– This combination has the potential to be
the first treatment option combining an antibody-drug conjugate
plus an immunotherapy in this treatment setting –
– FDA granted the applications Priority
Review with a PDUFA date of April 21,
2023 –
TOKYO, BOTHELL,
Wash. and RAHWAY,
N.J., Dec. 20, 2022 /PRNewswire/ -- Astellas
Pharma Inc. (TSE:4503, President and CEO: Kenji Yasukawa,
Ph.D., "Astellas"), Seagen Inc. (Nasdaq: SGEN) and Merck (NYSE:
MRK), known as MSD outside of the United
States and Canada, today
announced the U.S. Food and Drug Administration (FDA) has accepted
for Priority Review supplemental Biologics License Applications
(sBLAs) for PADCEV® (enfortumab vedotin-ejfv) and
KEYTRUDA® (pembrolizumab) for use of these two
agents in combination for the treatment of patients with locally
advanced or metastatic urothelial cancer (la/mUC) who are not
eligible to receive cisplatin-containing chemotherapy. The
respective applications are intended to expand both labels for
PADCEV and KEYTRUDA. The agency set a Prescription Drug User Fee
Act (PDUFA) goal date for each application of April 21, 2023.
"We look forward to working closely with the FDA as we seek
potential accelerated approval for this combination in the hopes
that it can be another treatment option for patients with locally
advanced or metastatic urothelial cancer who are not eligible for
cisplatin-containing chemotherapy," said Ahsan Arozullah, M.D.,
M.P.H., Senior Vice President and Head of Development Therapeutic
Areas, Astellas.
The combination therapy was granted Breakthrough Therapy
designation by the FDA in February
2020. The respective sBLAs are supported by efficacy and
safety data from the phase 1b/2
EV-103 trial (NCT03288545, also known as KEYNOTE-869) Dose
Escalation/Cohort A and Cohort K. Results from Dose
Escalation/Cohort A were published in the Journal of Clinical
Oncology.1 Results from Cohort K were presented in a
late-breaking session at the 2022 European Society for Medical
Oncology (ESMO) Congress.2
"Urothelial cancer, the most common type of bladder cancer, is
associated with poor survival in the advanced stage," said
Marjorie Green, M.D., Senior Vice
President and Head of Late-Stage Development, Seagen. "The
investigational results from our clinical development program
support the combination of PADCEV and KEYTRUDA as a potential
treatment for this patient population."
Please see Important Safety Information at the end of this press
release for both drugs, including a warning and precaution for
immune-mediated adverse reactions for pembrolizumab and BOXED
WARNING for PADCEV (enfortumab vedotin-ejfv) for serious skin
reactions.
"Despite advancements in treatment options, approximately half
of advanced bladder cancer patients in the U.S. are ineligible for
cisplatin-based chemotherapy, and these patients need new
options. We are encouraged by the investigational results of the
combination of PADCEV and KEYTRUDA for this patient population and
are fully committed to work to bring this new approach forward to
patients," said Dr. Eliav Barr,
Senior Vice President, Head of Global Clinical Development and
Chief Medical Officer, Merck Research Laboratories.
Astellas, Seagen and Merck are further investigating enfortumab
vedotin plus pembrolizumab in the ongoing phase 3 EV-302 study
(NCT04223856, also known as KEYNOTE-A39), evaluating the clinical
benefit for the investigational treatment combination in
patients with previously untreated advanced urothelial cancer. The
trial is intended to serve as the confirmatory trial for the
potential accelerated approval in the U.S. and serve as the basis
for global registration.
The studies are part of an extensive program evaluating this
combination in multiple stages of urothelial cancer, including two
phase 3 clinical trials in muscle-invasive bladder cancer in
EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303
(NCT03924895, also known as KEYNOTE-905).
About Bladder and Urothelial Cancer
It is estimated
that approximately 81,180 people in the U.S. were diagnosed with
bladder cancer in 2022.3 Urothelial cancer accounts for
90% of all bladder cancers and can also be found in the renal
pelvis, ureter and urethra.4 Approximately 12% of cases
are locally advanced or metastatic urothelial cancer at
diagnosis.5 Globally, approximately 573,000 new cases of
bladder cancer and 212,000 deaths are reported
annually.6
About the EV-103/KEYNOTE-869 Trial
The
EV-103 trial (NCT03288545) is an ongoing, multi-cohort,
open-label, multicenter phase 1b/2
study of enfortumab vedotin alone or in combination
with pembrolizumab and/or chemotherapy in first- or second-line
settings in patients with locally advanced or metastatic urothelial
cancer (la/mUC) and in patients with muscle-invasive bladder
cancer.
About PADCEV
PADCEV (enfortumab vedotin-ejfv) is a
first-in-class antibody-drug conjugate (ADC) that is directed
against Nectin-4, a protein located on the surface of cells and
highly expressed in bladder cancer.7 Nonclinical data
suggest the anticancer activity of PADCEV is due to its binding to
Nectin-4-expressing cells followed by the internalization and
release of the anti-tumor agent monomethyl auristatin E (MMAE) into
the cell, which result in the cell not reproducing (cell cycle
arrest) and in programmed cell death (apoptosis).8
PADCEV (enfortumab vedotin-ejfv) U.S. Indication &
Important Safety Information
BOXED WARNING: SERIOUS SKIN REACTIONS
- PADCEV can cause severe and fatal cutaneous adverse reactions
including Stevens-Johnson syndrome
(SJS) and Toxic Epidermal Necrolysis (TEN), which occurred
predominantly during the first cycle of treatment, but may occur
later.
- Closely monitor patients for skin reactions.
- Immediately withhold PADCEV and consider referral for
specialized care for suspected SJS or TEN or severe skin
reactions.
- Permanently discontinue PADCEV in patients with confirmed SJS
or TEN; or Grade 4 or recurrent Grade 3 skin reactions.
Indication
PADCEV® is indicated for the treatment of adult patients
with locally advanced or metastatic urothelial cancer (mUC)
who:
- have previously received a programmed death receptor-1 (PD-1)
or programmed death-ligand 1 (PD-L1) inhibitor and
platinum-containing chemotherapy, or
- are ineligible for cisplatin-containing chemotherapy and have
previously received one or more prior lines of
therapy.8
Important Safety Information
Warnings and Precautions
Skin reactions Severe cutaneous adverse reactions,
including fatal cases of SJS or TEN, occurred in patients treated
with PADCEV. SJS and TEN occurred predominantly during the first
cycle of treatment but may occur later. Skin reactions
occurred in 55% of the 680 patients treated with PADCEV in clinical
trials. Twenty-three percent (23%) of patients had maculo-papular
rash and 33% had pruritus. Grade 3-4 skin reactions occurred
in 13% of patients, including maculo-papular rash, rash
erythematous, rash or drug eruption, symmetrical drug-related
intertriginous and flexural exanthema (SDRIFE), dermatitis bullous,
dermatitis exfoliative, and palmar-plantar erythrodysesthesia.
In clinical trials, the median time to onset of severe skin
reactions was 0.6 months (range: 0.1 to 6.4 months). Among patients
experiencing a skin reaction leading to dose interruption who
then restarted PADCEV (n=59), 24% of patients restarting at the
same dose and 16% of patients restarting at a reduced dose
experienced recurrent severe skin reactions. Skin reactions led to
discontinuation of PADCEV in 2.6% of patients. Monitor patients
closely throughout treatment for skin reactions. Consider topical
corticosteroids and antihistamines, as clinically indicated. For
persistent or recurrent Grade 2 skin reactions, consider
withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for
specialized care for suspected SJS, TEN or for Grade 3 skin
reactions. Permanently discontinue PADCEV in patients with
confirmed SJS or TEN, or for Grade 4 or recurrent Grade 3 skin
reactions.
Hyperglycemia and diabetic ketoacidosis (DKA), including
fatal events, occurred in patients with and without
pre-existing diabetes mellitus, treated with PADCEV. Patients with
baseline hemoglobin A1C ≥8% were excluded from clinical
trials. In clinical trials, 14% of the 680 patients treated with
PADCEV developed hyperglycemia; 7% of patients developed Grade
3-4 hyperglycemia. The incidence of Grade 3-4 hyperglycemia
increased consistently in patients with higher body mass index and
in patients with higher baseline A1C. Five percent (5%) of
patients required initiation of insulin therapy for treatment
of hyperglycemia. The median time to onset of hyperglycemia
was 0.6 months (range: 0.1 to 20.3). Hyperglycemia led to
discontinuation of PADCEV in 0.6% of patients. Closely monitor
blood glucose levels in patients with, or at risk for,
diabetes mellitus or hyperglycemia. If blood glucose is
elevated (>250 mg/dL), withhold PADCEV.
Pneumonitis Severe, life-threatening or fatal
pneumonitis occurred in patients treated with PADCEV.
In clinical trials, 3.1% of the 680 patients treated with
PADCEV had pneumonitis of any grade and 0.7% had Grade 3-4. In
clinical trials, the median time to onset of pneumonitis was 2.9
months (range: 0.6 to 6 months). Monitor patients for signs
and symptoms indicative of pneumonitis, such as hypoxia, cough,
dyspnea or interstitial infiltrates on radiologic exams.
Evaluate and exclude infectious, neoplastic and other causes for
such signs and symptoms through appropriate investigations.
Withhold PADCEV for patients who develop persistent or
recurrent Grade 2 pneumonitis and consider dose reduction.
Permanently discontinue PADCEV in all patients with Grade 3 or 4
pneumonitis.
Peripheral neuropathy (PN) occurred in 52% of the
680 patients treated with PADCEV in clinical trials, including 39%
with sensory neuropathy, 7% with muscular weakness and 6% with
motor neuropathy; 4% experienced Grade 3-4 reactions. PN
occurred in patients treated with PADCEV with or without
pre-existing PN. The median time to onset of Grade ≥2 PN was
4.6 months (range: 0.1 to 15.8 months). Neuropathy led to
treatment discontinuation in 5% of patients. Monitor patients for
symptoms of new or worsening peripheral neuropathy and
consider dose interruption or dose reduction of PADCEV when PN
occurs. Permanently discontinue PADCEV in patients who develop
Grade ≥3 PN.
Ocular disorders were reported in 40% of the 384
patients treated with PADCEV in clinical trials in which
ophthalmologic exams were scheduled. The majority
of these events involved the cornea and included events
associated with dry eye such as keratitis, blurred vision,
increased lacrimation, conjunctivitis, limbal stem cell deficiency,
and keratopathy. Dry eye symptoms occurred in 34% of patients, and
blurred vision occurred in 13% of patients, during treatment with
PADCEV. The median time to onset to symptomatic ocular disorder was
1.6 months (range: 0 to 19.1 months). Monitor patients for ocular
disorders. Consider artificial tears for prophylaxis of dry eyes
and ophthalmologic evaluation if ocular symptoms occur or do not
resolve. Consider treatment with ophthalmic topical steroids, if
indicated after an ophthalmic exam. Consider dose interruption or
dose reduction of PADCEV for symptomatic ocular
disorders.
Infusion site extravasation Skin and soft tissue
reactions secondary to extravasation have been observed after
administration of PADCEV. Of the 680 patients, 1.6% of patients
experienced skin and soft tissue reactions, including 0.3% who
experienced Grade 3-4 reactions. Reactions may be
delayed. Erythema, swelling, increased temperature, and pain
worsened until 2-7 days after extravasation and resolved
within 1-4 weeks of peak. Two patients (0.3%) developed
extravasation reactions with secondary cellulitis, bullae, or
exfoliation. Ensure adequate venous access prior to starting PADCEV
and monitor for possible extravasation during administration.
If extravasation occurs, stop the infusion and monitor for
adverse reactions.
Embryo-fetal toxicity PADCEV can cause fetal harm
when administered to a pregnant woman. Advise patients of the
potential risk to the fetus. Advise female patients of reproductive
potential to use effective contraception during PADCEV treatment
and for 2 months after the last dose. Advise male patients with
female partners of reproductive potential to use effective
contraception during treatment with PADCEV and for 4 months
after the last dose.
Adverse Reactions
Most Common Adverse Reactions, Including Laboratory
Abnormalities (≥20%)
Rash, aspartate aminotransferase (AST) increased, glucose
increased, creatinine increased, fatigue, PN, lymphocytes
decreased, alopecia, decreased appetite, hemoglobin decreased,
diarrhea, sodium decreased, nausea, pruritus, phosphate decreased,
dysgeusia, alanine aminotransferase (ALT) increased, anemia,
albumin decreased, neutrophils decreased, urate increased, lipase
increased, platelets decreased, weight decreased and dry
skin.
EV-301 Study: 296 patients previously treated with a PD-1/L1
inhibitor and
platinum-based chemotherapy.
Serious adverse reactions occurred in 47% of patients treated with
PADCEV; the most common (≥2%) were urinary tract infection, acute
kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions
occurred in 3% of patients, including multiorgan dysfunction
(1.0%), hepatic dysfunction, septic shock, hyperglycemia,
pneumonitis and pelvic abscess (0.3% each). Adverse reactions
leading to discontinuation occurred in 17% of patients; the
most common (≥2%) were PN (5%) and rash (4%). Adverse
reactions leading to dose interruption occurred in 61% of patients;
the most common (≥4%) were PN (23%), rash (11%) and fatigue
(9%). Adverse reactions leading to dose reduction occurred
in 34% of patients; the most common (≥2%) were PN (10%), rash
(8%), decreased appetite and fatigue (3% each). Clinically
relevant adverse reactions (<15%) include vomiting (14%), AST
increased (12%), hyperglycemia (10%), ALT increased (9%),
pneumonitis (3%) and infusion site extravasation (0.7%).
EV-201, Cohort 2 Study: 89 patients previously treated with a
PD-1/L1 inhibitor and not eligible for platinum-based
chemotherapy.
Serious adverse reactions occurred in 39% of patients treated with
PADCEV; the most common (≥3%) were pneumonia, sepsis and diarrhea
(5% each). Fatal adverse reactions occurred in 8% of
patients, including acute kidney injury (2.2%), metabolic
acidosis, sepsis, multiorgan dysfunction, pneumonia
and pneumonitis (1.1% each). Adverse reactions leading to
discontinuation occurred in 20% of patients; the most common
(≥2%) was PN (7%). Adverse reactions leading to dose interruption
occurred in 60% of patients; the most common (≥3%) were PN
(19%), rash (9%), fatigue (8%), diarrhea (5%), AST
increased and hyperglycemia (3% each). Adverse reactions
leading to dose reduction occurred in 49% of patients; the
most common (≥3%) were PN (19%), rash (11%) and fatigue (7%).
Clinically relevant adverse reactions (<15%) include vomiting
(13%), AST increased (12%), lipase increased (11%), ALT
increased (10%), pneumonitis (4%) and infusion site
extravasation (1%).
Drug Interactions
Effects of other drugs on
PADCEV (Dual P-gp and Strong CYP3A4
Inhibitors)
Concomitant use with a dual P-gp and strong CYP3A4 inhibitors
may increase unconjugated monomethyl auristatin E exposure,
which may increase the incidence or severity of PADCEV toxicities.
Closely monitor patients for signs of toxicity when PADCEV is
given concomitantly with dual P-gp and strong CYP3A4
inhibitors.
Specific Populations
Lactation Advise lactating women not to breastfeed
during treatment with PADCEV and for at least 3 weeks after the
last dose.
Hepatic impairment Avoid the use of PADCEV in
patients with moderate or severe hepatic impairment.
For more information, please see the full Prescribing
Information including BOXED WARNING for
PADCEV here.
About KEYTRUDA® (pembrolizumab) injection, 100
mg
KEYTRUDA is an anti-programmed death receptor-1
(PD-1) therapy that works by increasing the ability of the body's
immune system to help detect and fight tumor cells. KEYTRUDA is a
humanized monoclonal antibody that blocks the interaction between
PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T
lymphocytes which may affect both tumor cells and healthy
cells.
Merck has the industry's largest immuno-oncology clinical
research program. There are currently more than 1,600 trials
studying KEYTRUDA across a wide variety of cancers and treatment
settings. The KEYTRUDA clinical program seeks to understand the
role of KEYTRUDA across cancers and the factors that may predict a
patient's likelihood of benefitting from treatment with KEYTRUDA,
including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications in
the U.S.
Urothelial Carcinoma
KEYTRUDA is
indicated for the treatment of patients with locally advanced or
metastatic urothelial carcinoma (mUC):
- who are not eligible for any platinum-containing chemotherapy,
or
- who have disease progression during or following
platinum-containing chemotherapy or within 12 months of neoadjuvant
or adjuvant treatment with platinum-containing chemotherapy.
Non-muscle Invasive Bladder Cancer
KEYTRUDA is
indicated for the treatment of patients with Bacillus
Calmette-Guerin-unresponsive, high-risk, non-muscle invasive
bladder cancer (NMIBC) with carcinoma in situ with or without
papillary tumors who are ineligible for or have elected not to
undergo cystectomy.
See additional selected indications for KEYTRUDA in the U.S.
after the Selected Important Safety Information.
Selected Important Safety Information for
KEYTRUDA
Severe and Fatal Immune-Mediated Adverse
Reactions
KEYTRUDA is a monoclonal antibody that belongs to
a class of drugs that bind to either the PD-1 or the 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.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL
receiving KEYTRUDA as a single agent, including Grades 3-4 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 5.4% (21) of patients. Of the patients who developed
pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA,
and 77% had resolution.
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.
KEYTRUDA With Axitinib
KEYTRUDA in combination with
axitinib can cause hepatic toxicity. Monitor liver enzymes before
initiation of and periodically throughout treatment. Consider
monitoring more frequently 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. With the combination of KEYTRUDA and
axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT)
(20%) and increased aspartate aminotransferase (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 upper limit of
normal (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.
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. 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 adult patients with cHL
(17%) receiving KEYTRUDA as a single agent, including Grade 1
(6.2%) and Grade 2 (10.8%) hypothyroidism.
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.
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 treatment
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-006, KEYTRUDA was
discontinued due to adverse reactions in 9% of 555 patients with
advanced melanoma; adverse reactions leading to permanent
discontinuation in more than one patient were colitis (1.4%),
autoimmune hepatitis (0.7%), allergic reaction (0.4%),
polyneuropathy (0.4%), and cardiac failure (0.4%). The most common
adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea
(26%), rash (24%), and nausea (21%).
In KEYNOTE-054, when KEYTRUDA was administered as a single agent
to patients with stage III melanoma, KEYTRUDA was permanently
discontinued due to adverse reactions in 14% of 509 patients; the
most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and
diarrhea (1%). Serious adverse reactions occurred in 25% of
patients receiving KEYTRUDA. The most common adverse reaction
(≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when
KEYTRUDA was administered as a single agent to patients with stage
IIB or IIC melanoma, adverse reactions occurring in patients with
stage IIB or IIC melanoma were similar to those occurring in 1011
patients with stage III melanoma from KEYNOTE-054.
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed
and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA
was discontinued due to adverse reactions in 20% of 405 patients.
The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney
injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA
were nausea (56%), fatigue (56%), constipation (35%), diarrhea
(31%), decreased appetite (28%), rash (25%), vomiting (24%), cough
(21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin
and either paclitaxel or paclitaxel protein-bound in metastatic
squamous NSCLC, 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,
pneumonia, and urinary tract infection. 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.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse
reactions in 19% of 636 patients with advanced NSCLC; the most
common were pneumonitis (3%), death due to unknown cause (1.6%),
and pneumonia (1.4%). The most frequent serious adverse reactions
reported in at least 2% of patients were pneumonia (7%),
pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion
(2.2%). The most common adverse reaction (≥20%) was fatigue
(25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC; the
most common was pneumonitis (1.8%). The most common adverse
reactions (≥20%) were decreased appetite (25%), fatigue (25%),
dyspnea (23%), and nausea (20%).
In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to
adverse events in 12% of 300 patients with HNSCC; the most common
adverse reactions leading to permanent discontinuation were sepsis
(1.7%) and pneumonia (1.3%). The most common adverse reactions
(≥20%) were fatigue (33%), constipation (20%), and rash (20%).
In KEYNOTE-048, when KEYTRUDA was administered in combination
with platinum (cisplatin or carboplatin) and FU chemotherapy,
KEYTRUDA was discontinued due to adverse reactions in 16% of 276
patients with HNSCC. The most common adverse reactions resulting in
permanent discontinuation of KEYTRUDA were pneumonia (2.5%),
pneumonitis (1.8%), and septic shock (1.4%). The most common
adverse reactions (≥20%) were nausea (51%), fatigue (49%),
constipation (37%), vomiting (32%), mucosal inflammation (31%),
diarrhea (29%), decreased appetite (29%), stomatitis (26%), and
cough (22%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse
reactions in 17% of 192 patients with HNSCC. Serious adverse
reactions occurred in 45% of patients. The most frequent serious
adverse reactions reported in at least 2% of patients were
pneumonia, dyspnea, confusional state, vomiting, pleural effusion,
and respiratory failure. The most common adverse reactions (≥20%)
were fatigue, decreased appetite, and dyspnea. Adverse reactions
occurring in patients with HNSCC were generally similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy, with the exception of increased incidences of
facial edema and new or worsening hypothyroidism.
In KEYNOTE-204, KEYTRUDA was discontinued due to adverse
reactions in 14% of 148 patients with cHL. Serious adverse
reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1%
were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney
injury, febrile neutropenia, and sepsis. Three patients died from
causes other than disease progression: 2 from complications after
allogeneic HSCT and 1 from unknown cause. The most common adverse
reactions (≥20%) were upper respiratory tract infection (41%),
musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue,
rash, and cough (20% each).
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse
reactions in 5% of 210 patients with cHL. Serious adverse reactions
occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis,
pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from
causes other than disease progression: 1 from GVHD after subsequent
allogeneic HSCT and 1 from septic shock. The most common adverse
reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse
reactions in 8% of 53 patients with PMBCL. Serious adverse
reactions occurred in 26% of patients and included arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial
effusion (2%), and pericarditis (2%). Six (11%) patients died
within 30 days of start of treatment. The most common adverse
reactions (≥20%) were musculoskeletal pain (30%), upper respiratory
tract infection and pyrexia (28% each), cough (26%), fatigue (23%),
and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or mUC.
Serious adverse reactions occurred in 42% of patients; those ≥2%
were urinary tract infection, hematuria, acute kidney injury,
pneumonia, and urosepsis. The most common adverse reactions (≥20%)
were fatigue (38%), musculoskeletal pain (24%), decreased appetite
(22%), constipation (21%), rash (21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse
reactions in 8% of 266 patients with locally advanced or mUC. The
most common adverse reaction resulting in permanent discontinuation
of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions
occurred in 39% of KEYTRUDA-treated patients; those ≥2% were
urinary tract infection, pneumonia, anemia, and pneumonitis. The
most common adverse reactions (≥20%) in patients who received
KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus
(23%), decreased appetite (21%), nausea (21%), and rash (20%).
In KEYNOTE-057, KEYTRUDA was discontinued due to adverse
reactions in 11% of 148 patients with high-risk NMIBC. The most
common adverse reaction resulting in permanent discontinuation of
KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred
in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia
(2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and
urinary tract infection (2%). The most common adverse reactions
(≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).
Adverse reactions occurring in patients with MSI-H or dMMR CRC
were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
In KEYNOTE-811, when KEYTRUDA was administered in combination
with trastuzumab, fluoropyrimidine- and platinum-containing
chemotherapy, KEYTRUDA was discontinued due to adverse reactions in
6% of 217 patients with locally advanced unresectable or metastatic
HER2+ gastric or GEJ adenocarcinoma. The most common adverse
reaction resulting in permanent discontinuation was pneumonitis
(1.4%). In the KEYTRUDA arm versus placebo, there was a difference
of ≥5% incidence between patients treated with KEYTRUDA versus
standard of care for diarrhea (53% vs 44%) and nausea (49% vs
44%).
The most common adverse reactions (reported in ≥20%) in patients
receiving KEYTRUDA in combination with chemotherapy were
fatigue/asthenia, nausea, constipation, diarrhea, decreased
appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia,
peripheral neuropathy, mucosal inflammation, stomatitis, headache,
weight loss, abdominal pain, arthralgia, myalgia, and insomnia.
In KEYNOTE-590, when KEYTRUDA was administered with cisplatin
and fluorouracil to patients with metastatic or locally advanced
esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above
the GEJ) carcinoma who were not candidates for surgical resection
or definitive chemoradiation, KEYTRUDA was discontinued due to
adverse reactions in 15% of 370 patients. The most common adverse
reactions resulting in permanent discontinuation of KEYTRUDA (≥1%)
were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia
(1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in
combination with chemotherapy were nausea (67%), fatigue (57%),
decreased appetite (44%), constipation (40%), diarrhea (36%),
vomiting (34%), stomatitis (27%), and weight loss (24%).
Adverse reactions occurring in patients with esophageal cancer
who received KEYTRUDA as a monotherapy were similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy.
In KEYNOTE-826, when KEYTRUDA was administered in combination
with paclitaxel and cisplatin or paclitaxel and carboplatin, with
or without bevacizumab (n=307), to patients with persistent,
recurrent, or first-line metastatic cervical cancer regardless of
tumor PD-L1 expression who had not been treated with chemotherapy
except when used concurrently as a radio-sensitizing agent, fatal
adverse reactions occurred in 4.6% of patients, including 3 cases
of hemorrhage, 2 cases each of sepsis and due to unknown causes,
and 1 case each of acute myocardial infarction, autoimmune
encephalitis, cardiac arrest, cerebrovascular accident, femur
fracture with perioperative pulmonary embolus, intestinal
perforation, and pelvic infection. Serious adverse reactions
occurred in 50% of patients receiving KEYTRUDA in combination with
chemotherapy with or without bevacizumab; those ≥3% were febrile
neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%),
and acute kidney injury and sepsis (3.3% each).
KEYTRUDA was discontinued in 15% of patients due to adverse
reactions. The most common adverse reaction resulting in permanent
discontinuation (≥1%) was colitis (1%).
For patients treated with KEYTRUDA, chemotherapy, and
bevacizumab (n=196), the most common adverse reactions (≥20%) were
peripheral neuropathy (62%), alopecia (58%), anemia (55%),
fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea
(39%), hypertension and thrombocytopenia (35% each), constipation
and arthralgia (31% each), vomiting (30%), urinary tract infection
(27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and
decreased appetite (21%).
For patients treated with KEYTRUDA in combination with
chemotherapy with or without bevacizumab, the most common adverse
reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%),
fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%),
arthralgia (27%), vomiting (26%), hypertension and urinary tract
infection (24% each), and rash (22%).
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with previously treated recurrent or
metastatic cervical cancer. Serious adverse reactions occurred in
39% of patients receiving KEYTRUDA; the most frequent included
anemia (7%), fistula, hemorrhage, and infections [except urinary
tract infections] (4.1% each). The most common adverse reactions
(≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea
(23%), pain and abdominal pain (22% each), and decreased appetite
(21%).
Adverse reactions occurring in patients with HCC were generally
similar to those in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy, with the exception of increased
incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis
(2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a
higher incidence were elevated AST (20%), ALT (9%), and
hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017,
adverse reactions occurring in patients with MCC were generally
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy. Laboratory abnormalities
(Grades 3-4) that occurred at a higher incidence were elevated AST
(11%) and hyperglycemia (19%).
In KEYNOTE-426, when KEYTRUDA was administered in combination
with axitinib, fatal adverse reactions occurred in 3.3% of 429
patients. Serious adverse reactions occurred in 40% of patients,
the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%),
acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).
Permanent discontinuation due to an adverse reaction occurred in
31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the
combination (8%); the most common were hepatotoxicity (13%),
diarrhea/colitis (1.9%), acute kidney injury (1.6%), and
cerebrovascular accident (1.2%). The most common adverse reactions
(≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension
(48%), hepatotoxicity (39%), hypothyroidism (35%), decreased
appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea
(28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash
(25%), cough (21%), and constipation (21%).
In KEYNOTE-564, when KEYTRUDA was administered as a single agent
for the adjuvant treatment of renal cell carcinoma, serious adverse
reactions occurred in 20% of patients receiving KEYTRUDA; the
serious adverse reactions (≥1%) were acute kidney injury, adrenal
insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1%
each). Fatal adverse reactions occurred in 0.2% including 1 case of
pneumonia. Discontinuation of KEYTRUDA due to adverse reactions
occurred in 21% of 488 patients; the most common (≥1%) were
increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%).
The most common adverse reactions (≥20%) were musculoskeletal pain
(41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%),
and hypothyroidism (21%).
Adverse reactions occurring in patients with MSI-H or dMMR
endometrial carcinoma who received KEYTRUDA as a single agent were
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with TMB-H cancer were
similar to those occurring in patients with other solid tumors who
received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with recurrent or
metastatic cSCC or locally advanced cSCC were similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy.
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%).
In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel,
paclitaxel protein-bound, or gemcitabine and carboplatin) were
administered to patients with locally recurrent unresectable or
metastatic TNBC who had not been previously treated with
chemotherapy in the metastatic setting (n=596), fatal adverse
reactions occurred in 2.5% of patients, including
cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious
adverse reactions occurred in 30% of patients receiving KEYTRUDA in
combination with chemotherapy; the serious reactions in ≥2% were
pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).
KEYTRUDA was discontinued in 11% of patients due to adverse
reactions. The most common reactions resulting in permanent
discontinuation (≥1%) were Increased ALT (2.2%), increased AST
(1.5%), and pneumonitis (1.2%). The most common adverse reactions
(≥20%) in patients receiving KEYTRUDA in combination with
chemotherapy were fatigue (48%), nausea (44%), alopecia (34%),
diarrhea and constipation (28% each), vomiting and rash (26% each),
cough (23%), decreased appetite (21%), and headache (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 final dose.
Pediatric Use
In KEYNOTE-051, 161 pediatric patients
(62 pediatric patients aged 6 months to younger than 12 years and
99 pediatric patients aged 12 years to 17 years) were administered
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 were pyrexia (33%),
vomiting (30%), leukopenia (30%), upper respiratory tract infection
(29%), neutropenia (26%), headache (25%), and Grade 3 anemia
(17%).
Additional Indications for KEYTRUDA in the
U.S.
Melanoma
KEYTRUDA is indicated for the
treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and
pediatric (12 years and older) patients with stage IIB, IIC, or III
melanoma following complete resection.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination
with pemetrexed and platinum chemotherapy, is indicated for the
first-line treatment of patients with metastatic nonsquamous
non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic
tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel
or paclitaxel protein-bound, is indicated for the first-line
treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with NSCLC expressing PD-L1 [tumor proportion
score (TPS) ≥1%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations, and is:
- stage III where patients are not candidates for surgical
resection or definitive chemoradiation, or
- metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%)
as determined by an FDA-approved test, with disease progression on
or after platinum-containing chemotherapy. Patients with EGFR or
ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
KEYTRUDA.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in
combination with platinum and fluorouracil (FU), is indicated for
the first-line treatment of patients with metastatic or with
unresectable, recurrent head and neck squamous cell carcinoma
(HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with metastatic or with unresectable,
recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score
(CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic HNSCC with disease
progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for
the treatment of adult patients with relapsed or refractory
classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients
with refractory cHL, or cHL that has relapsed after 2 or more lines
of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is
indicated for the treatment of adult and pediatric patients with
refractory primary mediastinal large B-cell lymphoma (PMBCL), or
who have relapsed after 2 or more prior lines of therapy.
KEYTRUDA is not recommended for treatment of patients with PMBCL
who require urgent cytoreductive therapy.
Microsatellite Instability-High or Mismatch Repair Deficient
Cancer
KEYTRUDA is indicated for the treatment of adult and
pediatric patients with unresectable or metastatic microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR) solid
tumors, as determined by an FDA-approved test, that have progressed
following prior treatment and who have no satisfactory alternative
treatment options.
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. The
safety and effectiveness of KEYTRUDA in pediatric patients with
MSI-H central nervous system cancers have not been established.
Microsatellite Instability-High or Mismatch Repair Deficient
Colorectal Cancer
KEYTRUDA is indicated for the treatment of
patients with unresectable or metastatic MSI-H or dMMR colorectal
cancer (CRC) as determined by an FDA-approved test.
Gastric Cancer
KEYTRUDA, in combination with
trastuzumab, fluoropyrimidine- and platinum-containing
chemotherapy, is indicated for the first-line treatment of patients
with locally advanced unresectable or metastatic HER2-positive
gastric or gastroesophageal junction (GEJ) adenocarcinoma.
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.
Esophageal Cancer
KEYTRUDA is indicated for the
treatment of patients with locally advanced or metastatic
esophageal or gastroesophageal junction (GEJ) (tumors with
epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not
amenable to surgical resection or definitive chemoradiation
either:
- in combination with platinum- and fluoropyrimidine-based
chemotherapy, or
- as a single agent after one or more prior lines of systemic
therapy for patients with tumors of squamous cell histology that
express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA, in combination with
chemotherapy, with or without bevacizumab, is indicated for the
treatment of patients with persistent, recurrent, or metastatic
cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined
by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic cervical cancer with disease
progression on or after chemotherapy whose tumors express PD-L1
(CPS ≥1) as determined by an FDA-approved test.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the
treatment of patients with hepatocellular carcinoma (HCC) who have
been previously treated with sorafenib. 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.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the
treatment of adult and pediatric patients with recurrent locally
advanced or metastatic Merkel cell carcinoma (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.
Renal Cell Carcinoma
KEYTRUDA, in combination with
axitinib, is indicated for the first-line treatment of adult
patients with advanced renal cell carcinoma (RCC).
KEYTRUDA is indicated for the adjuvant treatment of patients
with RCC at intermediate-high or high risk of recurrence following
nephrectomy, or following nephrectomy and resection of metastatic
lesions.
Endometrial Carcinoma
KEYTRUDA, as a single agent, is
indicated for the treatment of patients with advanced endometrial
carcinoma that is MSI-H or dMMR, as determined by an FDA-approved
test, who have disease progression following prior systemic therapy
in any setting and are not candidates for curative surgery or
radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is
indicated for the treatment of adult and pediatric patients with
unresectable or metastatic tumor mutational burden-high (TMB-H)
[≥10 mutations/megabase] solid tumors, as determined by an
FDA-approved test, that have progressed following prior treatment
and who have no satisfactory alternative treatment options. 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. The safety and
effectiveness of KEYTRUDA in pediatric patients with TMB-H central
nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is
indicated for the treatment of patients with recurrent or
metastatic cutaneous squamous cell carcinoma (cSCC) or locally
advanced cSCC that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
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.
KEYTRUDA, in combination with chemotherapy, is indicated for the
treatment of patients with locally recurrent unresectable or
metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined
by an FDA-approved test.
Please see Prescribing Information for KEYTRUDA
(pembrolizumab) at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and Medication Guide for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
About Astellas
Astellas Pharma Inc. is a
pharmaceutical company conducting business in more than 70
countries around the world. We are promoting the Focus Area
Approach that is designed to identify opportunities for the
continuous creation of new drugs to address diseases with high
unmet medical needs by focusing on Biology and Modality.
Furthermore, we are also looking beyond our foundational Rx focus
to create Rx+® healthcare solutions that combine our
expertise and knowledge with cutting-edge technology in different
fields of external partners. Through these efforts, Astellas stands
on the forefront of healthcare change to turn innovative science
into VALUE for patients. For more information, please visit
our website at https://www.astellas.com/en.
About Seagen
Seagen Inc. is a global
biotechnology company that discovers, develops and commercializes
transformative cancer medicines to make a meaningful difference in
people's lives. Seagen is headquartered in the
Seattle, Washington area, and has
locations in California,
Canada, Switzerland and the European Union. For more
information on the company's marketed products and robust pipeline,
visit www.seagen.com and follow @SeagenGlobal on
Twitter.
Merck's focus on cancer
Our goal is to
translate breakthrough science into innovative oncology medicines
to help people with cancer worldwide. At Merck, the potential to
bring new hope to people with cancer drives our purpose and
supporting accessibility to our cancer medicines is our commitment.
As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the largest development
programs in the industry across more than 30 tumor types. We also
continue to strengthen our portfolio through strategic acquisitions
and are prioritizing the development of several promising oncology
candidates with the potential to improve the treatment of advanced
cancers. For more information about our oncology clinical trials,
visit www.merck.com/clinicaltrials.
About Merck
At Merck, known as MSD outside of
the United States and Canada, we are unified around our purpose: We
use the power of leading-edge science to save and improve lives
around the world. For more than 130 years, we have brought hope to
humanity through the development of important medicines and
vaccines. We aspire to be the premier research-intensive
biopharmaceutical company in the world – and today, we are at the
forefront of research to deliver innovative health solutions that
advance the prevention and treatment of diseases in people and
animals. We foster a diverse and inclusive global workforce and
operate responsibly every day to enable a safe, sustainable and
healthy future for all people and communities. For more
information, visit www.merck.com and connect with us
on Twitter, Facebook, Instagram, YouTube and LinkedIn.
About the Astellas, Seagen and Merck
Collaboration
Astellas and Seagen entered a clinical
collaboration agreement with Merck to evaluate the combination of
Astellas' and Seagen's PADCEV® (enfortumab
vedotin-ejfv) and Merck's KEYTRUDA® (pembrolizumab) in
patients with previously untreated metastatic urothelial cancer.
KEYTRUDA is a registered trademark of Merck Sharp & Dohme
Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Astellas Cautionary Notes
In this press release,
statements made with respect to current plans, estimates,
strategies and beliefs and other statements that are not historical
facts are forward-looking statements about the future performance
of Astellas. These statements are based on management's current
assumptions and beliefs in light of the information currently
available to it and involve known and unknown risks and
uncertainties. A number of factors could cause actual results to
differ materially from those discussed in the forward-looking
statements. Such factors include, but are not limited to: (i)
changes in general economic conditions and in laws and regulations,
relating to pharmaceutical markets, (ii) currency exchange rate
fluctuations, (iii) delays in new product launches, (iv) the
inability of Astellas to market existing and new products
effectively, (v) the inability of Astellas to continue to
effectively research and develop products accepted by customers in
highly competitive markets, and (vi) infringements of Astellas'
intellectual property rights by third parties.
Information about pharmaceutical products (including products
currently in development), which is included in this press release,
is not intended to constitute an advertisement or medical
advice.
Seagen Forward-Looking Statements
Certain statements made in this press release are forward-looking,
such as those, among others, relating to the potential for FDA
approval in the referenced indication; the timing of any potential
approval; the therapeutic potential of PADCEV alone or in
combination; its possible efficacy, safety and therapeutic uses;
development plans; planned and ongoing clinical trials; and the
potential for EV-302 to serve as a confirmatory trial in the U.S.
or as the basis for global registration. Actual results or
developments may differ materially from those projected or implied
in these forward-looking statements. Factors that may cause such a
difference include, without limitation, the possibility that the
referenced sBLAs may not be approved by the FDA in a timely manner
or at all or with the requested label; the risk of adverse events
and the potential for newly-emerging safety signals; the risk of
adverse regulatory actions; and the risk of delays, setbacks or
failures in clinical development and regulatory activities, the
submission of regulatory applications and the regulatory review
process for a variety of reasons, including without limitation the
inherent difficulty and uncertainty of pharmaceutical product
development, possible required modifications to clinical trials,
the inability to provide information and institute safety
mitigation measures as may be required by the FDA or other
regulatory authorities from time to time, failure to properly
conduct or manage clinical trials, and failure of clinical results
to support continued development or regulatory approvals. More
information about the risks and uncertainties faced by Seagen is
contained under the caption "Risk Factors" included in the
company's Quarterly Report on Form 10-Q for the quarter ended
September 30, 2022 filed with the
Securities and Exchange Commission. Seagen disclaims any intention
or obligation to update or revise any forward-looking statements,
whether as a result of new information, future events or otherwise,
except as required by law.
Forward-Looking Statement of Merck & Co., Inc.,
Rahway, N.J., USA
This news
release of Merck & Co., Inc., Rahway,
N.J., USA (the "company") includes "forward-looking
statements" within the meaning of the safe harbor provisions of the
U.S. Private Securities Litigation Reform Act of 1995. These
statements are based upon the current beliefs and expectations of
the company's management and are subject to significant risks and
uncertainties. There can be no guarantees with respect to pipeline
candidates that the candidates will receive the necessary
regulatory approvals or that they will prove to be commercially
successful. If underlying assumptions prove inaccurate or risks or
uncertainties materialize, actual results may differ materially
from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of the global outbreak of novel coronavirus disease
(COVID-19); the impact of pharmaceutical industry regulation and
health care legislation in the United
States and internationally; global trends toward health care
cost containment; technological advances, new products and patents
attained by competitors; challenges inherent in new product
development, including obtaining regulatory approval; the company's
ability to accurately predict future market conditions;
manufacturing difficulties or delays; financial instability of
international economies and sovereign risk; dependence on the
effectiveness of the company's patents and other protections for
innovative products; and the exposure to litigation, including
patent litigation, and/or regulatory actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company's Annual
Report on Form 10-K for the year ended December 31, 2021 and the company's other filings
with the Securities and Exchange Commission (SEC) available at the
SEC's Internet site (www.sec.gov).
1 Hoimes C, Flaig T, Milowsky M, et al. Enfortumab
Vedotin Plus Pembrolizumab in Previously Untreated Advanced
Urothelial Cancer. J Clin Oncol 2022.
2 Rosenberg J, Milowsky M, Ramamurthy C, et al. Study
EV-103 Cohort K: Antitumor activity of enfortumab vedotin
monotherapy or in combination with pembrolizumab in previously
untreated cisplatin-ineligible patients with locally advanced or
metastatic urothelial cancer (la/mUC) [abstract]. In 2022 European
Society for Medical Oncology; 2022 Sept
9-13; Paris, France, ESMO
2022. Abstract 2895.
3 American Cancer Society. Cancer Facts & Figures.
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf.
Accessed December 19, 2022.
4 American Society of Clinical Oncology. Bladder Cancer:
Introduction (12-21).
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed December 19, 2022.
5 National Cancer Institute Surveillance, Epidemiology,
and End Results Program. Cancer stat facts: bladder cancer. 2022.
Available at https://seer.cancer.gov/statfacts/html/urinb.html.
Accessed December 19, 2022.
6 International Agency for Research on Cancer. Cancer
Tomorrow: Bladder. http://gco.iarc.fr/tomorrow. Accessed
December 19, 2022.
7 Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab
Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly
Potent Therapeutic Agent in Multiple Preclinical Cancer Models.
Cancer Res 2016;76(10):3003-13.
8 PADCEV [package insert]. Northbrook, IL: Astellas Pharma US, Inc.
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SOURCE Astellas Pharma Inc.