Overall survival (OS) data for KEYTRUDA®
(pembrolizumab) in earlier stages of women’s cancers, including
high-risk early-stage triple-negative breast cancer (KEYNOTE-522)
and high-risk locally advanced cervical cancer (KEYNOTE-A18),
selected for Presidential Symposium sessions
Ten-year OS data from KEYNOTE-006 and final
OS data from KEYNOTE-811 reinforce important role of KEYTRUDA for
certain patients with advanced melanoma and HER2-positive gastric
or gastroesophageal junction adenocarcinoma
Data presented at ESMO highlight progress in
Merck’s pipeline of antibody-drug conjugates (ADCs), including
patritumab deruxtecan (HER3-DXd), sacituzumab tirumotecan (sac-TMT)
and ifinatamab deruxtecan (I-DXd)
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced that new data for four approved medicines
and six pipeline candidates in more than 20 types of cancer will be
presented at the European Society for Medical Oncology (ESMO)
Congress 2024 in Barcelona, Spain, from Sept. 13-17. Study findings
from the Phase 3 KEYNOTE-522 trial (#LBA4) in high-risk early-stage
triple-negative breast cancer (TNBC), the Phase 3 KEYNOTE-A18 trial
(#709O) in high-risk locally advanced cervical cancer and the Phase
3 LEAP-012 trial (#LBA3) in unresectable, non-metastatic
hepatocellular carcinoma, in collaboration with Eisai, have been
selected for the ESMO Presidential Symposium Sessions. Data being
shared at the Congress showcase the company’s continued progress in
advancing clinical research for Merck’s broad portfolio and diverse
pipeline of investigational candidates, with a total of 80
abstracts being presented.
“Over the past decade, data on KEYTRUDA have contributed to
paradigm shifts in the treatment of some of the deadliest forms of
cancer and the rewriting of medical textbooks. We are very proud
that today marks ten years since KEYTRUDA received its first
approval in the U.S.,” said Dr. Eliav Barr, senior vice president
and head of global clinical development, chief medical officer,
Merck Research Laboratories. “The compelling data for KEYTRUDA at
this year’s ESMO are demonstrative of KEYTRUDA’s impressive
journey, from 10-year survival data in unresectable or metastatic
melanoma to new overall survival data in earlier stages of two
types of women’s cancers. We’re also excited to show how we’re
building on our leadership in oncology with data from our broad and
diverse pipeline as we work toward improved outcomes for as many
patients as possible.”
Presentations at the Congress will feature new or updated
findings from Merck’s broad portfolio of cancer medicines:
KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy; WELIREG®
(belzutifan); LENVIMA® (lenvatinib), in collaboration with Eisai;
and LYNPARZA® (olaparib), in collaboration with AstraZeneca.
Key data from Merck’s portfolio to be presented at ESMO
Congress 2024:
- First-time overall survival (OS) results from the Phase 3
KEYNOTE-522 trial evaluating KEYTRUDA in combination with
chemotherapy as neoadjuvant treatment and then continuing as single
agent as adjuvant treatment in patients with high-risk early-stage
TNBC (Presentation #LBA4; Presidential Symposium II:
Practice-changing trials).
- OS data from the Phase 3 KEYNOTE-A18 trial evaluating KEYTRUDA
in combination with concurrent chemoradiotherapy (CRT) as treatment
for patients with high-risk locally advanced cervical cancer
(Presentation #709O; Presidential Symposium I: Practice-changing
trials).1
- First presentation of results from the first interim analysis
of the Phase 3 LEAP-012 trial evaluating KEYTRUDA plus LENVIMA in
combination with transarterial chemoembolization (TACE) in patients
with unresectable, non-metastatic hepatocellular carcinoma
(Presentation #LBA3; Presidential Symposium I: Practice-changing
trials).2
- Ten-year OS data from the Phase 3 KEYNOTE-006 trial evaluating
KEYTRUDA compared to ipilimumab as first-line treatment for
patients with advanced melanoma (Presentation #LBA44; Mini oral
session: Melanoma and other skin tumours).
- OS data from the per protocol final analysis of the Phase 3
KEYNOTE-811 trial evaluating KEYTRUDA plus trastuzumab and
chemotherapy as first-line treatment for patients with advanced
human epidermal growth factor receptor 2 (HER2)-positive gastric or
gastroesophageal junction (GEJ) adenocarcinoma (Presentation
#1400O; Proffered paper session 2: GI tumours, upper
digestive).
- Data from the per protocol final analysis of the Phase 3
LITESPARK-005 trial evaluating WELIREG as treatment for adult
patients with advanced renal cell carcinoma that progressed
following PD-1/L1 inhibitor and vascular endothelial growth factor
tyrosine kinase inhibitor (VEGF-TKI) therapies (Presentation
#LBA74; Proffered paper session 1: GU tumours, non-prostate).
Additionally, new data on investigational candidates from
Merck’s pipeline will be presented at the Congress, including for:
patritumab deruxtecan (HER3-DXd), a HER3-directed antibody-drug
conjugate (ADC), and ifinatamab deruxtecan (I-DXd; also known as
MK-2400) being developed in collaboration with Daiichi Sankyo;
sacituzumab tirumotecan (sac-TMT; also known as MK-2870/SKB264), an
investigational anti-TROP2 ADC being developed in collaboration
with Kelun-Biotech; and opevesostat (also known as
MK-5684/ODM-208), an investigational steroid synthesis inhibitor in
collaboration with Orion.
Key data on investigational candidates from Merck’s pipeline
to be presented at ESMO Congress 2024:
- Data from the Phase 2 ICARUS-BREAST01 trial evaluating HER3-DXd
as treatment for patients with hormone-receptor
(HR)-positive/HER2-negative advanced breast cancer (Presentation
#340O; Proffered paper session: Breast cancer, metastatic).3
- First-time data from a Phase 2 study conducted in China,
independently led by Kelun-Biotech, evaluating sac-TMT as treatment
for patients with previously treated advanced endometrial carcinoma
and ovarian cancer (Presentation #715MO; Mini oral session 2:
Gynaecological cancers).4
- Findings from a Phase 2 study conducted in China, independently
led by Kelun-Biotech, evaluating sac-TMT plus KEYTRUDA as treatment
for patients with recurrent or metastatic cervical cancer
(Presentation #716MO; Mini oral session 2: Gynaecological
cancers).4
Details on abstracts listed above and additional key
abstracts for Merck
Breast cancer
Neoadjuvant pembrolizumab or
placebo plus chemotherapy followed by adjuvant pembrolizumab or
placebo for high-risk early-stage TNBC: Overall survival results
from the Phase 3 KEYNOTE-522 study. P. Schmid.
Presentation #LBA4, Presidential
Symposium II: Practice-changing trials
Efficacy, safety and biomarker
analysis of ICARUS-BREAST01: a Phase 2 Study of Patritumab
Deruxtecan (HER3-DXd), in patients (pts) with HR+/HER2- advanced
breast cancer (ABC). B. Pistilli.3
Presentation #340O, Proffered
paper session: Breast cancer, metastatic
Intensified alkylating
chemotherapy with autologous stem cell rescue (IACT) or
conventional chemotherapy followed by olaparib (CCT-O) in stage
III, HER2-negative, homologous recombination deficient (HRD) breast
cancer (BC): Survival results of the randomized-controlled SUBITO
trial. S. Linn.5
Presentation #LBA14, Mini oral
session: Breast cancer, early stage
Gastrointestinal
cancers
Transarterial Chemoembolization
(TACE) With or Without Lenvatinib (len) + Pembrolizumab (pembro)
for Intermediate-Stage Hepatocellular Carcinoma (HCC): Phase 3
LEAP-012 Study. J. Llovet.2
Presentation #LBA3, Presidential
Symposium I: Practice-changing trials
Final overall survival for the
Phase 3, KEYNOTE-811 study of pembrolizumab plus trastuzumab and
chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ
adenocarcinoma. S. Lonardi.
Presentation #1400O, Proffered
paper session 2: GI tumours, upper digestive
Genitourinary cancers
Final analysis of the Phase 3
LITESPARK-005 study of belzutifan versus everolimus in participants
(pts) with previously treated advanced clear cell renal cell
carcinoma (ccRCC). B. I. Rini.
Presentation #LBA74, Proffered
paper session 1: GU tumours, non-prostate
Opevesostat (MK-5684/ODM-208), an
oral CYP11A1 inhibitor, in metastatic castration-resistant prostate
cancer (mCRPC): updated CYPIDES Phase 2 results. K. Fizazi.6
Presentation #1605P, Poster
Alliance A031501: AMBASSADOR
Study of Adjuvant Pembrolizumab (Pembro) in Muscle-Invasive
Urothelial Carcinoma (MIUC) vs Observation (Obs): Extended
follow-up disease-free survival (DFS) results and metastatic (met)
disease recurrence distribution. A. B. Apolo.7
Presentation #1964MO, Mini oral
session: GU tumours, non-prostate
Study EV-103 Dose
Escalation/Cohort A (DE/A): 5y Follow-Up Of First-Line (1L)
Enfortumab Vedotin (EV) + Pembrolizumab (P) in Cisplatin
(cis)-Ineligible Locally Advanced Or Metastatic Urothelial
Carcinoma (la/mUC). J. E. Rosenberg.8
Presentation #1968P, Poster
Preliminary Efficacy And Safety
Of Disitamab Vedotin (DV) With Pembrolizumab (P) In Treatment
(Tx)-Naive HER2-Expressing, Locally Advanced Or Metastatic
Urothelial Carcinoma (la/mUC): RC48G001 Cohort C. M. D.
Galsky.8
Presentation #1967MO, Mini oral
session: GU tumours, non-prostate
Gynecologic cancers
Pembrolizumab plus
chemoradiotherapy for high-risk locally advanced cervical cancer:
Overall survival results from the randomized, double-blind, Phase 3
ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. D. Lorusso.1
Presentation #709O, Presidential
Symposium I: Practice-changing trials
Safety and Efficacy of
Sacituzumab Tirumotecan (sac-TMT) in Patients (pts) with Previously
Treated Advanced Endometrial Carcinoma (EC) and Ovarian Cancer (OC)
from a Phase 2 Study. D. Wang.4
Presentation #715MO, Mini oral
session 2: Gynaecological cancers
Efficacy and Safety of
Sacituzumab Tirumotecan (sac-TMT) Plus Pembrolizumab in Patients
with Recurrent or Metastatic Cervical Cancer. X. Wu.4
Presentation #716MO, Mini oral
session 2: Gynaecological cancers
Lung cancer
Neoadjuvant Pembrolizumab
(pembro) or Placebo (pbo) Plus Chemotherapy and Adjuvant Pembro or
Pbo for Early-Stage NSCLC: Subgroup Analyses of the Phase 3
KEYNOTE-671 Study. M. C. Garassino.
Presentation #1210P, Poster
Ifinatamab deruxtecan (I-DXd;
DS-7300) in patients with advanced solid tumors: Updated clinical
and biomarker results from a phase I/II study. M. R. Patel. 3
Presentation #690P, Poster
Melanoma and other skin
cancers
Pembrolizumab vs Ipilimumab in
Advanced Melanoma: 10-Year Follow-Up of the Phase 3 KEYNOTE-006
Study. C. Robert
Presentation #LBA44, Mini oral
session: Melanoma and other skin tumours
Pembrolizumab versus placebo
after a complete resection of high-risk stage III melanoma: 7-year
results of the EORTC 1325-MG/Keynote-054 double-blind Phase 3
trial. A. M. Eggermont.
Presentation #1095P, Poster
KEYMAKER-U02 substudy 02C:
neoadjuvant pembrolizumab (pembro) and investigational agents
followed by adjuvant pembro for stage IIIB-D melanoma. G. V.
Long.
Presentation #1082O, Proffered
paper session: Melanoma and other skin tumours
Pembrolizumab (pembro) vs placebo
as adjuvant therapy for high-risk stage II melanoma: Long-term
follow-up, rechallenge, and crossover in KEYNOTE-716. J. J.
Luke.
Presentation #1078MO, Mini oral
session: Melanoma and other skin tumours
KEYMAKER 02B: A randomized trial
of pembrolizumab (pembro) alone or with investigational agents as
first-line treatment for advanced melanoma. R. Dummer.
Presentation #1083P, Poster
Primary Results from TACTI-003: A
Randomized Phase IIb Trial Comparing Eftilagimod Alpha (soluble
LAG-3) Plus Pembrolizumab Versus Pembrolizumab Alone in First-Line
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with
CPS ≥1. C. A. Kristensen.9
Presentation #LBA35, Proffered
paper session: Head and neck cancer
1 In collaboration with the European Network for Gynaecological
Oncology Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) 2
In collaboration with Eisai 3 In collaboration with Daiichi Sankyo
4 Independent study led by Kelun-Biotech 5 In collaboration with
AstraZeneca 6 In collaboration with Orion Pharma 7 Sponsored by
U.S. National Cancer Institute (NCI)/led by Alliance for Clinical
Trials in Oncology 8 In collaboration with Astellas/Pfizer 9 In
collaboration with Immutep
About Merck’s early-stage cancer clinical program
Finding cancer at an earlier stage may give patients a greater
chance of long-term survival. Many cancers are considered most
treatable and potentially curable in their earliest stage of
disease. Building on the strong understanding of the role of
KEYTRUDA in later-stage cancers, Merck is evaluating our portfolio
of medicines and pipeline candidates in earlier disease states,
with more than 30 ongoing registrational studies across multiple
types of cancer.
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.
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.
KEYTRUDA is indicated for the treatment of patients with
resectable (tumors ≥4 cm or node positive) NSCLC in combination
with platinum-containing chemotherapy as neoadjuvant treatment, and
then continued as a single agent as adjuvant treatment after
surgery.
KEYTRUDA, as a single agent, is indicated as adjuvant treatment
following resection and platinum-based chemotherapy for adult
patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
Urothelial Cancer
KEYTRUDA, in combination with enfortumab vedotin, is indicated
for the treatment of adult patients with locally advanced or
metastatic urothelial cancer.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with locally advanced or metastatic urothelial
carcinoma:
- 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.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with Bacillus Calmette-Guerin (BCG)-unresponsive,
high-risk, non-muscle invasive bladder cancer (NMIBC) with
carcinoma in situ (CIS) with or without papillary tumors who are
ineligible for or have elected not to undergo cystectomy.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and
platinum containing chemotherapy, is indicated for the first-line
treatment of adults with locally advanced unresectable or
metastatic HER2-positive gastric or gastroesophageal junction (GEJ)
adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by
an FDA-approved test.
This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval
of this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
KEYTRUDA, in combination with fluoropyrimidine- and
platinum-containing chemotherapy, is indicated for the first-line
treatment of adults with locally advanced unresectable or
metastatic HER2-negative gastric or gastroesophageal junction (GEJ)
adenocarcinoma.
Cervical Cancer
KEYTRUDA, in combination with chemoradiotherapy (CRT), is
indicated for the treatment of patients with FIGO 2014 Stage
III-IVA 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) secondary to hepatitis B who have
received prior systemic therapy other than a PD-1/PD-L1-containing
regimen.
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.
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 programmed death receptor-1 (PD-1) or
the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1
pathway, thereby removing inhibition of the immune response,
potentially breaking peripheral tolerance and inducing
immune-mediated adverse reactions. Immune-mediated adverse
reactions, which may be severe or fatal, can occur in any organ
system or tissue, can affect more than one body system
simultaneously, and can occur at any time after starting treatment
or after discontinuation of treatment. Important immune-mediated
adverse reactions listed here may not include all possible severe
and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be
clinical manifestations of underlying immune-mediated adverse
reactions. Early identification and management are essential to
ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver
enzymes, creatinine, and thyroid function at baseline and
periodically during treatment. 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.
Pneumonitis occurred in 7% (41/580) of adult patients with
resected NSCLC who received KEYTRUDA as a single agent for adjuvant
treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and
Grade 3 (1%) adverse reactions. Patients received high-dose
corticosteroids for a median duration of 10 days (range: 1 day to
2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26
(4.5%) of patients. Of the patients who developed pneumonitis, 54%
interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had
resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present
with diarrhea. Cytomegalovirus 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. The incidence of new or
worsening hyperthyroidism was higher in 580 patients with resected
NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single
agent as adjuvant treatment, including Grade 3 (0.2%)
hyperthyroidism. The incidence of new or worsening hypothyroidism
was higher in 580 patients with resected NSCLC, occurring in 22% of
patients receiving KEYTRUDA as a single agent as adjuvant treatment
(KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.
Type 1 Diabetes Mellitus (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, other
transplant (including corneal graft) 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 treatments and
allogeneic HSCT. Follow patients closely for evidence of these
complications and intervene promptly. Consider the benefit vs risks
of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic
HSCT.
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-671, adverse reactions occurring in patients with
resectable NSCLC receiving KEYTRUDA in combination with
platinum-containing chemotherapy, given as neoadjuvant treatment
and continued as single-agent adjuvant treatment, were generally
similar to those occurring in patients in other clinical trials
across tumor types receiving KEYTRUDA in combination with
chemotherapy.
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, insomnia, palmar-
plantar erythrodysesthesia, urinary tract infection, and
hypothyroidism.
In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was
administered in combination with platinum-containing chemotherapy
as neoadjuvant treatment, serious adverse reactions occurred in 34%
of 396 patients. The most frequent (≥2%) serious adverse reactions
were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia
(2%). Fatal adverse reactions occurred in 1.3% of patients,
including death due to unknown cause (0.8%), sepsis (0.3%), and
immune-mediated lung disease (0.3%). Permanent discontinuation of
any study drug due to an adverse reaction occurred in 18% of
patients who received KEYTRUDA in combination with
platinum-containing chemotherapy; the most frequent adverse
reactions (≥1%) that led to permanent discontinuation of any study
drug were acute kidney injury (1.8%), interstitial lung disease
(1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia
(1.3%).
Of the KEYTRUDA-treated patients who received neoadjuvant
treatment, 6% of 396 patients did not receive surgery due to
adverse reactions. The most frequent (≥1%) adverse reaction that
led to cancellation of surgery in the KEYTRUDA arm was interstitial
lung disease (1%).
In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was
administered as a single agent as adjuvant treatment, serious
adverse reactions occurred in 14% of 290 patients. The most
frequent serious adverse reaction was pneumonia (3.4%). One fatal
adverse reaction of pulmonary hemorrhage occurred. Permanent
discontinuation of KEYTRUDA due to an adverse reaction occurred in
12% of patients who received KEYTRUDA as a single agent, given as
adjuvant treatment; the most frequent adverse reactions (≥1%) that
led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%),
interstitial lung disease (1.4%), increased aspartate
aminotransferase (1%), and musculoskeletal pain (1%).
Adverse reactions observed in KEYNOTE-091 were generally similar
to those occurring in other patients with NSCLC receiving KEYTRUDA
as a single agent, with the exception of hypothyroidism (22%),
hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse
reactions of myocarditis occurred.
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-A39, when KEYTRUDA was administered in combination
with enfortumab vedotin to patients with locally advanced or
metastatic urothelial cancer (n=440), fatal adverse reactions
occurred in 3.9% of patients, including acute respiratory failure
(0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious
adverse reactions occurred in 50% of patients receiving KEYTRUDA in
combination with enfortumab vedotin; the serious adverse reactions
in ≥2% of patients were rash (6%), acute kidney injury (5%),
pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea
(3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).
Permanent discontinuation of KEYTRUDA occurred in 27% of patients.
The most common adverse reactions (≥2%) resulting in permanent
discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash
(3.4%). The most common adverse reactions (≥20%) occurring in
patients treated with KEYTRUDA in combination with enfortumab
vedotin were rash (68%), peripheral neuropathy (67%), fatigue
(51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss
(33%), decreased appetite (33%), nausea (26%), constipation (26%),
dry eye (24%), dysgeusia (21%), and urinary tract infection
(21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
metastatic urothelial carcinoma. 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 metastatic
urothelial carcinoma. 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-158 and KEYNOTE-164, adverse reactions occurring in
patients with MSI-H or dMMR cancer were similar to those occurring
in patients with other solid tumors who received KEYTRUDA as a
single agent.
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 vs standard
of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).
In KEYNOTE-859, when KEYTRUDA was administered in combination
with fluoropyrimidine- and platinum-containing chemotherapy,
serious adverse reactions occurred in 45% of 785 patients. Serious
adverse reactions in >2% of patients included pneumonia (4.1%),
diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal
adverse reactions occurred in 8% of patients who received KEYTRUDA
including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was
permanently discontinued due to adverse reactions in 15% of
patients. The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and
diarrhea (1.0%). The most common adverse reactions (reported in
≥20%) in patients receiving KEYTRUDA in combination with
chemotherapy were peripheral neuropathy (47%), nausea (46%),
fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite
(29%), abdominal pain (26%), palmar-plantar erythrodysesthesia
syndrome (25%), constipation (22%), and weight loss (20%).
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-A18, when KEYTRUDA was administered with CRT
(cisplatin plus external beam radiation therapy [EBRT] followed by
brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA
cervical cancer, fatal adverse reactions occurred in 1.4% of 292
patients, including 1 case each (0.3%) of large intestinal
perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious
adverse reactions occurred in 30% of patients; those ≥1% included
urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%).
KEYTRUDA was discontinued for adverse reactions in 7% of patients.
The most common adverse reaction (≥1%) resulting in permanent
discontinuation was diarrhea (1%). For patients treated with
KEYTRUDA in combination with CRT, the most common adverse reactions
(≥10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary
tract infection (32%), fatigue (26%), hypothyroidism (20%),
constipation (18%), decreased appetite and weight loss (17% each),
abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria,
rash (11% each), and pelvic pain (10%).
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%).
In KEYNOTE-394, KEYTRUDA was discontinued due to adverse
reactions in 13% of 299 patients with previously treated
hepatocellular carcinoma. The most common adverse reaction
resulting in permanent discontinuation of KEYTRUDA was ascites
(2.3%). The most common adverse reactions in patients receiving
KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%),
decreased appetite (15%), pruritis (12%), upper respiratory tract
infection (11%), cough (11%), and hypothyroidism (10%).
In KEYNOTE-966, when KEYTRUDA was administered in combination
with gemcitabine and cisplatin, KEYTRUDA was discontinued for
adverse reactions in 15% of 529 patients with locally advanced
unresectable or metastatic biliary tract cancer. The most common
adverse reaction resulting in permanent discontinuation of KEYTRUDA
(≥1%) was pneumonitis (1.3%). Adverse reactions leading to the
interruption of KEYTRUDA occurred in 55% of patients. The most
common adverse reactions or laboratory abnormalities leading to
interruption of KEYTRUDA (≥2%) were decreased neutrophil count
(18%), decreased platelet count (10%), anemia (6%), decreased white
blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis
(2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary
obstruction (2.3%).
In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in
patients with MCC (n=105) were generally similar to those occurring
in patients with melanoma or NSCLC who received KEYTRUDA as a
single agent.
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-581, when KEYTRUDA was administered in combination
with LENVIMA to patients with advanced renal cell carcinoma
(n=352), fatal adverse reactions occurred in 4.3% of patients.
Serious adverse reactions occurred in 51% of patients; the most
common (≥2%) were hemorrhagic events (5%), diarrhea (4%),
hypertension, myocardial infarction, pneumonitis, and vomiting (3%
each), acute kidney injury, adrenal insufficiency, dyspnea, and
pneumonia (2% each).
Permanent discontinuation of KEYTRUDA, LENVIMA, or both due to
an adverse reaction occurred in 37% of patients; 29% KEYTRUDA only,
26% LENVIMA only, and 13% both. The most common adverse reaction
(≥2%) resulting in permanent discontinuation of KEYTRUDA, LENVIMA,
or the combination were pneumonitis, myocardial infarction,
hepatotoxicity, acute kidney injury, rash (3% each), and diarrhea
(2%).
The most common adverse reactions (≥20%) observed with KEYTRUDA
in combination with LENVIMA were fatigue (63%), diarrhea (62%),
musculoskeletal disorders (58%), hypothyroidism (57%), hypertension
(56%), stomatitis (43%), decreased appetite (41%), rash (37%),
nausea (36%), weight loss, dysphonia and proteinuria (30% each),
palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain
and hemorrhagic events (27% each), vomiting (26%), constipation and
hepatotoxicity (25% each), headache (23%), and acute kidney injury
(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%).
In KEYNOTE-868, when KEYTRUDA was administered in combination
with chemotherapy (paclitaxel and carboplatin) to patients with
advanced or recurrent endometrial carcinoma (n=382), serious
adverse reactions occurred in 35% of patients receiving KEYTRUDA in
combination with chemotherapy, compared to 19% of patients
receiving placebo in combination with chemotherapy (n=377). Fatal
adverse reactions occurred in 1.6% of patients receiving KEYTRUDA
in combination with chemotherapy, including COVID-19 (0.5%) and
cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse
reaction in 14% of patients. Adverse reactions occurring in
patients treated with KEYTRUDA and chemotherapy were generally
similar to those observed with KEYTRUDA alone or chemotherapy
alone, with the exception of rash (33% all Grades; 2.9% Grades
3-4).
In KEYNOTE-775, when KEYTRUDA was administered in combination
with LENVIMA to patients with advanced endometrial carcinoma that
was pMMR or not MSI-H (n=342), fatal adverse reactions occurred in
4.7% of patients. Serious adverse reactions occurred in 50% of
these patients; the most common (≥3%) were hypertension (4.4%) and
urinary tract infections (3.2%).
Discontinuation of KEYTRUDA due to an adverse reaction occurred
in 15% of these patients. The most common adverse reaction leading
to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).
The most common adverse reactions for KEYTRUDA in combination
with LENVIMA (reported in ≥20% patients) were hypothyroidism and
hypertension (67% each), fatigue (58%), diarrhea (55%),
musculoskeletal disorders (53%), nausea (49%), decreased appetite
(44%), vomiting (37%), stomatitis (35%), abdominal pain and weight
loss (34% each), urinary tract infections (31%), proteinuria (29%),
constipation (27%), headache (26%), hemorrhagic events (25%),
palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash
(20%).
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 last dose.
Pediatric Use
In KEYNOTE-051, 173 pediatric patients (65 pediatric patients
aged 6 months to younger than 12 years and 108 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 25 months).
Adverse reactions that occurred at a ≥10% higher rate in
pediatric patients when compared to adults were pyrexia (33%),
leukopenia (31%), vomiting (29%), neutropenia (28%), headache
(25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia
(17%), decreased lymphocyte count (13%), and decreased white blood
cell count (11%).
Geriatric Use
Of the 564 patients with locally advanced or metastatic
urothelial cancer treated with KEYTRUDA in combination with
enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144)
were 75 years or older. No overall differences in safety or
effectiveness were observed between patients 65 years of age or
older and younger patients. Patients 75 years of age or older
treated with KEYTRUDA in combination with enfortumab vedotin
experienced a higher incidence of fatal adverse reactions than
younger patients. The incidence of fatal adverse reactions was 4%
in patients younger than 75 and 7% in patients 75 years or
older.
Additional Selected KEYTRUDA Indications in the U.S.
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.
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.
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.
Biliary Tract Cancer
KEYTRUDA, in combination with gemcitabine and cisplatin, is
indicated for the treatment of patients with locally advanced
unresectable or metastatic biliary tract cancer (BTC).
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with recurrent locally advanced or metastatic Merkel cell
carcinoma (MCC).
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, in combination with lenvatinib, is indicated for the
first-line treatment of adult patients with advanced 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, in combination with carboplatin and paclitaxel,
followed by KEYTRUDA as a single agent, is indicated for the
treatment of adult patients with primary advanced or recurrent
endometrial carcinoma.
KEYTRUDA, in combination with lenvatinib, is indicated for the
treatment of adult patients with advanced endometrial carcinoma
that is mismatch repair proficient (pMMR) as determined by an
FDA-approved test or not MSI-H, who have disease progression
following prior systemic therapy in any setting are not candidates
for curative surgery or radiation.
KEYTRUDA, as a single agent, is indicated for the treatment of
adult 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 (mut/Mb)] 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.
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 LENVIMA® (lenvatinib); available as 10 mg and 4 mg
capsules
LENVIMA, discovered and developed by Eisai, is an orally
available multiple receptor tyrosine kinase inhibitor that inhibits
the kinase activities of vascular endothelial growth factor (VEGF)
receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA
inhibits other kinases that have been implicated in pathogenic
angiogenesis, tumor growth, and cancer progression in addition to
their normal cellular functions, including fibroblast growth factor
(FGF) receptors FGFR1-4, the platelet derived growth factor
receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor
models, LENVIMA decreased tumor-associated macrophages, increased
activated cytotoxic T cells, and demonstrated greater antitumor
activity in combination with an anti-PD-1 monoclonal antibody
compared to either treatment alone.
LENVIMA® (lenvatinib) Indications in the U.S.
- For the treatment of adult patients with locally recurrent or
metastatic, progressive, radioactive iodine-refractory
differentiated thyroid cancer (DTC).
- In combination with pembrolizumab, for the first-line treatment
of adult patients with advanced renal cell carcinoma (RCC).
- In combination with everolimus, for the treatment of adult
patients with advanced renal cell carcinoma (RCC) following one
prior anti-angiogenic therapy.
- For the first-line treatment of patients with unresectable
hepatocellular carcinoma (HCC).
- In combination with pembrolizumab, for the treatment of
patients with advanced endometrial carcinoma (EC) that is mismatch
repair proficient (pMMR), as determined by an FDA-approved test, or
not microsatellite instability-high (MSI-H), who have disease
progression following prior systemic therapy in any setting and are
not candidates for curative surgery or radiation.
Selected Safety Information for LENVIMA
Warnings and Precautions
Hypertension. In differentiated thyroid cancer (DTC),
hypertension occurred in 73% of patients on LENVIMA (44% grade
3-4). In advanced renal cell carcinoma (RCC), hypertension occurred
in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic
blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had
diastolic blood pressure ≥100 mmHg. In unresectable hepatocellular
carcinoma (HCC), hypertension occurred in 45% of LENVIMA-treated
patients (24% grade 3). Grade 4 hypertension was not reported in
HCC.
Serious complications of poorly controlled hypertension have
been reported. Control blood pressure prior to initiation. Monitor
blood pressure after 1 week, then every 2 weeks for the first 2
months, and then at least monthly thereafter during treatment.
Withhold and resume at reduced dose when hypertension is controlled
or permanently discontinue based on severity.
Cardiac Dysfunction. Serious and fatal cardiac
dysfunction can occur with LENVIMA. Across clinical trials in 799
patients with DTC, RCC, and HCC, grade 3 or higher cardiac
dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for
clinical symptoms or signs of cardiac dysfunction. Withhold and
resume at reduced dose upon recovery or permanently discontinue
based on severity.
Arterial Thromboembolic Events. Among patients receiving
LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of
any severity occurred in 2% of patients in RCC and HCC and 5% in
DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3%
across all clinical trials.
Among patients receiving LENVIMA with KEYTRUDA, arterial
thrombotic events of any severity occurred in 5% of patients in
CLEAR, including myocardial infarction (3.4%) and cerebrovascular
accident (2.3%).
Permanently discontinue following an arterial thrombotic event.
The safety of resuming after an arterial thromboembolic event has
not been established and LENVIMA has not been studied in patients
who have had an arterial thromboembolic event within the previous 6
months.
Hepatotoxicity. Across clinical studies enrolling 1,327
LENVIMA-treated patients with malignancies other than HCC, serious
hepatic adverse reactions occurred in 1.4% of patients. Fatal
events, including hepatic failure, acute hepatitis and hepatorenal
syndrome, occurred in 0.5% of patients. In HCC, hepatic
encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade
3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated
patients. 2% of patients discontinued LENVIMA due to hepatic
encephalopathy and 1% discontinued due to hepatic failure.
Monitor liver function prior to initiation, then every 2 weeks
for the first 2 months, and at least monthly thereafter during
treatment. Monitor patients with HCC closely for signs of hepatic
failure, including hepatic encephalopathy. Withhold and resume at
reduced dose upon recovery or permanently discontinue based on
severity.
Renal Failure or Impairment. Serious including fatal
renal failure or impairment can occur with LENVIMA. Renal
impairment was reported in 14% and 7% of LENVIMA-treated patients
in DTC and HCC, respectively. Grade 3-5 renal failure or impairment
occurred in 3% of patients with DTC and 2% of patients with HCC,
including 1 fatal event in each study. In RCC, renal impairment or
renal failure was reported in 18% of LENVIMA + everolimus–treated
patients (10% grade 3).
Initiate prompt management of diarrhea or
dehydration/hypovolemia. Withhold and resume at reduced dose upon
recovery or permanently discontinue for renal failure or impairment
based on severity.
Proteinuria. In DTC and HCC, proteinuria was reported in
34% and 26% of LENVIMA-treated patients, respectively. Grade 3
proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In
RCC, proteinuria occurred in 31% of patients receiving LENVIMA +
everolimus (8% grade 3). Monitor for proteinuria prior to
initiation and periodically during treatment. If urine dipstick
proteinuria ≥2+ is detected, obtain a 24-hour urine protein.
Withhold and resume at reduced dose upon recovery or permanently
discontinue based on severity.
Diarrhea. Of the 737 LENVIMA-treated patients in DTC and
HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea
occurred in 81% of LENVIMA + everolimus–treated patients (19% grade
3). Diarrhea was the most frequent cause of dose
interruption/reduction, and diarrhea recurred despite dose
reduction. Promptly initiate management of diarrhea. Withhold and
resume at reduced dose upon recovery or permanently discontinue
based on severity.
Fistula Formation and Gastrointestinal Perforation. Of
the 799 patients treated with LENVIMA or LENVIMA + everolimus in
DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred
in 2%. Permanently discontinue in patients who develop
gastrointestinal perforation of any severity or grade 3-4
fistula.
QT Interval Prolongation. In DTC, QT/QTc interval
prolongation occurred in 9% of LENVIMA-treated patients and QT
interval prolongation of >500 ms occurred in 2%. In RCC, QTc
interval increases of >60 ms occurred in 11% of patients
receiving LENVIMA + everolimus and QTc interval >500 ms occurred
in 6%. In HCC, QTc interval increases of >60 ms occurred in 8%
of LENVIMA-treated patients and QTc interval >500 ms occurred in
2%.
Monitor and correct electrolyte abnormalities at baseline and
periodically during treatment. Monitor electrocardiograms in
patients with congenital long QT syndrome, congestive heart
failure, bradyarrhythmias, or those who are taking drugs known to
prolong the QT interval, including Class Ia and III
antiarrhythmics. Withhold and resume at reduced dose upon recovery
based on severity.
Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in
9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia
improved or resolved following calcium supplementation with or
without dose interruption or dose reduction. In RCC, grade 3-4
hypocalcemia occurred in 6% of LENVIMA + everolimus–treated
patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of
LENVIMA-treated patients. Monitor blood calcium levels at least
monthly and replace calcium as necessary during treatment. Withhold
and resume at reduced dose upon recovery or permanently discontinue
depending on severity.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS).
Across clinical studies of 1,823 patients who received LENVIMA as a
single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with
MRI. Withhold and resume at reduced dose upon recovery or
permanently discontinue depending on severity and persistence of
neurologic symptoms.
Hemorrhagic Events. Serious including fatal hemorrhagic
events can occur with LENVIMA. In DTC, RCC, and HCC clinical
trials, hemorrhagic events, of any grade, occurred in 29% of the
799 patients treated with LENVIMA as a single agent or in
combination with everolimus. The most frequently reported
hemorrhagic events (all grades and occurring in at least 5% of
patients) were epistaxis and hematuria. In DTC, grade 3-5
hemorrhage occurred in 2% of LENVIMA-treated patients, including 1
fatal intracranial hemorrhage among 16 patients who received
LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5
hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients,
including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage
occurred in 5% of LENVIMA-treated patients, including 7 fatal
hemorrhagic events. Serious tumor-related bleeds, including fatal
hemorrhagic events, occurred in LENVIMA-treated patients in
clinical trials and in the postmarketing setting. In postmarketing
surveillance, serious and fatal carotid artery hemorrhages were
seen more frequently in patients with anaplastic thyroid carcinoma
(ATC) than other tumors. Safety and effectiveness of LENVIMA in
patients with ATC have not been demonstrated in clinical
trials.
Consider the risk of severe or fatal hemorrhage associated with
tumor invasion or infiltration of major blood vessels (eg, carotid
artery). Withhold and resume at reduced dose upon recovery or
permanently discontinue based on severity.
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid
Dysfunction. LENVIMA impairs exogenous thyroid suppression. In
DTC, 88% of patients had baseline thyroid stimulating hormone (TSH)
level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation
of TSH level >0.5 mU/L was observed post baseline in 57% of
LENVIMA-treated patients. In RCC and HCC, grade 1 or 2
hypothyroidism occurred in 24% of LENVIMA + everolimus–treated
patients and 21% of LENVIMA-treated patients, respectively. In
patients with normal or low TSH at baseline, elevation of TSH was
observed post baseline in 70% of LENVIMA-treated patients in HCC
and 60% of LENVIMA + everolimus–treated patients in RCC.
Monitor thyroid function prior to initiation and at least
monthly during treatment. Treat hypothyroidism according to
standard medical practice.
Impaired Wound Healing. Impaired wound healing has been
reported in patients who received LENVIMA. Withhold LENVIMA for at
least 1 week prior to elective surgery. Do not administer for at
least 2 weeks following major surgery and until adequate wound
healing. The safety of resumption of LENVIMA after resolution of
wound healing complications has not been established.
Osteonecrosis of the Jaw (ONJ). ONJ has been reported in
patients receiving LENVIMA. Concomitant exposure to other risk
factors, such as bisphosphonates, denosumab, dental disease or
invasive dental procedures, may increase the risk of ONJ.
Perform an oral examination prior to treatment with LENVIMA and
periodically during LENVIMA treatment. Advise patients regarding
good oral hygiene practices and to consider having preventive
dentistry performed prior to treatment with LENVIMA and throughout
treatment with LENVIMA.
Avoid invasive dental procedures, if possible, while on LENVIMA
treatment, particularly in patients at higher risk. Withhold
LENVIMA for at least 1 week prior to scheduled dental surgery or
invasive dental procedures, if possible. For patients requiring
invasive dental procedures, discontinuation of bisphosphonate
treatment may reduce the risk of ONJ.
Withhold LENVIMA if ONJ develops and restart based on clinical
judgement of adequate resolution.
Embryo‐Fetal Toxicity. Based on its mechanism of action
and data from animal reproduction studies, LENVIMA can cause fetal
harm when administered to pregnant women. In animal reproduction
studies, oral administration of LENVIMA during organogenesis at
doses below the recommended clinical doses resulted in
embryotoxicity, fetotoxicity, and teratogenicity in rats and
rabbits. Advise pregnant women of the potential risk to a fetus;
and advise females of reproductive potential to use effective
contraception during treatment with LENVIMA and for 30 days after
the last dose.
Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in
LENVIMA-treated patients were hypertension (73%), fatigue (67%),
diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%),
decreased weight (51%), nausea (47%), stomatitis (41%), headache
(38%), vomiting (36%), proteinuria (34%), palmar-plantar
erythrodysesthesia syndrome (32%), abdominal pain (31%), and
dysphonia (31%). The most common serious adverse reactions (≥2%)
were pneumonia (4%), hypertension (3%), and dehydration (3%).
Adverse reactions led to dose reductions in 68% of LENVIMA-treated
patients; 18% discontinued LENVIMA. The most common adverse
reactions (≥10%) resulting in dose reductions were hypertension
(13%), proteinuria (11%), decreased appetite (10%), and diarrhea
(10%); the most common adverse reactions (≥1%) resulting in
discontinuation of LENVIMA were hypertension (1%) and asthenia
(1%).
In RCC, the most common adverse reactions (≥20%) observed in
LENVIMA + KEYTRUDA-treated patients were fatigue (63%), diarrhea
(62%), musculoskeletal pain (58%), hypothyroidism (57%),
hypertension (56%), stomatitis (43%), decreased appetite (41%),
rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%),
proteinuria (30%), palmar-plantar erythrodysesthesia syndrome
(29%), abdominal pain (27%), hemorrhagic events (27%), vomiting
(26%), constipation (25%), hepatotoxicity (25%), headache (23%),
and acute kidney injury (21%).Fatal adverse reactions occurred in
4.3% of patients receiving LENVIMA in combination with KEYTRUDA,
including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one
case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea,
hypertensive crisis, increased blood creatinine, multiple organ
dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis,
pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious
adverse reactions occurred in 51% of patients receiving LENVIMA and
KEYTRUDA. Serious adverse reactions in ≥2% of patients were
hemorrhagic events (5%), diarrhea (4%), hypertension (3%),
myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute
kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and
pneumonia (2%).Permanent discontinuation of LENVIMA, KEYTRUDA, or
both due to an adverse reaction occurred in 37% of patients; 26%
LENVIMA only, 29% KEYTRUDA only, and 13% both drugs. The most
common adverse reactions (≥2%) leading to permanent discontinuation
of LENVIMA, KEYTRUDA, or both were pneumonitis (3%), myocardial
infarction (3%), hepatotoxicity (3%), acute kidney injury (3%),
rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA,
KEYTRUDA, or both due to an adverse reaction occurred in 78% of
patients receiving LENVIMA in combination with KEYTRUDA. LENVIMA
was interrupted in 73% of patients and both drugs were interrupted
in 39% of patients. LENVIMA was dose reduced in 69% of patients.
The most common adverse reactions (≥5%) resulting in dose reduction
or interruption of LENVIMA were diarrhea (26%), fatigue (18%),
hypertension (17%), proteinuria (13%), decreased appetite (12%),
palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis
(9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%),
abdominal pain (6%), vomiting (6%), increased ALT (5%), and
increased amylase (5%).
In RCC, the most common adverse reactions (≥30%) observed in
LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue
(73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting
(48%), nausea (45%), stomatitis (44%), hypertension (42%),
peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea
(35%), rash (35%), decreased weight (34%), hemorrhagic events
(32%), and proteinuria (31%). The most common serious adverse
reactions (≥5%) were renal failure (11%), dehydration (10%), anemia
(6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and
dyspnea (5%). Adverse reactions led to dose reductions or
interruption in 89% of patients. The most common adverse reactions
(≥5%) resulting in dose reductions were diarrhea (21%), fatigue
(8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and
proteinuria (5%). Treatment discontinuation due to an adverse
reaction occurred in 29% of patients.
In HCC, the most common adverse reactions (≥20%) observed in
LENVIMA-treated patients were hypertension (45%), fatigue (44%),
diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%),
decreased weight (31%), abdominal pain (30%), palmar-plantar
erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia
(24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea
(20%). The most common serious adverse reactions (≥2%) were hepatic
encephalopathy (5%), hepatic failure (3%), ascites (3%), and
decreased appetite (2%). Adverse reactions led to dose reductions
or interruption in 62% of patients. The most common adverse
reactions (≥5%) resulting in dose reductions were fatigue (9%),
decreased appetite (8%), diarrhea (8%), proteinuria (7%),
hypertension (6%), and palmar-plantar erythrodysesthesia syndrome
(5%). Treatment discontinuation due to an adverse reaction occurred
in 20% of patients. The most common adverse reactions (≥1%)
resulting in discontinuation of LENVIMA were fatigue (1%), hepatic
encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure
(1%).
In endometrial carcinoma, the most common adverse reactions
(≥20%) observed in LENVIMA + KEYTRUDA-treated patients were
hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea
(55%), musculoskeletal disorders (53%), nausea (49%), decreased
appetite (44%), vomiting (37%), stomatitis (35%), decreased weight
(34%), abdominal pain (34%), urinary tract infection (31%),
proteinuria (29%), constipation (27%), headache (26%), hemorrhagic
events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia
(22%), and rash (20%). Fatal adverse reactions among these patients
occurred in 4.7% of those treated with LENVIMA and KEYTRUDA,
including 2 cases of pneumonia, and 1 case of the following: acute
kidney injury, acute myocardial infarction, colitis, decreased
appetite, intestinal perforation, lower gastrointestinal
hemorrhage, malignant gastrointestinal obstruction, multiple organ
dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism,
and right ventricular dysfunction. Serious adverse reactions
occurred in 50% of these patients receiving LENVIMA and KEYTRUDA.
Serious adverse reactions with frequency ≥3% were hypertension
(4.4%), and urinary tract infection (3.2%). Discontinuation of
LENVIMA due to an adverse reaction occurred in 26% of these
patients. The most common (≥1%) adverse reactions leading to
discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%),
diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and
vomiting (1.2%). Dose reductions of LENVIMA due to adverse
reactions occurred in 67% of patients. The most common (≥5%)
adverse reactions resulting in dose reduction of LENVIMA were
hypertension (18%), diarrhea (11%), palmar-plantar
erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%),
decreased appetite (6%), asthenia (5%), and weight decreased (5%).
Dose interruptions of LENVIMA due to an adverse reaction occurred
in 58% of these patients. The most common (≥2%) adverse reactions
leading to interruption of LENVIMA were hypertension (11%),
diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting
(5%), increased alanine aminotransferase (3.5%), fatigue (3.5%),
nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%),
urinary tract infection (2.6%), increased aspartate
aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar
erythrodysesthesia (2%).
Use in Specific Populations
Because of the potential for serious adverse reactions in
breastfed children, advise women to discontinue breastfeeding
during treatment and for 1 week after last dose. LENVIMA may impair
fertility in males and females of reproductive potential.
No dose adjustment is recommended for patients with mild
(creatine clearance [CLcr] 60-89 mL/min) or moderate (CLcr 30-59
mL/min) renal impairment. LENVIMA concentrations may increase in
patients with DTC, RCC, or endometrial carcinoma and severe (CLcr
15-29 mL/min) renal impairment. Reduce the dose for patients with
DTC, RCC, or endometrial carcinoma and severe renal impairment.
There is no recommended dose for patients with HCC and severe renal
impairment. LENVIMA has not been studied in patients with end stage
renal disease.
No dose adjustment is recommended for patients with HCC and mild
hepatic impairment (Child-Pugh A). There is no recommended dose for
patients with HCC with moderate (Child-Pugh B) or severe
(Child-Pugh C) hepatic impairment. No dose adjustment is
recommended for patients with DTC, RCC, or endometrial carcinoma
and mild or moderate hepatic impairment. LENVIMA concentrations may
increase in patients with DTC, RCC, or endometrial carcinoma and
severe hepatic impairment. Reduce the dose for patients with DTC,
RCC, or endometrial carcinoma and severe hepatic impairment.
Please see Prescribing Information for LENVIMA (lenvatinib)
at
http://www.lenvima.com/pdfs/prescribing-information.pdf.
About LYNPARZA® (olaparib)
LYNPARZA is a first-in-class PARP inhibitor and the first
targeted treatment to potentially exploit DNA damage response (DDR)
pathway deficiencies, such as BRCA mutations, to preferentially
kill cancer cells. Inhibition of PARP with LYNPARZA leads to the
trapping of PARP bound to DNA single-strand breaks, stalling of
replication forks, their collapse and the generation of DNA
double-strand breaks and cancer cell death. LYNPARZA is being
tested in a range of tumor types with defects and dependencies in
the DDR.
LYNPARZA, which is being jointly developed and commercialized by
AstraZeneca and Merck, has a broad clinical trial development
program, and AstraZeneca and Merck are working together to
understand how it may affect multiple PARP-dependent tumors as a
monotherapy and in combination across multiple cancer types.
INDICATIONS
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor
indicated:
First-Line Maintenance BRCAm Advanced Ovarian Cancer
For the maintenance treatment of adult patients with deleterious
or suspected deleterious germline or somatic BRCA-mutated (gBRCAm
or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary
peritoneal cancer who are in complete or partial response to
first-line platinum-based chemotherapy. Select patients for therapy
based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance HRD-Positive Advanced Ovarian Cancer
in Combination with Bevacizumab
In combination with bevacizumab for the maintenance treatment of
adult patients with advanced epithelial ovarian, fallopian tube or
primary peritoneal cancer who are in complete or partial response
to first-line platinum-based chemotherapy and whose cancer is
associated with homologous recombination deficiency (HRD)-positive
status defined by either:
- a deleterious or suspected deleterious BRCA mutation,
and/or
- genomic instability
Select patients for therapy based on an FDA-approved companion
diagnostic for LYNPARZA.
Maintenance BRCA-mutated Recurrent Ovarian Cancer
For the maintenance treatment of adult patients with deleterious
or suspected deleterious germline or somatic BRCA-mutated (gBRCAm
or sBRCAm) recurrent epithelial ovarian, fallopian tube, or primary
peritoneal cancer, who are in complete or partial response to
platinum-based chemotherapy. Select patients for therapy based on
an FDA-approved companion diagnostic for LYNPARZA.
Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early
Breast Cancer
For the adjuvant treatment of adult patients with deleterious or
suspected deleterious gBRCAm, human epidermal growth factor
receptor 2 (HER2)-negative high-risk early breast cancer who have
been treated with neoadjuvant or adjuvant chemotherapy. Select
patients for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
gBRCAm, HER2-Negative Metastatic Breast Cancer
For the treatment of adult patients with deleterious or
suspected deleterious gBRCAm, human epidermal growth factor
receptor 2 (HER2)-negative metastatic breast cancer who have been
treated with chemotherapy in the neoadjuvant, adjuvant, or
metastatic setting. Patients with hormone receptor (HR)-positive
breast cancer should have been treated with a prior endocrine
therapy or be considered inappropriate for endocrine therapy.
Select patients for therapy based on an FDA-approved companion
diagnostic for LYNPARZA.
First-Line Maintenance gBRCAm Metastatic Pancreatic
Cancer
For the maintenance treatment of adult patients with deleterious
or suspected deleterious gBRCAm metastatic pancreatic
adenocarcinoma whose disease has not progressed on at least 16
weeks of a first-line platinum-based chemotherapy regimen. Select
patients for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
HRR Gene-mutated Metastatic Castration-Resistant Prostate
Cancer
For the treatment of adult patients with deleterious or
suspected deleterious germline or somatic homologous recombination
repair (HRR) gene-mutated metastatic castration-resistant prostate
cancer (mCRPC) who have progressed following prior treatment with
enzalutamide or abiraterone. Select patients for therapy based on
an FDA-approved companion diagnostic for LYNPARZA.
BRCAm Metastatic Castration-Resistant Prostate Cancer in
Combination with Abiraterone and Prednisone or Prednisolone
In combination with abiraterone and prednisone or prednisolone
(abi/pred) for the treatment of adult patients with deleterious or
suspected deleterious BRCA-mutated (BRCAm) metastatic
castration-resistant prostate cancer (mCRPC). Select patients for
therapy based on an FDA-approved companion diagnostic for
LYNPARZA.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML): Occurred in approximately 1.2% of patients with
various BRCAm, gBRCAm, HRR gene-mutated or HRD-positive cancers who
received LYNPARZA as a single agent or as part of a combination
regimen, consistent with the approved indications, and the majority
of events had a fatal outcome. The median duration of therapy in
patients who developed MDS/AML was approximately 2 years (range:
<6 months to >4 years). All of these patients had previous
chemotherapy with platinum agents and/or other DNA-damaging agents,
including radiotherapy.
In SOLO-1, patients with newly diagnosed advanced BRCAm ovarian
cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who
received LYNPARZA and 0.8% (1/130) in patients who received placebo
based on an updated analysis. In PAOLA-1, of patients with newly
diagnosed advanced ovarian cancer with HRD-positive status, the
incidence of MDS/AML was 1.6% (4/255) in patients who received
LYNPARZA and 2.3% (3/131) in the control arm.
In SOLO-2, patients with BRCAm platinum-sensitive relapsed
ovarian cancer, the incidence of MDS/AML was 8% (15/195) in
patients who received LYNPARZA and 4% (4/99) in patients who
received placebo. The duration of LYNPARZA treatment prior to the
diagnosis of MDS/AML ranged from 0.6 years to 4.5 years.
Do not start LYNPARZA until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤Grade 1).
Monitor complete blood count for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. For
prolonged hematological toxicities, interrupt LYNPARZA and monitor
blood count weekly until recovery.
If the levels have not recovered to Grade 1 or less after 4
weeks, refer the patient to a hematologist for further
investigations, including bone marrow analysis and blood sample for
cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.
Pneumonitis: Occurred in 0.8% of patients exposed to
LYNPARZA monotherapy, and some cases were fatal. If patients
present with new or worsening respiratory symptoms such as dyspnea,
cough, and fever, or a radiological abnormality occurs, interrupt
LYNPARZA treatment and initiate prompt investigation. Discontinue
LYNPARZA if pneumonitis is confirmed and treat patient
appropriately.
Venous Thromboembolism (VTE): Including severe or fatal
pulmonary embolism (PE) occurred in patients treated with LYNPARZA.
In the combined data of two randomized, placebo-controlled clinical
studies (PROfound and PROpel) in patients with metastatic
castration-resistant prostate cancer (N=1180), VTE occurred in 8%
of patients who received LYNPARZA, including pulmonary embolism in
6%. In the control arms, VTE occurred in 2.5%, including pulmonary
embolism in 1.5%. Monitor patients for signs and symptoms of venous
thrombosis and pulmonary embolism, and treat as medically
appropriate, which may include long-term anticoagulation as
clinically indicated.
Embryo-Fetal Toxicity: Based on its mechanism of action
and findings in animals, LYNPARZA can cause fetal harm. Verify
pregnancy status in females of reproductive potential prior to
initiating treatment.
Females
Advise females of reproductive potential of the potential risk
to a fetus and to use effective contraception during treatment and
for 6 months following the last dose.
Males
Advise male patients with female partners of reproductive
potential or who are pregnant to use effective contraception during
treatment and for 3 months following the last dose of LYNPARZA and
to not donate sperm during this time.
ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced
Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA in the first-line maintenance setting
for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain
(45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation
(28%), upper respiratory tract
infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia
(26%), decreased appetite (20%), dizziness (20%), neutropenia
(17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), urinary
tract infection (13%), thrombocytopenia (11%), and stomatitis
(11%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the first-line maintenance
setting for SOLO-1 were: decrease in hemoglobin (87%),
increase in mean corpuscular volume (87%), decrease in leukocytes
(70%), decrease in lymphocytes (67%), decrease in absolute
neutrophil count (51%), decrease in platelets (35%), and increase
in serum creatinine (34%).
ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian
Cancer in Combination with Bevacizumab
Most common adverse reactions (Grades 1-4) in ≥10% of patients
treated with LYNPARZA/bevacizumab and at a ≥5% frequency compared
to placebo/bevacizumab in the first-line maintenance setting
for PAOLA-1 were: nausea (53%), fatigue (including asthenia)
(53%), anemia (41%), lymphopenia (24%), vomiting (22%), and
leukopenia (18%). In addition, the most common adverse reactions
(≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of
the frequency compared with the placebo/bevacizumab arm were:
diarrhea (18%), neutropenia (18%), urinary tract infection (15%),
and headache (14%).
In addition, venous thromboembolic events occurred more commonly
in patients receiving LYNPARZA/bevacizumab (5%) than in those
receiving placebo/bevacizumab (1.9%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients for LYNPARZA in combination with bevacizumab in the
first-line maintenance setting for PAOLA-1 were:
decrease in hemoglobin (79%), decrease in lymphocytes (63%),
increase in serum creatinine (61%), decrease in leukocytes (59%),
decrease in absolute neutrophil count (35%), and decrease in
platelets (35%).
ADVERSE REACTIONS—Maintenance gBRCAm Recurrent Ovarian
Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
who received LYNPARZA in the maintenance setting for
SOLO-2 were: nausea (76%), fatigue (including asthenia)
(66%), anemia (44%), vomiting (37%), nasopharyngitis/upper
respiratory tract infection (URI)/influenza (36%), diarrhea (33%),
arthralgia/myalgia (30%), dysgeusia (27%), headache (26%),
decreased appetite (22%), and stomatitis (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the maintenance setting for
SOLO-2 were: increase in mean corpuscular volume (89%),
decrease in hemoglobin (83%), decrease in leukocytes (69%),
decrease in lymphocytes (67%), decrease in absolute neutrophil
count (51%), increase in serum creatinine (44%), and decrease in
platelets (42%).
ADVERSE REACTIONS—Adjuvant Treatment of gBRCAm,
HER2-Negative, High-Risk Early Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA in the adjuvant setting for
OlympiA were: nausea (57%), fatigue (including asthenia)
(42%), anemia (24%), vomiting (23%), headache (20%), diarrhea
(18%), leukopenia (17%), neutropenia (16%), decreased appetite
(13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the adjuvant setting for
OlympiA were: decrease in lymphocytes (77%), increase in
mean corpuscular volume (67%), decrease in hemoglobin (65%),
decrease in leukocytes (64%), and decrease in absolute neutrophil
count (39%).
ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast
Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
who received LYNPARZA in the metastatic setting for
OlympiAD were: nausea (58%), anemia (40%), fatigue
(including asthenia) (37%), vomiting (30%), neutropenia (27%),
respiratory tract infection (27%), leukopenia (25%), diarrhea
(21%), and headache (20%).
Most common laboratory abnormalities (Grades 1-4) in >25% of
patients who received LYNPARZA in the metastatic setting for
OlympiAD were: decrease in hemoglobin (82%), decrease in
lymphocytes (73%), decrease in leukocytes (71%), increase in mean
corpuscular volume (71%), decrease in absolute neutrophil count
(46%), and decrease in platelets (33%).
ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic
Pancreatic Adenocarcinoma
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA in the first-line maintenance setting
for POLO were: fatigue (60%), nausea (45%), abdominal pain
(34%), diarrhea (29%), anemia (27%), decreased appetite (25%),
constipation (23%), vomiting (20%), back pain (19%), arthralgia
(15%), rash (15%), thrombocytopenia (14%), dyspnea (13%),
neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and
stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the first-line maintenance
setting for POLO were: increase in serum creatinine
(99%), decrease in hemoglobin (86%), increase in mean corpuscular
volume (71%), decrease in lymphocytes (61%), decrease in platelets
(56%), decrease in leukocytes (50%), and decrease in absolute
neutrophil count (25%).
ADVERSE REACTIONS—HRR Gene-mutated Metastatic
Castration-Resistant Prostate Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA for PROfound were: anemia (46%),
fatigue (including asthenia) (41%), nausea (41%), decreased
appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia
(12%), cough (11%), and dyspnea (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA for PROfound were: decrease
in hemoglobin (98%), decrease in lymphocytes (62%), decrease in
leukocytes (53%), and decrease in absolute neutrophil count
(34%).
ADVERSE REACTIONS—Metastatic Castration-Resistant Prostate
Cancer in Combination with Abiraterone and Prednisone or
Prednisolone
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA/abiraterone with a difference of ≥5% compared
to placebo for PROpel were: anemia (48%), fatigue (including
asthenia) (38%), nausea (30%), diarrhea (19%), decreased appetite
(16%), lymphopenia (14%), dizziness (14%), and abdominal pain
(13%). Most common laboratory abnormalities (Grades 1-4) in ≥20% of
patients who received LYNPARZA/abiraterone for PROpel were:
decrease in hemoglobin (97%), decrease in lymphocytes (70%),
decrease in platelets (23%), and decrease in absolute neutrophil
count (23%).
DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA with
other myelosuppressive anticancer agents, including DNA-damaging
agents, indicate a potentiation and prolongation of
myelosuppressive toxicity.
CYP3A Inhibitors: Avoid coadministration of strong or
moderate CYP3A inhibitors when using LYNPARZA. If a strong or
moderate CYP3A inhibitor must be coadministered, reduce the dose of
LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice,
Seville oranges, and Seville orange juice during LYNPARZA
treatment.
CYP3A Inducers: Avoid coadministration of strong or
moderate CYP3A inducers when using LYNPARZA.
USE IN SPECIFIC POPULATIONS
Lactation: No data are available regarding the presence
of olaparib in human milk, its effects on the breastfed infant or
on milk production. Because of the potential for serious adverse
reactions in the breastfed infant, advise a lactating woman not to
breastfeed during treatment with LYNPARZA and for 1 month after
receiving the final dose.
Pediatric Use: The safety and efficacy of LYNPARZA have
not been established in pediatric patients.
Hepatic Impairment: No adjustment to the starting dose is
required in patients with mild or moderate hepatic impairment
(Child-Pugh classification A and B). There are no data in patients
with severe hepatic impairment (Child-Pugh classification C).
Renal Impairment: No dosage modification is recommended
in patients with mild renal impairment (CLcr 51-80 mL/min estimated
by Cockcroft-Gault). In patients with moderate renal impairment
(CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice
daily. There are no data in patients with severe renal impairment
or end-stage renal disease (CLcr ≤30 mL/min).
Please see complete Prescribing Information,
including Medication Guide.
About WELIREG® (belzutifan) 40 mg tablets, for oral
use
Indications in the U.S.
Certain von Hippel-Lindau (VHL) disease-associated tumors
WELIREG (belzutifan) is indicated for the treatment of adult
patients with von Hippel-Lindau (VHL) disease who require therapy
for associated renal cell carcinoma (RCC), central nervous system
(CNS) hemangioblastomas, or pancreatic neuroendocrine tumors
(pNET), not requiring immediate surgery.
Advanced Renal Cell Carcinoma (RCC)
WELIREG is indicated for the treatment of adult patients with
advanced renal cell carcinoma (RCC) following a programmed death
receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor
and a vascular endothelial growth factor tyrosine kinase inhibitor
(VEGF-TKI).
Selected Safety Information for WELIREG
Warning: Embryo-Fetal Toxicity
Exposure to WELIREG during pregnancy can cause embryo-fetal
harm. Verify pregnancy status prior to the initiation of WELIREG.
Advise patients of these risks and the need for effective
non-hormonal contraception as WELIREG can render some hormonal
contraceptives ineffective.
Anemia
WELIREG can cause severe anemia that can require blood
transfusion. Monitor for anemia before initiation of, and
periodically throughout, treatment. Transfuse patients as
clinically indicated. For patients with hemoglobin <8 g/dL,
withhold WELIREG until ≥8 g/dL, then resume at the same or reduced
dose or permanently discontinue WELIREG, depending on the severity
of anemia. For life-threatening anemia or when urgent intervention
is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then
resume at a reduced dose or permanently discontinue WELIREG.
In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of
patients with VHL disease and 7% had Grade 3 events. Median time to
onset of anemia was 31 days (range: 1 day to 8.4 months).
The safety of erythropoiesis-stimulating agents (ESAs) for
treatment of anemia in patients with VHL disease treated with
WELIREG has not been established.
In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88%
of patients with advanced RCC and 29% had Grade 3 events. Median
time to onset of anemia was 29 days (range: 1 day to 16.6 months).
Of the patients with anemia, 22% received transfusions only, 20%
received ESAs only, and 12% received both transfusion and ESAs.
Hypoxia
WELIREG can cause severe hypoxia that may require
discontinuation, supplemental oxygen, or hospitalization.
Monitor oxygen saturation before initiation of, and periodically
throughout, treatment. For decreased oxygen saturation with
exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider
withholding WELIREG until pulse oximetry with exercise is greater
than 88%, then resume at the same or a reduced dose. For decreased
oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55
mm Hg) or when urgent intervention is indicated, withhold WELIREG
until resolved and resume at a reduced dose or discontinue. For
life-threatening or recurrent symptomatic hypoxia, permanently
discontinue WELIREG. Advise patients to report signs and symptoms
of hypoxia immediately to a healthcare provider.
In LITESPARK-004, hypoxia occurred in 1.6% of patients.
In LITESPARK-005, hypoxia occurred in 15% of patients and 10%
had Grade 3 events. Of the patients with hypoxia, 69% were treated
with oxygen therapy. Median time to onset of hypoxia was 30.5 days
(range: 1 day to 21.1 months).
Embryo-Fetal Toxicity
Based on findings in animals, WELIREG can cause fetal harm when
administered to a pregnant woman.
Advise pregnant women and females of reproductive potential of
the potential risk to the fetus. Advise females of reproductive
potential to use effective non-hormonal contraception during
treatment with WELIREG and for 1 week after the last dose. WELIREG
can render some hormonal contraceptives ineffective. Advise male
patients with female partners of reproductive potential to use
effective contraception during treatment with WELIREG and for 1
week after the last dose.
Adverse Reactions
In LITESPARK-004, serious adverse reactions occurred in 15% of
patients, including anemia, hypoxia, anaphylaxis reaction, retinal
detachment, and central retinal vein occlusion (1 patient
each).
WELIREG was permanently discontinued due to adverse reactions in
3.3% of patients for dizziness and opioid overdose (1.6% each).
Dosage interruptions due to an adverse reaction occurred in 39%
of patients. Those which required dosage interruption in >2% of
patients were fatigue, decreased hemoglobin, anemia, nausea,
abdominal pain, headache, and influenza-like illness.
Dose reductions due to an adverse reaction occurred in 13% of
patients. The most frequently reported adverse reaction which
required dose reduction was fatigue (7%).
The most common adverse reactions (≥25%), including laboratory
abnormalities, that occurred in patients who received WELIREG were
decreased hemoglobin (93%), fatigue (64%), increased creatinine
(64%), headache (39%), dizziness (38%), increased glucose (34%),
and nausea (31%).
In LITESPARK-005, serious adverse reactions occurred in 38% of
patients. The most frequently reported serious adverse reactions
were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%),
and pleural effusion (2.2%). Fatal adverse reactions occurred in
3.2% of patients who received WELIREG, including sepsis (0.5%) and
hemorrhage (0.5%).
WELIREG was permanently discontinued due to adverse reactions in
6% of patients. Adverse reactions which resulted in permanent
discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage
(0.5%).
Dosage interruptions due to an adverse reaction occurred in 39%
of patients. Of the patients who received WELIREG, 28% were 65 to
74 years, and 10% were 75 years and over. Dose interruptions
occurred in 48% of patients ≥65 years of age and in 34% of younger
patients. Adverse reactions which required dosage interruption in
≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%),
fatigue (3.2%), and hemorrhage (2.2%).
Dose reductions due to an adverse reaction occurred in 13% of
patients. Dose reductions occurred in 18% of patients ≥65 years of
age and in 10% of younger patients. The most frequently reported
adverse reactions which required dose reduction (≥1.0%) were
hypoxia (5%) and anemia (3.2%).
The most common (≥25%) adverse reactions, including laboratory
abnormalities, were decreased hemoglobin (88%), fatigue (43%),
musculoskeletal pain (33%), increased creatinine (34%), decreased
lymphocytes (34%), increased alanine aminotransferase (32%),
decreased sodium (31%), increased potassium (29%), and increased
aspartate aminotransferase (27%).
Drug Interactions
Coadministration of WELIREG with inhibitors of UGT2B17 or
CYP2C19 increases plasma exposure of belzutifan, which may increase
the incidence and severity of adverse reactions. Monitor for anemia
and hypoxia and reduce the dosage of WELIREG as recommended.
Coadministration of WELIREG with CYP3A4 substrates decreases
concentrations of CYP3A4 substrates, which may reduce the efficacy
of these substrates or lead to therapeutic failures. Avoid
coadministration with sensitive CYP3A4 substrates. If
coadministration cannot be avoided, increase the sensitive CYP3A4
substrate dosage in accordance with its Prescribing Information.
Coadministration of WELIREG with hormonal contraceptives may lead
to contraceptive failure or an increase in breakthrough
bleeding.
Lactation
Because of the potential for serious adverse reactions in
breastfed children, advise women not to breastfeed during treatment
with WELIREG and for 1 week after the last dose.
Females and Males of Reproductive Potential
WELIREG can cause fetal harm when administered to a pregnant
woman. Verify the pregnancy status of females of reproductive
potential prior to initiating treatment with WELIREG.
Use of WELIREG may reduce the efficacy of hormonal
contraceptives. Advise females of reproductive potential to use
effective non-hormonal contraception during treatment with WELIREG
and for 1 week after the last dose. Advise males with female
partners of reproductive potential to use effective contraception
during treatment with WELIREG and for 1 week after the last
dose.
Based on findings in animals, WELIREG may impair fertility in
males and females of reproductive potential and the reversibility
of this effect is unknown.
Pediatric Use
Safety and effectiveness of WELIREG in pediatric patients under
18 years of age have not been established.
Please see Prescribing Information, including information for
the Boxed Warning about embryo-fetal toxicity, for WELIREG
(belzutifan) at
https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf
and Medication Guide for WELIREG at
https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_mg.pdf.
About the Merck and Eisai strategic collaboration
In March 2018, Eisai and Merck, known as MSD outside of the
United States and Canada, through an affiliate, entered into a
strategic collaboration for the worldwide co-development and
co-commercialization of LENVIMA. Under the agreement, the companies
jointly develop, manufacture and commercialize LENVIMA, both as
monotherapy and in combination with Merck’s anti-PD-1 therapy
KEYTRUDA. Eisai and Merck are studying the KEYTRUDA plus LENVIMA
combination through the LEAP (LEnvatinib And Pembrolizumab)
clinical program in various tumor types across multiple clinical
trials.
About the AstraZeneca and Merck strategic oncology
collaboration
In July 2017, AstraZeneca and Merck, known as MSD outside of the
United States and Canada, announced a global strategic oncology
collaboration to co-develop and co-commercialize certain oncology
products including LYNPARZA, the world’s first PARP inhibitor, for
multiple cancer types. Working together, the companies will develop
these products in combination with other potential new medicines
and as monotherapies. Independently, the companies will develop
these oncology products in combination with their respective PD-L1
and PD-1 medicines.
About the Astellas, Pfizer 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. Padcev® and the Padcev device are trademarks
jointly owned by Agensys, Inc., and Seagen Inc. Pfizer Inc.
completed its acquisition of Seagen on December 14, 2023.
About the Daiichi Sankyo and Merck collaboration
Daiichi Sankyo and Merck entered into a global collaboration in
October 2023 to jointly develop and commercialize patritumab
deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and
raludotatug deruxtecan (R-DXd), except in Japan where Daiichi
Sankyo will maintain exclusive rights. Daiichi Sankyo will be
solely responsible for manufacturing and supply.
Merck’s focus on cancer
Every day, we follow the science as we work to discover
innovations that can help patients, no matter what stage of cancer
they have. As a leading oncology company, we are pursuing research
where scientific opportunity and medical need converge, underpinned
by our diverse pipeline of more than 25 novel mechanisms. With one
of the largest clinical development programs across more than 30
tumor types, we strive to advance breakthrough science that will
shape the future of oncology. By addressing barriers to clinical
trial participation, screening and treatment, we work with urgency
to reduce disparities and help ensure patients have access to
high-quality cancer care. Our unwavering commitment is what will
bring us closer to our goal of bringing life to more patients with
cancer. For more information, visit
https://www.merck.com/research/oncology.
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 X (formerly Twitter), Facebook, Instagram, YouTube and
LinkedIn.
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 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 innovation 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, 2023 and the
company’s other filings with the Securities and Exchange Commission
(SEC) available at the SEC’s Internet site (www.sec.gov).
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version on businesswire.com: https://www.businesswire.com/news/home/20240904233606/en/
Media Contacts:
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Kristen Drake (908) 740-1679
Investor Contacts:
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Damini Chokshi (732) 594-1577
Merck (NYSE:MRK)
過去 株価チャート
から 8 2024 まで 9 2024
Merck (NYSE:MRK)
過去 株価チャート
から 9 2023 まで 9 2024