Prescribing Information Medication Guide

KEYTRUDA Is the First and Only FDA-Approved Anti–PD-1 Indicated as Part of a Complete Regimen for High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)1-7

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Cynthia Ma, MD

Professor of Medicine
Washington University
St. Louis, MO

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Mara Hofherr, PharmD

Oncology Clinical Pharmacist
Delbert Day Cancer Institute
St. Louis, MO

Explore this site to learn more from your colleagues about treatment with KEYTRUDA in combination with chemotherapy in the neoadjuvant setting and continued as a single agent in the adjuvant setting in appropriate patients with high-risk early-stage TNBC.

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KEYNOTE-522
Efficacy and
Safety

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KEYNOTE-522
Hypothetical
Patients

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KEYTRUDA
Dosing and
Administration

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Select NCCN
Guideline®
Recommendations

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High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)

KEYNOTE-522: Study Design, Efficacy, and Safety Data

KEYNOTE-522: Inclusion & Exclusion Criteria

Tumor Size and Nodal Involvement

  • >1 cm but ≤2 cm with nodal involvement (N+)
  • >2 cm regardless of nodal involvement (N+ or N-)

Key Inclusion Criteria

  • Newly diagnosed, previously untreated high-risk early-stage TNBC
  • Enrollment regardless of tumor PD-L1 expression
  • Tumor size >1 cm but ≤2 cm in diameter with nodal involvement or tumor size >2 cm in diameter regardless of nodal involvement

Key Exclusion Criteria

  • Active autoimmune disease that required systemic therapy within 2 years of treatment
  • A medical condition that required immunosuppression

Patients were included in the trial regardless of tumor PD-L1 expression.

Appropriate patients with tumors >2 cm, regardless of nodal involvement, were eligible to receive a regimen including KEYTRUDA in KEYNOTE-522.

N+ = nodal positive; N- = nodal negative; PD-L1 = programmed death ligand 1.

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KEYTRUDA is an anti–PD-1 indicated as part of a complete regimen for patients with high-risk early-stage TNBC. Tumor PD-L1 expression is not required for these patients to receive this regimen. If eligible, KEYTRUDA is given in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery.

Mara Hofherr, PharmD

Oncology Clinical Pharmacist
Delbert Day Cancer Institute
St. Louis, MO

KEYNOTE-522: Study Design

1,174 Patients With Newly Diagnosed, Previously Untreated High-Risk Early-Stage TNBC Were Evaluated in a Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial

Keynote-522 Study design

Main Efficacy Outcomes

  • Pathological complete response (pCR): Defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery
  • Event-free survival (EFS): Defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause

Additional Efficacy Outcome

  • Overall survival (OS): Defined as the time from randomization to death from any cause1

Randomization was stratified by nodal status (positive vs negative), tumor size (T1/T2 vs T3/T4), and choice of carboplatin (Q3W vs weekly).

The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment.

All study medications were administered intravenously.

Q3W = every 3 weeks; AUC = area under the curve.

Characteristics of Patients From KEYNOTE-522

Characteristics of patients table

ECOG PS = Eastern Cooperative Oncology Group performance status.

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I was pleased to see that in KEYNOTE-522, patients with high-risk early-stage TNBC who had tumors greater than 2 cm, regardless of nodal involvement, were eligible for participation.

Cynthia Ma, MD

Professor of Medicine
Washington University
St. Louis, MO

KEYNOTE-522: Pathological Complete Response (pCR) Rate

pCR With KEYTRUDA + Chemotherapya vs Placebo + Chemotherapya in the Neoadjuvant Setting

pCR rate table
  • pCR was defined as the absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery

Carboplatin/paclitaxel followed by AC or EC.

Based on the entire intention-to-treat population (N=1,174) patients.

Based on a pre-specified pCR interim analysis in patients (n=602), the pCR rate difference was statistically significant (P=0.00055 compared to a significance level of 0.003).

Based on Miettinen and Numinen method stratified by nodal status, tumor size, and choice of carboplatin.

Superior EFS With KEYTRUDA + Chemotherapya/KEYTRUDA vs Placebo + Chemotherapya/Placebo at IA42

Kaplan-Meier Estimates of EFSb

EFS data table
  • 37% reduction in the risk of an EFS eventb with KEYTRUDA + chemotherapya/KEYTRUDA vs placebo + chemotherapya/placebo (HRc=0.63; 95% CI, 0.48–0.82); Pd,e=0.00031
  • The number of patients with an event was 123/784 (16%) with KEYTRUDA + chemotherapya/KEYTRUDA vs 93/390 (24%) with placebo + chemotherapya/placebo

In combination with chemotherapya as neoadjuvant therapy, then as monotherapy adjuvant treatment,

KEYTRUDA is the only FDA-approved, anti–PD-1 to demonstrate a statistically significant improvement in EFS in high-risk early-stage TNBC vs placebo + chemotherapya/placebo.

Carboplatin/paclitaxel followed by AC or EC.

EFS was defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause.

HR based on stratified Cox regression model.

P value based on a pre-specified EFS interim analysis (compared to a significance level of 0.0052).

P value based on log-rank test stratified by nodal status, tumor size, and choice of carboplatin.

IA4 = fourth interim analysis; FDA = US Food and Drug Administration.

Dr headshot
The data from KEYNOTE-522 help inform treatment decisions for my appropriate patients with high-risk early-stage TNBC. In the study, KEYTRUDA + chemotherapy in the neoadjuvant setting, followed by KEYTRUDA as a single agent in the adjuvant setting exhibited superior results for EFS vs placebo + chemotherapy in the neoadjuvant setting, followed by placebo alone in the adjuvant setting.

Cynthia Ma, MD

Professor of Medicine
Washington University
St. Louis, MO

Superior Overall Survival (OS) With KEYTRUDA + Chemotherapya/KEYTRUDA vs Placebo + Chemotherapya/Placebo at IA7

Kaplan-Meier Estimates of OS

OS data table
  • The number of patients with an event was 115/784 (15%) with KEYTRUDA + chemotherapya/KEYTRUDA vs 85/390 (22%) with placebo + chemotherapya/placebo
  • 34% reduction in the risk of death with KEYTRUDA + chemotherapya/KEYTRUDA vs placebo + chemotherapya/placebo (HRb=0.66; 95% CI, 0.50–0.87); Pc,d=0.00150

In combination with chemotherapya as neoadjuvant therapy, then as monotherapy adjuvant treatment,

KEYTRUDA is the only FDA-approved, anti–PD-1 to demonstrate a statistically significant improvement in overall survival in high-risk early-stage TNBC vs placebo + chemotherapya/placebo.

Carboplatin/paclitaxel followed by AC or EC.

Based on stratified Cox regression model.

Based on log-rank test stratified by nodal status, tumor size, and choice of carboplatin.

Based on pre-specified OS interim analysis (compared to a significance level of 0.0050).

IA7 = seventh interim analysis.

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When selecting treatment options for appropriate patients with high-risk early-stage TNBC, I consider overall survival data. In KEYNOTE-522, KEYTRUDA in combination with chemotherapy in the neoadjuvant setting and continued as a single agent in the adjuvant setting demonstrated a statistically significant reduction in the risk of death vs placebo in combination with chemotherapy in the neoadjuvant setting, followed by placebo alone in the adjuvant setting.

Cynthia Ma, MD

Professor of Medicine
Washington University
St. Louis, MO

KEYNOTE-522: Overall Survival (OS) in Select Subgroups at IA73

LIMITATIONS: KEYNOTE-522 was not powered to detect differences in the treatment effect in these subgroups, and no statistical testing was planned for this analysis; therefore, no conclusions can be drawn. Results from exploratory subgroup analyses should be interpreted with caution because of the modest patient numbers and potential imbalances in baseline characteristics within the subgroups.

OS data in subgroups table

Carboplatin/paclitaxel followed by AC or EC.

CPS = combined positive score.

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The results from KEYNOTE-522 support the use of KEYTRUDA in combination with chemotherapy in the neoadjuvant setting, and then continuing KEYTRUDA as a single agent in the adjuvant setting after surgery for appropriate patients with high-risk early-stage TNBC.

Mara Hofherr, PharmD

Oncology Clinical Pharmacist
Delbert Day Cancer Institute
St. Louis, MO

KEYNOTE-522: Selected Safety Profile

The Safety Investigation of KEYNOTE-522 Included 778 Patients Who Received at Least 1 Dose of KEYTRUDA in Combination With Neoadjuvant Chemotherapya Followed by KEYTRUDA as Adjuvant Treatment After Surgery

The median duration of exposure to KEYTRUDA 200 mg Q3W was 13.3 months (range: 1 day–21.9 months).

Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of:

  • adrenal crisis
  • autoimmune encephalitis
  • hepatitis
  • pneumonia
  • pneumonitis
  • pulmonary embolism
  • sepsis in association with multiple organ dysfunction syndrome and myocardial infarction

Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA. Serious adverse reactions in ≥2% of patients who received KEYTRUDA included:

  • febrile neutropenia (15%)
  • pyrexia (3.7%)
  • anemia (2.6%)
  • neutropenia (2.2%)

Carboplatin/paclitaxel followed by AC or EC.

KEYTRUDA Was Discontinued for Adverse Reactions in 20% of Patients

The most common adverse reactions (≥1%) resulting in permanent discontinuation of KEYTRUDA were:

Adverse reactions table

Adverse Reactions Leading to the Interruption of KEYTRUDA Occurred in 57% of Patients

The most common adverse reactions (≥2%) leading to interruption of KEYTRUDA were:

Adverse reactions table

Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA

Adverse reactions bar graph

For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. Please see additional monitoring requirements in the Prescribing Information.

Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide.

Graded per NCI CTCAE v4.0.

Includes asthenia, fatigue.

Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, incision-site rash, injection-site rash, rash, rash erythematous, rash follicular, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash rubelliform, skin exfoliation, skin toxicity, toxic skin eruption, urticaria, vasculitic rash, viral rash.

Includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy.

Includes aphthous ulcer, cheilitis, lip pain, lip ulceration, mouth ulceration, mucosal inflammation, oral mucosal eruption, oral pain, stomatitis, tongue blistering, tongue ulceration.

Includes cough, productive cough, upper-airway cough syndrome.

Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness.

NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.

References: 1. Schmid P, Cortes J, Dent R, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer. N Engl J Med. Published online September 15, 2024. doi:10.1056/NEJMoa2409932 2. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556–567. doi:10.1056/NEJMoa2112651 3. Schmid P, Cortes J, Dent R, et al. Neoadjuvant pembrolizumab or placebo + chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage triple-negative breast cancer: overall survival results from the phase 3 KEYNOTE-522 study. Presented at: European Society for Medical Oncology (ESMO) Congress; September 13–17, 2024; Barcelona, Spain.

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Clinical Findings From KEYNOTE-522

Explore data on the efficacy and safety of KEYTRUDA in combination with chemotherapy in the neoadjuvant setting and continued as a single agent in the adjuvant setting.

Hypothetical Patients Based on KEYNOTE-522: Regina and Lauren

Patients With High-Risk Early-Stage TNBC May Be Eligible for a Regimen Including KEYTRUDA Regardless of Tumor PD-L1 Expression

Hypothetical patient Regina headshot + Hypothetical patient Lauren headshot + Hypothetical patient Anita headshot Hypothetical patient Regina headshot + Hypothetical patient Lauren headshot + Hypothetical patient Anita headshot

Consider all of your eligible patients for the KEYNOTE-522 regimen.

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There is value in consulting with a medical oncologist before surgery for patients with high-risk early-stage TNBC. Patients may be eligible for a treatment plan that includes neoadjuvant therapy with KEYTRUDA in combination with chemotherapy, followed by surgery, then KEYTRUDA as a single agent as adjuvant therapy after surgery.

Mara Hofherr, PharmD

Oncology Clinical Pharmacist
Delbert Day Cancer Institute
St. Louis, MO

REVIEW THE DATA FROM KEYNOTE-522
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Patient Profiles Based on KEYNOTE-522

Review the profiles of hypothetical patients who may be appropriate for treatment with a neoadjuvant/adjuvant regimen that includes KEYTRUDA.

Two Dosing Options Available for Your Appropriate Patients With TNBC

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

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Administered, after dilution, as an intravenous infusion over 30 minutes

Neoadjuvant Treatment (Followed by Adjuvant Treatment)

KEYTRUDA given in combination with chemotherapy for 24 weeks or until disease progression or unacceptable toxicity.

Every 3 week calendar icon

8 doses of 200 mg of
KEYTRUDA

or

Every 6 week calendar icon

4 doses of 400 mg of
KEYTRUDA

Adjuvant Treatment (Following Neoadjuvant Treatment and Surgery)

KEYTRUDA as a single agent for up to 27 weeks or until disease recurrence or unacceptable toxicity.

Every 3 week calendar icon

9 doses of 200 mg of
KEYTRUDA

or

Every 6 week calendar icon

5 doses of 400 mg of
KEYTRUDA

Additional Dosing Considerations

  • When administering KEYTRUDA in combination with chemotherapy for high-risk early-stage TNBC, administer KEYTRUDA prior to the other agents when given on the same day
  • Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate
  • Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA
LEARN MORE ABOUT THE EFFICACY AND SAFETY DATA FROM KEYNOTE-522
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KEYTRUDA Dosing Recommendations

Review the 2 dosing options for KEYTRUDA in patients with high-risk early-stage TNBC.

NCCN Guidelines

Pembrolizumab (KEYTRUDA) is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

Pembrolizumab (KEYTRUDA):

NCCN CATEGORY 1 PREFERRED

Treatment Option for Certain Patients With High-Risk Early-Stage (Stage II-III) TNBC for Neoadjuvant Followed by Adjuvant Therapy1

National
Comprehensive Cancer
Network® (NCCN®)

Preoperative pembrolizumab (KEYTRUDA) in combination with carboplatin + paclitaxel, followed by preoperative pembrolizumab in combination with cyclophosphamide + doxorubicin or epirubicin, followed by adjuvant pembrolizumab1

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

According to NCCN, preferred intervention = Intervention that is based on superior efficacy, safety, and evidence; and, when appropriate, affordability.1

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.

Reference: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.4.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed April 17, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org.

DISCOVER THE EFFICACY AND SAFETY DATA FROM KEYNOTE-522
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Discover a select recommendation from the NCCN Guidelines® for breast cancer.

INDICATION

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

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. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. 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-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

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.

Before prescribing KEYTRUDA, please read the accompanying Prescribing Information. The Medication Guide also is available.

PD-1 = programmed death receptor-1; ALT = alanine aminotransferase; AST = aspartate aminotransferase.

References: 1. Opdivo [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2024. 2. Libtayo [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; 2024. 3. Jemperli [package insert]. Philadelphia, PA: GlaxoSmithKline LLC; 2024. 4. Zynyz [package insert]. Wilmington DE: Incyte Corporation; 2024. 5. Loqtorzi [package insert]. Redwood City, CA: Coherus BioSciences; 2024. 6. Tevimbra Prescribing Information. San Mateo, CA: BeiGene USA, Inc.; 2024. 7. Opdivo Qvantig [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2024.