Phase 3 Data for KEYTRUDA® (pembrolizumab)
as Neoadjuvant Therapy in Combination with Chemotherapy in Patients
with Triple-Negative Breast Cancer (KEYNOTE-522) to be Featured in
ESMO Presidential Symposium and Official Press Program
Data for LYNPARZA Included in ESMO
Presidential Symposium and Official Press Program: in Metastatic
Castration-Resistant Prostate Cancer (PROfound) and in Advanced
Ovarian Cancer (PAOLA-1)
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced new data from its broad oncology portfolio
and pipeline will be presented at the European Society for Medical
Oncology (ESMO) 2019 Congress in Barcelona, Spain, from Sept.
27-Oct. 1, 2019. More than 80 abstracts involving Merck cancer
medicines and investigational candidates will be featured at the
congress, spanning over 18 tumor types. Three of these abstracts –
KEYTRUDA data in triple-negative breast cancer (TNBC), LYNPARZA
data in prostate cancer and LYNPARZA data in ovarian cancer – were
selected for inclusion in the ESMO Presidential Symposium
sessions.
“The breadth of data to be presented at ESMO reflect our
company’s commitment to advance KEYTRUDA and the other medicines in
our portfolio across cancer types and stages of disease to help
improve outcomes for cancer patients,” said Dr. Roy Baynes, senior
vice president and head of global clinical development, chief
medical officer, Merck Research Laboratories. “Five years ago,
KEYTRUDA received its first worldwide approval, and today new
KEYTRUDA data will be presented at ESMO across more than 15 types
of cancer, including first-time results in triple-negative breast
cancer, in addition to new data for LYNPARZA, LENVIMA and our
investigational candidates.”
Key abstracts to be presented at ESMO include:
- First presentation of results from the pivotal Phase 3
KEYNOTE-522 trial evaluating KEYTRUDA in combination with
chemotherapy as neoadjuvant therapy in patients with TNBC, which
will be featured in the ESMO Presidential Symposium and Press
Program (Abstract #LBA8). As previously announced, KEYNOTE-522 met
one of the dual primary endpoints of pathological complete response
(pCR) following the neoadjuvant part of the neoadjuvant/adjuvant
study regimen in patients with TNBC. Based on an interim analysis,
KEYTRUDA in combination with chemotherapy demonstrated a
statistically significant improvement in pCR rates compared with
chemotherapy alone, regardless of PD-L1 status.
- First presentation of results from the Phase 3 PROfound trial
evaluating Merck and AstraZeneca’s PARP inhibitor LYNPARZA in
patients with metastatic castration-resistant prostate cancer
(mCRPC) selected for BRCA 1/2 or ATM gene mutations, a
subpopulation of homologous recombination repair gene mutations
(HRRm), and who have progressed on prior treatment with new
hormonal anticancer treatments. These data will be featured in the
ESMO Presidential Symposium and Press Program (Abstract #LBA12). As
previously announced, the PROfound trial met its primary endpoint,
showing a statistically significant and clinically meaningful
improvement in radiographic progression-free survival compared to
enzalutamide or abiraterone.
- First presentation of results from the Phase 3 PAOLA-1 trial
evaluating LYNPARZA plus bevacizumab as maintenance therapy in
patients with advanced ovarian cancer who responded to first-line
platinum-based chemotherapy and bevacizumab, which will be featured
in the ESMO Presidential Symposium and Press Program (Abstract
#LBA2). As previously announced, PAOLA-1 met its primary endpoint,
significantly reducing the risk of disease progression or death in
women taking LYNPARZA plus bevacizumab versus those taking
bevacizumab alone.
- First presentation of final results from the endometrial cohort
from the Phase 1b/2 KEYNOTE-146/Study 111 trial evaluating KEYTRUDA
plus LENVIMA in patients with advanced endometrial carcinoma
(Abstract #994O) (in collaboration with Eisai).
- Presentation of final results from the pivotal Phase 3
KEYNOTE-407 study evaluating KEYTRUDA plus chemotherapy in patients
with metastatic squamous non-small cell lung cancer (NSCLC)
(Abstract #LBA82).
- Initial results from the KEYNOTE-869/EV-103 trial evaluating
KEYTRUDA plus enfortumab vedotin in locally advanced or metastatic
urothelial cancer (Abstract #901O).
- A first-in-human Phase 1/2 trial of the oral HIF-2a inhibitor
PT2977 in patients with advanced renal cell carcinoma (RCC)
(Abstract #911PD). PT2977 is now part of Merck’s broad early stage
oncology pipeline following the acquisition of Peloton
Therapeutics.
Details on Abstracts Listed Above & Other Late-breaking
and/or Proffered Paper Sessions
KEYTRUDA
Breast Cancer
- Abstract #LBA8, Proffered Paper Session: KEYNOTE-522: Phase 3
Study of Pembrolizumab (Pembro) + Chemotherapy (Chemo) vs Placebo
(Pbo) + Chemo as Neoadjuvant Treatment, Followed by Pembro vs Pbo
as Adjuvant Treatment for Early Triple-Negative Breast Cancer
(TNBC). P. Schmid. Sunday, September 29, 5:15-5:30 p.m. CEST.
Location: Barcelona Auditorium (Hall 2).
- Abstract #LBA21, Proffered Paper Session: KEYNOTE-119: Phase 3
Study of Pembrolizumab (Pembro) Versus Single-Agent Chemotherapy
(Chemo) for Metastatic Triple-Negative Breast Cancer (mTNBC). J.
Cortés. Saturday, September 28, 10:27-10:39 a.m. CEST. Location:
Barcelona Auditorium (Hall 2).
Lung Cancer
- Abstract #LBA82, Poster Discussion Session: Pembrolizumab
(Pembro) + Chemotherapy (Chemo) in Metastatic Squamous NSCLC: Final
Analysis and Progression After the Next Line of Therapy (PFS2) in
KEYNOTE-407. L. Paz-Ares. Sunday, September 29, 4:30-5:45 p.m. CEST
(poster). 4:30 p.m. CEST (discussion). Location: Cordoba Auditorium
(Hall 7).
- Abstract #1482O, Proffered Paper Session: Outcomes with
Pembrolizumab (Pembro) Monotherapy in Patients (Pts) with
PD-L1–Positive NSCLC with Brain Metastases: Pooled Analysis of
KEYNOTE-001, -010, -024, and -042. A. Mansfield. Monday, September
30, 9:30-9:45 a.m. CEST. Location: Madrid Auditorium (Hall 2).
- Abstract #LBA79, Proffered Paper Session: Association Between
Tissue TMB (tTMB) and Clinical Outcomes with Pembrolizumab
Monotherapy (Pembro) in PD-L1-Positive Advanced NSCLC in the
KEYNOTE-010 and -042 trials. R. Herbst. Friday, September 27,
4:39-4:51 p.m. CEST. Location: Barcelona Auditorium (Hall 2).
- Abstract #LBA80, Proffered Paper Session: Pembrolizumab
(Pembro) Plus Platinum-Based Chemotherapy (Chemo) for Metastatic
NSCLC: Tissue TMB (tTMB) and Outcomes in KEYNOTE-021, 189, and 407.
L. Paz-Ares. Friday, September 27, 4:51-5:03 p.m. CEST. Location:
Barcelona Auditorium (Hall 2).
Solid Tumors
- Abstract #440O, Proffered Paper Session: Phase 1 Study of the
Arginase Inhibitor INCB001158 (1158) Alone and in Combination with
Pembrolizumab (Pem) in Patients (Pts) with Advanced/Metastatic
(Adv/Met) Solid Tumors. A. Naing. Sunday, September 29, 4:56-5:06
p.m. CEST. Location: Malaga Auditorium (Hall 5).
- Abstract #1192O, Proffered Paper Session: Association of Tumor
Mutational Burden with Outcomes in Patients with Select Advanced
Solid Tumors Treated with Pembrolizumab in KEYNOTE-158. A.
Marabelle. Monday, September 30, 10:30-10:45 a.m. CEST. Location:
Barcelona Auditorium (Hall 2).
Microsatellite Instability High (MSI-H)
Cancers
- Abstract #1174O, Proffered Paper Session: Pembrolizumab in
Microsatellite Instability High Cancers: Updated Analysis of the
Phase 2 KEYNOTE-164 and KEYNOTE-158 Studies. L. Diaz. Monday,
September 30, 10:45-11:00 a.m. CEST. Location: Barcelona Auditorium
(Hall 2).
Gastric Cancers
- Abstract #LBA44, Proffered Paper Session: Pembrolizumab with or
without Chemotherapy vs Chemotherapy in Patients with Advanced
G/GEJ Cancer (GC) Including Outcomes According to Microsatellite
Instability-High (MSI-H) Status in KEYNOTE-062. K. Shitara. Sunday,
September 29, 11:15-11:30 a.m. CEST. Location: Madrid Auditorium
(Hall 2).
- Abstract #LBA45, Poster Discussion Session: Health-Related
Quality of Life (HRQoL) Impact of Pembrolizumab (P) Versus
Chemotherapy (C) as First-Line (1L) Treatment in PD-L1–Positive
Advanced Gastric or Gastroesophageal Junction (G/GEJ)
Adenocarcinoma. E. Van Cutsem. Saturday, September 28, 4:30-5:50
p.m. CEST (poster). 4:50 p.m. CEST (discussion). Location:
Tarragona Auditorium (Hall 7).
Skin Cancer
- Abstract #LBA72, Poster Discussion Session: Pembrolizumab for
Recurrent/Metastatic Cutaneous Squamous Cell Carcinoma (cSCC):
Efficacy and Safety Results From the Phase 2 KEYNOTE-629 Study. J.
Grob. Saturday, September 28, 2:45-4:00 p.m. CEST (poster). 3:02
p.m. CEST (discussion). Location: Granada Auditorium (Hall 3).
LYNPARZA (olaparib) (in collaboration with
AstraZeneca)
Prostate Cancer
- Abstract #LBA12, Proffered Paper Session: PROfound: Phase 3
Study of Olaparib Versus Enzalutamide or Abiraterone for Metastatic
Castration-Resistant Prostate Cancer (mCRPC) with Homologous
Recombination Repair (HRR) Gene Alterations. M. Hussain. Monday,
September 30, 5:09-5:21 p.m. CEST. Location: Barcelona Auditorium
(Hall 2).
Ovarian Cancer
- Abstract #LBA2, Proffered Paper Session: Phase 3
PAOLA-1/ENGOT-ov25 Trial: Olaparib plus Bevacizumab (Bev) as
Maintenance Therapy in Patients (Pts) with Newly Diagnosed,
Advanced Ovarian Cancer (OC) Treated with Platinum-Based
Chemotherapy (PCh) Plus Bev. I. Ray-Coquard. Saturday, September
28, 4:42-4:54 p.m. CEST. Location: Barcelona Auditorium (Hall
2).
KEYTRUDA + LENVIMA (lenvatinib) (in collaboration with
Eisai)
Endometrial Cancer
- Abstract #994O, Proffered Paper Session: Lenvatinib (LEN) and
Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC). V.
Makker. Sunday, September 29, 9:30-9:45 a.m. CEST. Location: Madrid
Auditorium (Hall 2).
Pipeline/Early Oncology
Bladder Cancer
- Abstract #901O, Proffered Paper Session: EV-103: Initial
Results of Enfortumab Vedotin Plus Pembrolizumab for Locally
Advanced or Metastatic Urothelial Carcinoma. C. Hoimes. Saturday,
September 28, 9:15-9:30 a.m. CEST. Location: Barcelona Auditorium
(Hall 2).
Renal Cell Carcinoma
- Abstract #911PD, Poster Discussion Session: A First-in-Human
Phase 1/2 Trial of the Oral HIF-2a Inhibitor PT2977 in Patients
with Advanced RCC. E. Jonasch. Sunday, September 29, 3:00-4:15 p.m.
CEST (poster). 3:35 p.m. CEST (discussion). Location: Pamplona
Auditorium (Hall 2).
For more information, including a complete list of abstract
titles and presentation dates and times for Merck’s oncology
portfolio and pipeline, please visit the ESMO website at
https://cslide.ctimeetingtech.com/esmo2019/attendee/confcal.
About KEYTRUDA® (pembrolizumab) Injection, 100mg
KEYTRUDA is an anti-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 1,000 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.
KEYTRUDA® (pembrolizumab) Indications
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of patients
with melanoma with involvement of lymph node(s) 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.
Small Cell Lung Cancer
KEYTRUDA is indicated for the treatment of patients with
metastatic small cell lung cancer (SCLC) with disease progression
on or after platinum-based chemotherapy and at least one other
prior line of therapy. 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
confirmatory trials.
Head and Neck 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 and pediatric
patients with refractory classical Hodgkin lymphoma (cHL), or who
have relapsed after 3 or more prior lines of therapy. 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.
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. 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 confirmatory trials.
KEYTRUDA is not recommended for the treatment of patients with
PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who are not
eligible for cisplatin-containing chemotherapy and whose tumors
express PD-L1 [CPS ≥10] as determined by an FDA-approved test, or
in patients who are not eligible for any platinum-containing
chemotherapy regardless of PD-L1 status. This indication is
approved under accelerated approval based on tumor response rate
and duration of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in the confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who have disease
progression during or following platinum-containing chemotherapy or
within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.
Microsatellite Instability-High (MSI-H) 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 that have progressed following prior treatment and
who have no satisfactory alternative treatment options, or
- colorectal cancer that has progressed following treatment with
fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials. The
safety and effectiveness of KEYTRUDA in pediatric patients with
MSI-H central nervous system cancers have not been established.
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma whose tumors express
PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease
progression on or after two or more prior lines of therapy
including fluoropyrimidine- and platinum-containing chemotherapy
and if appropriate, HER2/neu-targeted therapy. This indication is
approved under accelerated approval based on tumor response rate
and durability of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in the confirmatory trials.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent locally advanced or metastatic squamous cell carcinoma of
the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by
an FDA-approved test, with disease progression after one or more
prior lines of systemic therapy.
Cervical Cancer
KEYTRUDA 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. 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.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with recurrent locally advanced or metastatic Merkel cell
carcinoma. This indication is approved under accelerated approval
based on tumor response rate and durability of response. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the
first-line treatment of patients with advanced renal cell carcinoma
(RCC).
Selected Important Safety Information for KEYTRUDA
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis, including fatal
cases. Pneumonitis occurred in 3.4% (94/2799) of patients with
various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2
(1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in
8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single
agent, including Grades 3-4 in 3.2% of patients, and occurred more
frequently in patients with a history of prior thoracic radiation
(17%) compared to those without (7.7%). Pneumonitis occurred in 6%
(18/300) of HNSCC patients receiving KEYTRUDA as a single agent,
including Grades 3-5 in 1.6% of patients, and occurred in 5.4%
(15/276) of patients receiving KEYTRUDA in combination with
platinum and FU as first-line therapy for advanced disease,
including Grade 3-5 in 1.5% of patients.
Monitor patients for signs and symptoms of pneumonitis. Evaluate
suspected pneumonitis with radiographic imaging. Administer
corticosteroids for Grade 2 or greater pneumonitis. Withhold
KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3
or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in
1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2
(0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 or
greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently
discontinue KEYTRUDA for Grade 4 colitis.
Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity
(KEYTRUDA in Combination with Axitinib)
Immune-Mediated Hepatitis
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred
in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in
liver function. Administer corticosteroids for Grade 2 or greater
hepatitis and, based on severity of liver enzyme elevations,
withhold or discontinue KEYTRUDA.
Hepatotoxicity in Combination with Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity
with higher than expected frequencies of Grades 3 and 4 ALT and AST
elevations compared to KEYTRUDA alone. With the combination of
KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and
increased AST (13%) were seen. Monitor liver enzymes before
initiation of and periodically throughout treatment. Consider more
frequent monitoring of liver enzymes 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.
Immune-Mediated Endocrinopathies
KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1
diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of
patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%).
Hypothyroidism occurred in 8.5% (237/2799) of patients, including
Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening
hypothyroidism was higher in 1185 patients with HNSCC (16%),
receiving KEYTRUDA, as a single agent or in combination with
platinum and FU, including Grade 3 (0.3%) hypothyroidism.
Hyperthyroidism occurred in 3.4% (96/2799) of patients, including
Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6%
(16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes
mellitus, including diabetic ketoacidosis, occurred in 0.2%
(6/2799) of patients.
Monitor patients for signs and symptoms of hypophysitis
(including hypopituitarism and adrenal insufficiency), thyroid
function (prior to and periodically during treatment), and
hyperglycemia. For hypophysitis, administer corticosteroids and
hormone replacement as clinically indicated. Withhold KEYTRUDA for
Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis.
Administer hormone replacement for hypothyroidism and manage
hyperthyroidism with thionamides and beta-blockers as appropriate.
Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.
Administer insulin for type 1 diabetes and withhold KEYTRUDA and
administer antihyperglycemics in patients with severe
hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred
in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in
1.7% (7/405) of patients receiving KEYTRUDA in combination with
pemetrexed and platinum chemotherapy. Monitor patients for changes
in renal function. Administer corticosteroids for Grade 2 or
greater nephritis. Withhold KEYTRUDA for Grade 2; permanently
discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
Immune-mediated rashes, including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN) (some cases with fatal
outcome), exfoliative dermatitis, and bullous pemphigoid, can
occur. Monitor patients for suspected severe skin reactions and
based on the severity of the adverse reaction, withhold or
permanently discontinue KEYTRUDA and administer corticosteroids.
For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer
the patient for specialized care for assessment and treatment. If
SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal,
can occur in any organ system or tissue in patients receiving
KEYTRUDA and may also occur after discontinuation of treatment. For
suspected immune-mediated adverse reactions, ensure adequate
evaluation to confirm etiology or exclude other causes. Based on
the severity of the adverse reaction, withhold KEYTRUDA and
administer corticosteroids. Upon improvement to Grade 1 or less,
initiate corticosteroid taper and continue to taper over at least 1
month. Based on limited data from clinical studies in patients
whose immune-related adverse reactions could not be controlled with
corticosteroid use, administration of other systemic
immunosuppressants can be considered. Resume KEYTRUDA when the
adverse reaction remains at Grade 1 or less following
corticosteroid taper. Permanently discontinue KEYTRUDA for any
Grade 3 immune-mediated adverse reaction that recurs and for any
life-threatening immune-mediated adverse reaction.
The following clinically significant immune-mediated adverse
reactions occurred in less than 1% (unless otherwise indicated) of
2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré
syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic
anemia, sarcoidosis, and encephalitis. In addition, myelitis and
myocarditis were reported in other clinical trials, including cHL,
and postmarketing use.
Treatment with KEYTRUDA may increase the risk of rejection in
solid organ transplant recipients. Consider the benefit of
treatment vs the risk of possible organ rejection in these
patients.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have
been reported in 0.2% (6/2799) of patients. Monitor patients for
signs and symptoms of infusion-related reactions. For Grade 3 or 4
reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
Immune-mediated complications, including fatal events, occurred
in patients who underwent allogeneic HSCT after treatment with
KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT
after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD)
(1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive
disease (VOD) after reduced-intensity conditioning (1 fatal case).
Cases of fatal hyperacute GVHD after allogeneic HSCT have also been
reported in patients with lymphoma who received a PD-1
receptor–blocking antibody before transplantation. Follow patients
closely for early evidence of transplant-related complications such
as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute
GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive
disease (VOD), and other immune-mediated adverse reactions.
In patients with a history of allogeneic HSCT, acute GVHD
(including fatal GVHD) has been reported after treatment with
KEYTRUDA. Patients who experienced GVHD after their transplant
procedure may be at increased risk for GVHD after KEYTRUDA.
Consider the benefit of KEYTRUDA vs the risk of GVHD in these
patients.
Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of
KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in
increased mortality. Treatment of these patients with a PD-1 or
PD-L1 blocking antibody 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, 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-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; 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%).
Adverse reactions occurring in patients with SCLC were similar
to those occurring in patients with other solid tumors who received
KEYTRUDA as a single agent.
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-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% included pneumonia,
pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two
patients died from causes other than disease progression; 1 from
GVHD after subsequent allogeneic HSCT and 1 from septic shock. The
most common adverse reactions (≥20%) were fatigue (26%), pyrexia
(24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and
rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse
reactions in 8% of 53 patients with PMBCL. Serious adverse
reactions occurred in 26% of patients and included arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial
effusion (2%), and pericarditis (2%). Six (11%) patients died
within 30 days of start of treatment. The most common adverse
reactions (≥20%) were musculoskeletal pain (30%), upper respiratory
tract infection and pyrexia (28% each), cough (26%), fatigue (23%),
and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
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%).
Adverse reactions occurring in patients with gastric cancer were
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy.
Adverse reactions occurring in patients with esophageal cancer
were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with recurrent or metastatic
cervical cancer. Serious adverse reactions occurred in 39% of
patients receiving KEYTRUDA; the most frequent included anemia
(7%), fistula, hemorrhage, and infections [except urinary tract
infections] (4.1% each). The most common adverse reactions (≥20%)
were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%),
pain and abdominal pain (22% each), and decreased appetite
(21%).
Adverse reactions occurring in patients with HCC were generally
similar to those in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy, with the exception of increased
incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis
(2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a
higher incidence were elevated AST (20%), ALT (9%), and
hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017,
adverse reactions occurring in patients with MCC were generally
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy. Laboratory abnormalities
(Grades 3-4) that occurred at a higher incidence were elevated AST
(11%) and hyperglycemia (19%).
In KEYNOTE-426, when KEYTRUDA was administered in combination
with axitinib, fatal adverse reactions occurred in 3.3% of 429
patients. Serious adverse reactions occurred in 40% of patients,
the most frequent of which (≥1%) included 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 adverse
reactions (>1%) resulting in permanent discontinuation of
KEYTRUDA, axitinib or the combination were hepatotoxicity (13%),
diarrhea/colitis (1.9%), acute kidney injury (1.6%), and
cerebrovascular accident (1.2%). When KEYTRUDA was used in
combination with axitinib, 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%).
Lactation
Because of the potential for serious adverse reactions in
breastfed children, advise women not to breastfeed during treatment
and for 4 months after the final dose.
Pediatric Use
There is limited experience in pediatric patients. In a trial,
40 pediatric patients (16 children aged 2 years to younger than 12
years and 24 adolescents aged 12 years to 18 years) with various
cancers, including unapproved usages, were administered KEYTRUDA 2
mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3
doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses
or more. The safety profile in these pediatric patients was similar
to that seen in adults; adverse reactions that occurred at a higher
rate (≥15% difference) in these patients when compared to adults
under 65 years of age were fatigue (45%), vomiting (38%), abdominal
pain (28%), increased transaminases (28%), and hyponatremia
(18%).
Please see Prescribing Information for KEYTRUDA 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 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 and advanced 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.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA
monotherapy, and the majority of events had a fatal outcome. The
duration of therapy in patients who developed secondary MDS/AML
varied from <6 months to >2 years. All of these patients had
previous chemotherapy with platinum agents and/or other
DNA-damaging agents, including radiotherapy, and some also had a
history of more than one primary malignancy or of bone marrow
dysplasia.
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 <1% of patients exposed to
LYNPARZA, 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.
Embryo-Fetal Toxicity: Based on its mechanism of action
and findings in animals, LYNPARZA can cause fetal harm. A pregnancy
test is recommended for 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
in clinical trials of 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%), UTI (13%), thrombocytopenia
(11%), and stomatitis (11%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of 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—Maintenance Recurrent Ovarian
Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of 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%).
Study 19: nausea (71%), fatigue (including asthenia)
(63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory
tract infection (22%), constipation (22%), headache (21%),
decreased appetite (21%), and dyspepsia (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the maintenance
setting (SOLO-2/Study 19) were: increase in mean corpuscular
volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in
leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease
in absolute neutrophil count (51%/47%), increase in serum
creatinine (44%/45%), and decrease in platelets (42%/36%).
ADVERSE REACTIONS—Advanced gBRCAm ovarian cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA for advanced gBRCAm ovarian
cancer after 3 or more lines of chemotherapy (pooled from 6
studies) were: fatigue/asthenia (66%), nausea (64%), vomiting
(43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper
respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia
(22%), decreased appetite (22%), and arthralgia/musculoskeletal
pain (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA for advanced gBRCAm
ovarian cancer (pooled from 6 studies) were: decrease in
hemoglobin (90%), mean corpuscular volume elevation (57%), decrease
in lymphocytes (56%), increase in serum creatinine (30%), decrease
in platelets (30%), and decrease in absolute neutrophil count
(25%).
ADVERSE REACTIONS—gBRCAm, HER2-negative metastatic breast
cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in 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 in 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%).
DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA in
combination with other myelosuppressive anticancer agents,
including DNA-damaging agents, indicate a potentiation and
prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid concomitant use of strong or
moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor
must be co-administered, reduce the dose of LYNPARZA. Advise
patients to avoid grapefruit, grapefruit juice, Seville oranges,
and Seville orange juice during LYNPARZA treatment.
CYP3A Inducers: Avoid concomitant use of strong or
moderate CYP3A inducers when using LYNPARZA. If a moderate inducer
cannot be avoided, there is a potential for decreased efficacy of
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 adjustment to the starting dose is
necessary in patients with mild renal impairment (CLcr=51-80
mL/min), but patients should be monitored closely for toxicity. In
patients with moderate renal impairment (CLcr=31-50 mL/min), reduce
the dose to 200 mg twice daily. There are no data in patients with
severe renal impairment or end-stage renal disease (CLcr ≤30
mL/min).
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 with gBRCAm
advanced epithelial ovarian, fallopian tube or primary peritoneal
cancer for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
Maintenance Recurrent Ovarian Cancer
For the maintenance treatment of adult patients with recurrent
epithelial ovarian, fallopian tube, or primary peritoneal cancer,
who are in complete or partial response to platinum-based
chemotherapy.
Advanced gBRCAm ovarian cancer
For the treatment of adult patients with deleterious or
suspected deleterious germline BRCA-mutated (gBRCAm) advanced
ovarian cancer who have been treated with 3 or more prior lines of
chemotherapy. Select patients for therapy based on an FDA-approved
companion diagnostic for LYNPARZA.
gBRCAm, HER2-negative metastatic breast cancer
In 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.
Please see complete Prescribing Information for LYNPARZA
(olaparib) tablets at
https://www.azpicentral.com/lynparza_tb/pi_lynparza_tb.pdf#page=1
and complete Prescribing Information for LYNPARZA capsules, at
https://www.azpicentral.com/Lynparza/pi_lynparza.pdf#page=1
including Patient Information (Medication Guides).
About LENVIMA® (lenvatinib) Capsules, 10 mg and 4 mg
LENVIMA® (lenvatinib) is a kinase inhibitor that is indicated in
the U.S.:
- For the treatment of patients with locally recurrent or
metastatic, progressive, radioactive iodine-refractory
differentiated thyroid cancer (RAI-refractory DTC)
- In combination with everolimus for the treatment of 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)
LENVIMA, discovered and developed by Eisai, is a 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. Lenvatinib also exhibited antiproliferative activity in
hepatocellular carcinoma cell lines dependent on activated FGFR
signaling with a concurrent inhibition of FGF-receptor substrate 2α
(FRS2α) phosphorylation.
Selected Safety Information
Warnings and Precautions
Hypertension. In DTC, hypertension occurred in 73% of
patients on LENVIMA (44% grade 3-4). In 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 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.
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. 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.
Wound Healing Complications. Wound healing complications,
including fistula formation and wound dehiscence, can occur with
LENVIMA. Withhold for at least 6 days prior to scheduled surgery.
Resume after surgery based on clinical judgment of adequate wound
healing. Permanently discontinue in patients with wound healing
complications.
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 lenvatinib 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 at least 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 (≥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%).
Use in Specific Populations
Because of the potential for serious adverse reactions in
breastfed infants, advise women to discontinue breastfeeding during
treatment and for at least 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 (CLcr
60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment.
LENVIMA concentrations may increase in patients with DTC or RCC and
severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for
patients with RCC or DTC 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 or RCC
and mild or moderate hepatic impairment. LENVIMA concentrations may
increase in patients with DTC or RCC and severe hepatic impairment.
Reduce the dose for patients with DTC or RCC and severe hepatic
impairment.
Please see Prescribing Information for LENVIMA (lenvatinib)
at http://www.lenvima.com/pdfs/prescribing-information.pdf.
About the AstraZeneca and Merck Strategic Oncology
Collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth,
NJ, US, known as MSD outside the United States and Canada,
announced a global strategic oncology collaboration to co-develop
and co-commercialize LYNPARZA, the world’s first PARP inhibitor,
and potential new medicine selumetinib, a MEK inhibitor, for
multiple cancer types. Working together, the companies will develop
LYNPARZA and selumetinib in combination with other potential new
medicines and as monotherapies. Independently, the companies will
develop LYNPARZA and selumetinib in combination with their
respective PD-L1 and PD-1 medicines.
About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside 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
will jointly develop, manufacture and commercialize LENVIMA, both
as monotherapy and in combination with Merck’s anti-PD-1 therapy
KEYTRUDA.
In addition to ongoing clinical studies evaluating the KEYTRUDA
plus LENVIMA combination across several different tumor types,
including renal cell carcinoma, the companies will jointly initiate
new clinical studies through the LEAP (LEnvatinib And
Pembrolizumab) clinical program, which will evaluate the
combination to support 11 potential indications in six types of
cancer (endometrial cancer, hepatocellular carcinoma, melanoma,
non-small cell lung cancer, squamous cell carcinoma of the head and
neck, and urothelial cancer). The LEAP clinical program also
includes a new basket trial targeting six additional cancer types
(biliary tract cancer, triple-negative breast cancer, colorectal
cancer, gastric cancer, glioblastoma and ovarian cancer). The
LENVIMA and KEYTRUDA combination is not approved in any cancer
types today.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
the potential to bring new hope to people with cancer drives our
purpose and supporting accessibility to our cancer medicines is our
commitment. As part of our focus on cancer, Merck is committed to
exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor
types. We also continue to strengthen our portfolio through
strategic acquisitions and are prioritizing the development of
several promising oncology candidates with the potential to improve
the treatment of advanced cancers. For more information about our
oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For more than a century, Merck, a leading global
biopharmaceutical company known as MSD outside of the United States
and Canada, has been inventing for life, bringing forward medicines
and vaccines for many of the world’s most challenging diseases.
Through our prescription medicines, vaccines, biologic therapies
and animal health products, we work with customers and operate in
more than 140 countries to deliver innovative health solutions. We
also demonstrate our commitment to increasing access to health care
through far-reaching policies, programs and partnerships. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer’s disease and
infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect with us on Twitter, Facebook,
Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, 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 products that
the products 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 innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2018
Annual Report on Form 10-K 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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