FDA-Approved Indication for KEYTRUDA® (pembrolizumab) for the Treatment of Adult and Pediatric Patients With Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma (MCC)
On January 8th, 2019
Merck is pleased to announce that KEYTRUDA has been approved by
the FDA for the treatment of adult and pediatric patients with recurrent locally
advanced or metastatic MCC. This indication is approved under accelerated
approval based on tumor response rate and durability of response. Continued
approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
· PD-L1 diagnostic testing is not required prior
to initiating treatment with KEYTRUDA in these patients.
FDA=Food
and Drug Administration; PD-L1=programmed death ligand 1.
Selected Safety Information for KEYTRUDA® (pembrolizumab)
injection 100 mg
· Immune-mediated adverse reactions, which may be severe or fatal,
can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis, severe skin reactions, solid organ transplant
rejection, and complications of allogeneic hematopoietic stem cell
transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA
should be withheld or discontinued and corticosteroids administered if appropriate.
For more information regarding immune-mediated adverse reactions, please read
the additional Selected Safety Information below.
KEYNOTE-017
The
efficacy of KEYTRUDA was investigated in Study KEYNOTE-017 (NCT02267603), a
multicenter, non-randomized, open-label trial that enrolled 50 patients with
recurrent locally advanced or metastatic MCC who had not received prior
systemic therapy for their advanced disease. Patients with active autoimmune
disease or a medical condition that required immunosuppression were ineligible.
Patients
received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease
progression that was symptomatic, rapidly progressive, required urgent
intervention, occurred with a decline in performance status, or was confirmed
at least 4 weeks later with repeat imaging. Patients without disease
progression were treated for up to 24 months. Assessment of tumor status was
performed at 13 weeks followed by every 9 weeks for the first year and every 12
weeks thereafter. The major efficacy outcome measures were objective response
rate (ORR) and duration of response as assessed by blinded independent central
review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Among
the 50 patients, the median age was 71 years (range: 46 to 91 years), with 80%
age 65 or older; 68% male; 90% White; and Eastern Cooperative Oncology Group
(ECOG) performance score (PS) was 0 (48%) and 1 (52%). Fourteen percent had
stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had
prior surgery and 70% had prior radiation therapy.
Efficacy
results are summarized below.
Efficacy Results in KEYNOTE-017
Endpoint
KEYTRUDA
2 mg/kg every 3 weeks
n=50
Objective Response Rate
ORR (95% CI)
56% (41, 70)
Complete response (CR) rate (95% CI)
24% (13, 38)
Partial response (PR) rate (95% CI)
32% (20, 47)
Duration of Response
Range in months*
5.9-34.5+
Patients with duration ≥6 months, n (%)
27 (96%)
Patients with duration ≥12 months, n (%)
15 (54%)
*
The median duration of
response was not reached.
CI=confidence
interval.
Recommended Dosage for MCC
The
recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous
infusion over 30 minutes every 3 weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease progression.
The
recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum
of 200 mg), administered as an intravenous infusion over 30 minutes every 3
weeks until disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
Selected Safety Information for KEYTRUDA® (pembrolizumab)
injection 100 mg(continued)
Immune-Mediated Pneumonitis
· KEYTRUDA can cause immune-mediated pneumonitis,
including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients
receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and
5 (0.1%), and occurred more frequently in patients with a history of prior
thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients
for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with
radiographic imaging. Administer corticosteroids for Grade 2 or greater
pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA
for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis
· KEYTRUDA can cause immune-mediated colitis.
Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including
Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis.
Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade
4 colitis.
Immune-Mediated Hepatitis
· KEYTRUDA can cause immune-mediated hepatitis.
Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including
Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in
liver function. Administer corticosteroids for Grade 2 or greater hepatitis
and, based on severity of liver enzyme elevations, withhold or discontinue
KEYTRUDA.
Immune-Mediated Endocrinopathies
· KEYTRUDA can cause hypophysitis, thyroid
disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799)
of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%).
Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2
(6.2%) and 3 (0.1%). Hyperthyroidism occurred in 3.4% (96/2799) of patients,
including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6%
(16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus,
including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.
· Monitor patients for signs and symptoms of
hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid
function (prior to and periodically during treatment), and hyperglycemia. For
hypophysitis, administer corticosteroids and hormone replacement as clinically
indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade
3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and
manage hyperthyroidism with thionamides and beta-blockers as appropriate.
Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer
insulin for type 1 diabetes, and withhold KEYTRUDA and administer
antihyperglycemics in patients with severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
· KEYTRUDA can cause immune-mediated nephritis.
Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including
Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for
changes in renal function. Administer corticosteroids for Grade 2 or greater
nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3
or 4 nephritis.
Immune-Mediated Skin Reactions
· Immune-mediated rashes, including
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases
with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur.
Monitor patients for suspected severe skin reactions and based on the severity
of the adverse reaction, withhold or permanently discontinue KEYTRUDA and
administer corticosteroids. For signs or symptoms of SJS or TEN, withhold
KEYTRUDA and refer the patient for specialized care for assessment and
treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions
· Immune-mediated adverse reactions, which may be
severe or fatal, can occur in any organ system or tissue in patients receiving
KEYTRUDA and may also occur after discontinuation of treatment. For suspected
immune-mediated adverse reactions, ensure adequate evaluation to confirm
etiology or exclude other causes. Based on the severity of the adverse
reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to
Grade 1 or less, initiate corticosteroid taper and continue to taper over at
least 1 month. Based on limited data from clinical studies in patients whose
immune-related adverse reactions could not be controlled with corticosteroid
use, administration of other systemic immunosuppressants can be considered.
Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following
corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3
immune-mediated adverse reaction that recurs and for any life-threatening
immune-mediated adverse reaction.
· The following clinically significant
immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated)
of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome,
myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and
encephalitis. In addition, myelitis and myocarditis were reported in other
clinical trials and postmarketing use.
· Treatment with KEYTRUDA may increase the risk of
rejection in solid organ transplant recipients. Consider the benefit of
treatment vs the risk of possible organ rejection in these patients.
Infusion-Related Reactions
· KEYTRUDA can cause severe or life-threatening
infusion-related reactions, including hypersensitivity and anaphylaxis, which
have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and
symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop
infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
· Immune-mediated complications, including fatal
events, occurred in patients who underwent allogeneic HSCT after treatment with
KEYTRUDA. Follow patients closely for early evidence of transplant-related
complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4
acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease
(VOD), and other immune-mediated adverse reactions.
· In patients with a history of allogeneic HSCT,
acute GVHD (including fatal GVHD) has been reported after treatment with
KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be
at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs
the risk of GVHD in these patients.
Increased Mortality in Patients With Multiple Myeloma
· In clinical trials in patients with multiple
myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone
resulted in increased mortality. Treatment of these patients with a programmed
death receptor-1 (PD-1) or PD-L1 blocking antibody in this combination is not
recommended outside of controlled clinical trials.
Embryofetal Toxicity
· Based on its mechanism of action, KEYTRUDA can
cause fetal harm when administered to a pregnant woman. If used during
pregnancy, or if the patient becomes pregnant during treatment, apprise the
patient of the potential hazard to a fetus. Advise females of reproductive
potential to use highly effective contraception during treatment and for 4
months after the last dose of KEYTRUDA.
Adverse Reactions
· The most common adverse reactions for KEYTRUDA
(reported in ≥20% of patients) were fatigue, musculoskeletal pain, decreased
appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea,
constipation, pain, and abdominal pain.
Lactation
· It is not known whether KEYTRUDA is excreted in
human milk. Because many drugs are excreted in human milk, instruct women to
discontinue nursing during treatment with KEYTRUDA and for 4 months after the
final dose.
Pediatric Use
· There is limited experience in pediatric
patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma,
or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety
profile was similar to that seen in adults treated with KEYTRUDA. Toxicities
that occurred at a higher rate (≥15% difference) in these patients when
compared to adults under 65 years of age were fatigue (45%), vomiting (38%),
abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).
Merck is pleased to announce that KEYTRUDA has been approved by the FDA for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
· PD-L1 diagnostic testing is not required prior to initiating treatment with KEYTRUDA in these patients.
FDA=Food and Drug Administration; PD-L1=programmed death ligand 1.
Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg
· Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information below.
KEYNOTE-017
The efficacy of KEYTRUDA was investigated in Study KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.
Patients received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Among the 50 patients, the median age was 71 years (range: 46 to 91 years), with 80% age 65 or older; 68% male; 90% White; and Eastern Cooperative Oncology Group (ECOG) performance score (PS) was 0 (48%) and 1 (52%). Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy.
Efficacy results are summarized below.
Efficacy Results in KEYNOTE-017
| Endpoint |
KEYTRUDA 2 mg/kg every 3 weeks n=50 |
| Objective Response Rate | |
| ORR (95% CI) | 56% (41, 70) |
| Complete response (CR) rate (95% CI) | 24% (13, 38) |
| Partial response (PR) rate (95% CI) | 32% (20, 47) |
| Duration of Response | |
| Range in months* | 5.9-34.5+ |
| Patients with duration ≥6 months, n (%) | 27 (96%) |
| Patients with duration ≥12 months, n (%) | 15 (54%) |
| * | The median duration of response was not reached. CI=confidence interval. |
Recommended Dosage for MCC
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg(continued)
Immune-Mediated Pneumonitis
· KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis
· KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
Immune-Mediated Hepatitis
· KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Immune-Mediated Endocrinopathies
· KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.
· Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
· KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
· Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions
· Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
· The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.
· Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.
Infusion-Related Reactions
· KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
· Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.
· In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.
Increased Mortality in Patients With Multiple Myeloma
· In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a programmed death receptor-1 (PD-1) or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.
Embryofetal Toxicity
· Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.
Adverse Reactions
· The most common adverse reactions for KEYTRUDA (reported in ≥20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
Lactation
· It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.
Pediatric Use
· There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).
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