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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 PD-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. Important immune-mediated adverse reactions listed as follows may not include all possible severe and fatal immune-mediated adverse reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. 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 [see Dosage & Administration]. 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 immune-mediated adverse reactions are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed as follows.
Immune-Mediated Pneumonitis: KEYTRUDA can cause immune-mediated pneumonitis. The incidence of pneumonitis 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%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) of patients and withholding of KEYTRUDA in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients.
In clinical studies enrolling 389 adult patients with cHL who received KEYTRUDA as a single agent, pneumonitis occurred in 31 (8%) patients, including Grades 3-4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 21 (5.4%) patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received KEYTRUDA as a single agent for adjuvant treatment, pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis: KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) 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%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) of patients and withholding of KEYTRUDA in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of colitis. 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%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) of patients and withholding of KEYTRUDA in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA 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. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed [see Dosage & Administration].
With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both KEYTRUDA and axitinib. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.
Immune-Mediated Endocrinopathies: Adrenal Insufficiency: KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage & Administration].
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%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA 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 [see Dosage & Administration].
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%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) of patients and withholding of KEYTRUDA 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 [see Dosage & Administration].
Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). No patients discontinued KEYTRUDA due to thyroiditis. 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%). Hyperthyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (2) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.2%) hyperthyroidism.
Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA 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.
The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.
The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.
Type 1 Diabetes Mellitus, 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 [see Dosage & Administration].
Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. Type 1 diabetes mellitus led to permanent discontinuation in <0.1% (1) of patients and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy.
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%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) of patients and withholding of KEYTRUDA in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of nephritis. 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, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage & Administration].
Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of KEYTRUDA in 0.1% (2) of patients 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 of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse 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 PD-1/PD-L1 blocking antibodies. 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.
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 patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage & Administration].
Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.
Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone: In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials.
Embryo-Fetal Toxicity: Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Pregnancy & Lactation].
Use in Children: The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma, cHL and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions, and Pharmacology: Pharmacokinetics and Clinical Studies under Actions].
In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive solid tumors received KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults included pyrexia (33%), vomiting (30%), upper respiratory tract infection (29%), and headache (25%). Laboratory abnormalities that occurred at a ≥10% higher rate in pediatric patients when compared to adults were leukopenia (30%), neutropenia (26%), and Grade 3 anemia (17%).
The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications/Uses].
Use in the Elderly: Of 3781 patients with melanoma, NSCLC, HNSCC, or urothelial carcinoma who were treated with KEYTRUDA in clinical studies, 48% were 65 years and over and 17% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
Of 389 adult patients with cHL who were treated with KEYTRUDA in clinical studies, 46 (12%) were 65 years and over. Patients aged 65 years and over had a higher incidence of serious adverse reactions (50%) than patients aged younger than 65 years (24%). Clinical studies of KEYTRUDA in cHL did not include sufficient numbers of patients aged 65 years and over to determine whether effectiveness differs from that in younger patients.
Of 506 adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy who were treated with KEYTRUDA in KEYNOTE-091, 242 (48%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
Of 596 adult patients with TNBC who were treated with KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin in KEYNOTE-355, 137 (23%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
Of 406 adult patients with endometrial carcinoma who were treated with KEYTRUDA in combination with lenvatinib in KEYNOTE-775, 201 (50%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
Of the 432 patients randomized to KEYTRUDA in combination with axitinib in the KEYNOTE-426 trial, 40% were 65 years or older. No overall difference in safety or efficacy was reported between patients who were ≥65 years of age and younger.
