– Results demonstrated a 64.5%
confirmed objective response rate in patients treated with
investigational combination of enfortumab vedotin and pembrolizumab
–
– Data highlighted in late-breaking
presentation at the European Society for Medical Oncology (ESMO)
Congress 2022 –
TOKYO and BOTHELL,
Wash. and RAHWAY,
N.J., Sept. 12, 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 results from the phase
1b/2 EV-103 clinical trial (also
known as KEYNOTE-869) Cohort K investigating PADCEV®
(enfortumab vedotin-ejfv) in combination with Merck's anti-PD-1
therapy KEYTRUDA® (pembrolizumab) and PADCEV alone as
first-line treatment in patients with unresectable locally advanced
or metastatic urothelial cancer (la/mUC) who are ineligible to
receive cisplatin-based chemotherapy. The findings were presented
today at the European Society for Medical Oncology (ESMO) Congress
as part of a late-breaking abstract presentation (Abstract
#LBA73).
In patients treated with enfortumab vedotin and pembrolizumab
(n=76), results demonstrated a 64.5% confirmed objective response
rate (ORR) (95% CI: 52.7 to 75.1) per RECIST v1.1 by blinded
independent central review (BICR), the primary endpoint of Cohort
K, with 10.5% of patients experiencing a complete response and
53.9% of patients experiencing a partial response. The median
duration of response (DOR) per BICR was not reached (95% CI: 10.25
months to NR). All-grade treatment-related adverse events (TRAEs)
of special interest for enfortumab vedotin in combination with
pembrolizumab were skin reactions (67.1%), peripheral
neuropathy (60.5%), ocular disorders (dry eye, blurred vision, and
corneal disorders) (26.3%), hyperglycemia (14.5%), and
infusion-related reactions (3.9%). Pembrolizumab adverse events of
special interest were consistent with previously observed safety
data from monotherapy with the exception of severe skin reactions.
Overall, the results were generally consistent with previously
reported efficacy and safety results of the EV-103/KEYNOTE-869
dose-escalation cohort and expansion Cohort A.1
Please see Important Safety Information at the end of this press
release for both drugs, including BOXED WARNING for enfortumab
vedotin and immune-mediated adverse reactions for
pembrolizumab.
Cohort K also included a monotherapy arm in which patients were
treated with enfortumab vedotin alone (n=73), though this study was
not designed to support a formal comparison between the two arms.
Results showed a 45.2% confirmed ORR (95% CI: 33.5 to 57.3) per
RECIST v1.1 by BICR, with 4.1% of patients experiencing a complete
response and 41.1% of patients experiencing a partial response. The
median DOR was 13.2 months (95% CI: 6.14 to 15.97) per RECIST v1.1
by BICR. All-grade TRAEs of special interest for enfortumab
vedotin were peripheral neuropathy (54.8%), skin reactions
(45.2%), ocular disorders (dry eye, blurred vision, and corneal
disorders) (28.8%), hyperglycemia (11.0%), and infusion-related
reactions (5.5%).
Additional secondary endpoints in the EV-103 Cohort K trial
included progression-free survival (PFS) and overall survival (OS).
Among patients treated with enfortumab vedotin and pembrolizumab,
median PFS was not reached (95% CI: 8.31 months to NR). Median OS
was 22.3 months (95% CI: 19.09 to NR). Among patients treated with
enfortumab vedotin, median PFS was 8.0 months (95% CI: 6.05 to
10.35) and median OS was 21.7 months (95% CI: 15.21 to NR).
TRAEs of any grade that occurred in more than 20% of patients
treated with enfortumab vedotin alone or in combination with
pembrolizumab were fatigue, peripheral sensory neuropathy,
alopecia, rash maculo-papular, pruritus, dysgeusia, weight
decreased, diarrhea, decreased appetite, nausea, and dry eye.
"Results from EV-103/KEYNOTE-869 Cohort K support the ongoing
investigation of enfortumab vedotin and pembrolizumab in
cisplatin-ineligible patients with locally advanced or metastatic
urothelial cancer who are in need of treatment options, and this
combination may be an important therapeutic option for these
patients," said Jonathan E.
Rosenberg, M.D., Chief, Genitourinary Medical Oncology
Service, Division of Solid Tumor Oncology, and Enno W. Ercklentz
Chair, Memorial Sloan Kettering Cancer Center and
EV-103/KEYNOTE-869 Cohort K primary investigator. Dr. Rosenberg has
consulting relationships with Astellas, Seagen and Merck.
"We're encouraged by these positive findings from the
combination of enfortumab vedotin and pembrolizumab in people with
advanced urothelial cancer who historically have had limited
treatment options in the first-line setting, and we intend to
discuss these results with regulatory authorities," said Ahsan
Arozullah, M.D., M.P.H., Senior Vice President and Head of
Development Therapeutic Areas, Astellas.
"Nearly sixty-five percent of patients who were treated with
enfortumab vedotin and pembrolizumab responded to the combination,
with almost eleven percent showing no detectable cancer following
treatment. These study results represent an encouraging finding for
people with advanced urothelial cancer who are not eligible for
cisplatin treatment," said Marjorie
Green, Senior Vice President and Head of Late Stage
Development, Seagen.
"We're pleased that this combination provided a meaningful
benefit to this group of advanced bladder cancer patients in this
study, and we will continue to investigate enfortumab vedotin plus
pembrolizumab through our collaboration," said Dr. Eliav Barr, Senior Vice President, Head of
Global Clinical Development and Chief Medical Officer, Merck
Research Laboratories.
In February 2020, the U.S. Food
and Drug Administration (FDA) granted Breakthrough Therapy
designation for enfortumab vedotin in combination with
pembrolizumab for patients with unresectable la/mUC who are
ineligible to receive cisplatin-based chemotherapy in the
first-line setting. The designation is based on results from the
dose-escalation cohort and expansion Cohort A of the phase
1b/2 trial, EV-103/KEYNOTE-869
(NCT03288545), evaluating patients with la/mUC who are ineligible
to receive cisplatin-based chemotherapy treated in the first-line
setting with enfortumab vedotin in combination with
pembrolizumab.
Astellas, Seagen and Merck are further investigating enfortumab
vedotin plus pembrolizumab in Phase 3 studies, including
EV-302/KEYNOTE-A39 (NCT04223856), which is intended to confirm
these results for the investigational treatment combination in
previously untreated la/mUC and in muscle-invasive bladder cancer
in EV-304/KEYNOTE-B15 (NCT04700124) and EV-303/KEYNOTE-905
(NCT03924895).
About Bladder and Urothelial Cancer
It is estimated
that approximately 83,730 people in the U.S. were diagnosed with
bladder cancer in 2021.2 Urothelial
cancer accounts for 90% of all bladder cancers and can also be
found in the renal pelvis, ureter and
urethra.3 Globally, approximately 573,000 new
cases of bladder cancer and 212,000 deaths are reported
annually.4
About the EV-103/KEYNOTE-869 Trial (Cohort
K)
The EV-103 trial (NCT03288545) is an ongoing,
multi-cohort, open-label, multicenter phase 1b/2 trial 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.
Cohort K of the EV-103/KEYNOTE-869 trial is a randomized 1:1
cohort investigating enfortumab vedotin alone (n=73) or in
combination with pembrolizumab (n=76) in adult patients with
unresectable la/mUC who are ineligible for cisplatin-based
chemotherapy and have received no prior treatment
for la/mUC. The enfortumab vedotin monotherapy study arm
is intended to characterize the activity of enfortumab vedotin
alone in this patient population. The key outcome measure of
EV-103/KEYNOTE-869 Cohort K is objective response rate (ORR) per
blinded independent central review (BICR) using RECIST 1.1.
Secondary endpoints include ORR per investigator assessment;
duration of response (DOR), disease control rate (DCR) and
progression-free survival (PFS) per BICR and investigator
assessment; overall survival (OS); and assessment of safety.
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.5 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).6
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.6
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). 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. Withhold PADCEV and refer for specialized care for
suspected SJS or TEN or for severe (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). 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 KEYTRUDA indications 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 therapeutic potential
of PADCEV alone or in combination, including its possible efficacy,
safety and therapeutic uses; plans to discuss Cohort K results with
regulatory authorities; and clinical development plans, including
planned and ongoing clinical trials. 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
data from the EV-103 trial may not be sufficient to support any
regulatory approval; the risk of adverse events, including the
potential for newly-emerging safety signals; adverse regulatory
actions; delays, setbacks or failures in clinical development
activities, the submission of regulatory applications and the
regulatory review process for a variety of reasons, including 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
June 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 C.J. Hoimes, J.E. Rosenberg et.al. EV-103: Initial
results of enfortumab vedotin plus pembrolizumab for locally
advanced or metastatic urothelial carcinoma. Annals of Oncology
2019; 30 (Supplement 5): v356–v402.
2 American Cancer Society. Cancer Facts & Figures.
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf.
Accessed September 10, 2022.
3 American Society of Clinical Oncology. Bladder Cancer:
Introduction (9-20).
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed September 10, 2022.
4 International Agency for Research on Cancer. Cancer
Tomorrow: Bladder. http://gco.iarc.fr/tomorrow. Accessed
September 10, 2022.
5 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.
6 PADCEV [package insert]. Northbrook, IL: Astellas Pharma US, Inc.
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