S, et al. Protocol for: Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117 2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117 3. Powles T, Valderrama BP, Gupta S, et al. Supplementary appendix to: Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

Clinical Findings From KEYNOTE-A39

Clinical Findings and Dosing Considerations From KEYNOTE-A39

Explore the efficacy, safety, and dosing schedule for KEYTRUDA + EV from the pivotal study.

Locally Advanced or Metastatic Urothelial Cancer (LA/mUC)
Two Dosing Options for KEYTRUDA

See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.

Dosing and administration KEYTRUDA Dosing and administration KEYTRUDA

DOSE MODIFICATIONS

  • No dose reduction for KEYTRUDA is recommended.
  • In general, withhold KEYTRUDA for severe (grade 3) immune-mediated adverse reactions.
    • In certain cases, treatment may be resumed in patients with complete or partial resolution (grades 0–1) after corticosteroid taper.
    • Presence of liver metastases
  • Permanently discontinue KEYTRUDA for:
    • Life-threatening (grade 4) immune-mediated adverse reactions.
    • Recurrent severe (grade 3) immune-mediated adverse reactions that require systemic immunosuppressive treatment.
    • Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.
CLICK TO DOWNLOAD THE KEYTRUDA DOSING BROCHURE CLICK TO DOWNLOAD THE KEYNOTE-A39 ADVERSE REACTIONS BROCHURE LEARN MORE ABOUT THE EFFICACY AND SAFETY DATA FROM KEYNOTE-A39
KEYTRUDA Dosing and KEYNOTE-A39 Dosing Schedule

KEYTRUDA Dosing

Review the 2 dosing options for KEYTRUDA patients with LA/mUC.

NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN®)
Updated select recommendations from the NCCN Guidelines® for Bladder Cancer1

Pembrolizumab (KEYTRUDA) + enfortumab vedotin

THE ONLY NCCN CATEGORY 1, PREFERRED, 1L systemic option recommended for patients with locally advanced or metastatic urothelial carcinoma1

Platinum eligibility no longer determines the preferred 1L locally advanced or metastatic urothelial carcinoma treatment recommendation by the NCCN.

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.

FDA-Approved Indication: KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with LA/mUC.

Category 1 = Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.1

1L = first line; FDA = US Food and Drug Administration.

LEARN MORE ABOUT THE EFFICACY AND SAFETY DATA FOR KEYTRUDA + EV IN PATIENTS WITH LA/mUC

Reference: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed April 1, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org.

NCCN Clinical Practice Guidelines in Oncology

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Discover select recommendations from the NCCN Guidelines® for bladder cancer.

INDICATION

KEYTRUDA® (pembrolizumab), in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced (LA) or metastatic urothelial cancer (mUC).

SELECTED SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

  • KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
  • Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
  • Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

  • KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Immune-Mediated Colitis

  • KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

  • KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

  • KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

  • KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

  • KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
  • Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

  • Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

  • KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

  • KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

  • The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Infusion-Related Reactions

  • KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

  • Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/ PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

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 an anti–PD-1/PD-L1 treatment 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-A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (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 last dose.

Geriatric Use

  • Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older.

Before prescribing KEYTRUDA, please read the additional Selected Safety Information on the previous pages, and the accompanying Prescribing Information. The Medication Guide also is available.

1L = first line; ILD = interstitial lung disease.

Reference: 1. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117