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.
aGrades 3–4.
- The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.
- Pneumonitis rates for adult patients with cHL were similar in patients with and without prior thoracic radiation.
- The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.
- Of 2,799 patients receiving KEYTRUDA, thyroiditis occurred in 16 (0.6%) patients, including Grade 2 (0.3%), and type 1 diabetes mellitus, which can present with diabetic ketoacidosis, occurred in 6 (0.2%) patients.
- Adult patients with cHL who developed pneumonitis received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
- Additional immunosuppressant therapy was required in 4.2% of patients with colitis and in 11% of patients with hepatitis.
- Of those with adrenal insufficiency or hypophysitis who required systemic corticosteroids, the majority of patients remained on systemic corticosteroids.
- The majority of patients with hypothyroidism required long-term thyroid hormone replacement.
- All patients with type 1 diabetes mellitus required long-term insulin therapy.
- All patients who were withheldb reinitiated KEYTRUDA after symptom improvement; of those:
- 23% had recurrence of pneumonitis and colitis.
- None had recurrence of hepatitis and nephritis.
- 6% had a recurrence of dermatologic adverse reactions.
- KEYTRUDA in combination with axitinib can cause hepatic toxicity. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen at a higher frequency compared to KEYTRUDA alone.
- 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.
- All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.
- 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.
- 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 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.
- KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2,799 patients.
- 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 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.
- 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.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; cHL = classical Hodgkin lymphoma; FU = fluorouracil; GVHD = graft-versus-host disease; HNSCC = head and neck squamous cell carcinoma; HSCT = hematopoietic stem cell transplantation; ULN = upper limit of normal.
- Permanent discontinuation rate due to adverse reactions: 20% with KEYTRUDA
-
Most common adverse reactions resulting in discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%).
bGraded per NCI-CTCAE v4.03.
cIncludes asthenia and fatigue.
dIncludes genital rash, rash, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, and rash pustular.
plat/pem = cisplatin or carboplatin and pemetrexed; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events.
- 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 (6%), pneumonia (6%), and urinary tract infection (3%).
- 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.
- Safety was evaluated in 1,251 patients with previously untreated stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC. All patients had tumors expressing PD-L1.
- Permanent discontinuation rate due to adverse reactions: 19% with KEYTRUDA.
- Most common adverse reactions resulting in discontinuation were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%).
eGraded per NCI-CTCAE v4.03.
fIncludes fatigue and asthenia.
gIncludes rash, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, and rash pustular.
- The adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg doses of KEYTRUDA; therefore, summary safety results are provided in a pooled analysis (n=682).
- KEYTRUDA 2 mg/kg or 10 mg/kg Q3W was discontinued due to adverse reactions in 8% of 682 patients with mNSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%).
hGraded per NCI-CTCAE v4.0.
iIncludes rash, rash erythematous, rash macular, rash maculopapular, rash papular, and rash pruritic.
- Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%),
asthenia (11%), and pyrexia (11%).
Q3W = every 3 weeks.