Merck Highlights Breadth of Immuno-Oncology Research Program in Genitourinary Cancers at ASCO GU
February 11, 2019 5:02 pm ET
First-Time Data from Pivotal Phase 3 KEYNOTE-426 Trial Showing KEYTRUDA ® (pembrolizumab) in Combination with Inlyta ® (axitinib) Significantly Improved OS, PFS and ORR Compared to Sunitinib Monotherapy in First-Line Treatment of Advanced Renal Cell Carcinoma
Three New KEYTRUDA Combination Datasets from the Largest Study of Anti-PD-1 Therapy in Metastatic Prostate Cancer (KEYNOTE-365)
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that new combination and monotherapy data from the
company’s broad immuno-oncology research program in genitourinary
cancers – renal, prostate and bladder − will be presented at the 2019
Genitourinary Cancers Symposium (ASCO GU) in San Francisco from February
14-16. Survival data from the pivotal Phase 3 KEYNOTE-426 trial with
KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with Inlyta
(axitinib), a tyrosine kinase inhibitor, for the first-line treatment of
advanced or metastatic renal cell carcinoma (RCC) will be presented for
the first-time (Abstract #543). In October 2018, Merck announced that
KEYNOTE-426 met both primary endpoints of overall survival (OS) and
progression-free survival (PFS), and the key secondary endpoint of
objective response rate (ORR). Data released today from the first
interim analysis showed KEYTRUDA in combination with axitinib, when
compared to sunitinib, significantly improved OS, reducing the risk of
death by nearly half, (HR 0.53 [95% CI 0.38-0.74]; P=0.0001), as well as
PFS (HR 0.69 [95% CI 0.57-0.84]; P=0.0001) and ORR (59.3% vs. 35.7%;
P=0.0001). Results across OS, PFS and ORR were consistent across all
IMDC risk groups and regardless of PD-L1 expression. Treatment-related
adverse events were grade 3-5 in 62.9 percent of patients in the
KEYTRUDA and axitinib arm vs 58.1 percent in the sunitinib arm and led
to regimen discontinuation in 6.3 percent vs 10.1 percent of patients in
those arms, respectively. Full results from KEYNOTE-426 will be
presented at the meeting.
“Merck is pursuing a broad clinical program in advanced cancers of the
kidney, prostate and bladder with the goal of advancing new treatment
options for patients afflicted by historically difficult to treat
malignancies,” said Dr. Roger M. Perlmutter, president, Merck Research
Laboratories. “The improvement in survival achieved with KEYTRUDA in
combination with axitinib for the first-line treatment of advanced renal
cell carcinoma, which will be described in detail at the ASCO GU
meeting, underscores this commitment.”
More than 20 abstracts across Merck’s oncology portfolio – across RCC,
prostate cancer, non-muscle invasive bladder cancer (NMIBC) and
urothelial carcinoma – have been accepted for presentation. Select data
highlights at ASCO GU include:
Renal Cell Carcinoma
-
Abstract #543 Oral Presentation: Pembrolizumab (pembro) plus axitinib
(axi) versus sunitinib as first-line therapy for locally advanced or
metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study.
T. Powles. Saturday, Feb. 16. 2:00 p.m.-3:30 p.m. PST. -
Abstract #546 Oral Presentation: First-line pembrolizumab (pembro)
monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC):
Results from KEYNOTE-427 cohort B. D. McDermott. Saturday, Feb. 16.
2:00 p.m.-3:30 p.m. PST.
Prostate Cancer
-
Abstract #145 Rapid Abstract Session: KEYNOTE-365 cohort A:
Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients
(pts) with metastatic castrate-resistant prostate cancer (mCRPC). E.
Yu. Thursday, Feb. 14. 4:35 p.m.-5:30 p.m. PST. -
Abstract #170 Poster Session: KEYNOTE-365 cohort B: Pembrolizumab
(pembro) plus docetaxel and prednisone in abiraterone (abi) or
enzalutamide (enza)-pretreated patients (pts) with metastatic castrate
resistant prostate cancer (mCRPC). C. Massard. Thursday, Feb. 14.
11:30 a.m.-1:00 p.m. and 5:30 p.m.-6:30 p.m. PST. -
Abstract #171 Poster Session: KEYNOTE-365 cohort C: Pembrolizumab
(pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated
patients (pts) with metastatic castrate resistant prostate cancer
(mCRPC). P. Fong. Thursday, Feb. 14. 11:30 a.m.-1:00 p.m. and
5:30 p.m.-6:30 p.m. PST. -
Abstract #216 Poster Session: Pembrolizumab for metastatic
castration-resistant prostate cancer (mCRPC) previously treated with
docetaxel: Updated analysis of KEYNOTE-199. E. Antonarakis. Thursday,
Feb. 14. 11:30 a.m.-1:00 p.m. and 5:30 p.m.-6:30 p.m. PST. -
Abstract #TPS340 Poster Session: PROPEL: A randomized, phase III trial
evaluating the efficacy and safety of olaparib combined with
abiraterone as first-line therapy in patients with metastatic
castration-resistant prostate cancer (mCRPC). N. Clarke. Thursday,
Feb. 14. 11:30 a.m.-1:00 p.m. and 5:30 p.m.-6:30 p.m. PST.
Bladder Cancer
-
Abstract #350 Welcome and General Session: KEYNOTE-057: Phase II trial
of Pembrolizumab (pembro) for patients (pts) with high-risk (HR)
nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus
calmette-guérin (BCG). A. Balar. Friday, Feb. 15. 7:55 a.m.-9:25 a.m.
PST. -
Abstract #433 Poster Session: Association between stromal/TGF-β/EMT
gene expression signature and response to pembrolizumab monotherapy in
cisplatin-ineligible patients with locally advanced (unresectable) or
metastatic urothelial carcinoma. P. Grivas. Friday, Feb. 15. 12:15
p.m.-1:45 p.m. and 5:15 p.m.- 6:15 p.m. PST.
For more information, including a complete list of abstract titles and
presentation dates and times for Merck’s oncology portfolio, please
visit the ASCO GU website at https://meetings.asco.org/gu.
About KEYNOTE-426
KEYNOTE-426 is a randomized, double-arm, Phase 3 trial
(ClinicalTrials.gov, NCT02853331) evaluating the safety and efficacy of
KEYTRUDA in combination with axitinib as first-line treatment for
advanced or metastatic RCC compared to sunitinib. The dual primary
endpoints of the study were OS and PFS, and the key secondary endpoint
was ORR. Additional secondary endpoints were disease control rate (DCR),
number of participants who experienced or discontinued the study due to
an adverse event (AE), duration of response (DOR), PFS at 12, 18 and 24
months and OS at 12, 18 and 24 months. In the trial, 861 patients were
randomly assigned to receive KEYTRUDA 200 mg intravenously every three
weeks plus axitinib 5 mg orally twice daily for up to 24 months, or
sunitinib 50 mg orally once daily for four weeks followed by no
treatment for two weeks, continuously.
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 900 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 and
Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic melanoma at a fixed dose of 200 mg every three weeks until
disease progression or unacceptable toxicity.
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
nab-paclitaxel, 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 metastatic NSCLC whose tumors have high PD-L1
expression [tumor proportion score (TPS) ≥50%] as determined by an
FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
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.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg
every three weeks until disease progression, unacceptable toxicity, or
up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA
should be administered prior to chemotherapy when given on the same day.
See also the Prescribing Information for the chemotherapy agents
administered in combination with KEYTRUDA, as appropriate.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or
metastatic head and neck squamous cell carcinoma (HNSCC) with disease
progression on or after platinum-containing chemotherapy. 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. In HNSCC, KEYTRUDA is
administered at a fixed dose of 200 mg every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression.
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. In adults with cHL, KEYTRUDA is administered at a
fixed dose of 200 mg every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression. In pediatric patients with cHL, KEYTRUDA is administered at
a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
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.
In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg
every three weeks until disease progression, unacceptable toxicity, or
up to 24 months in patients without disease progression. In pediatric
patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up
to a maximum of 200 mg) every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.
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
[combined positive score (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.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is
administered at a fixed dose of 200 mg every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in patients
without disease progression.
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.
In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed
dose of 200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease progression. In
children with MSI-H cancer, KEYTRUDA is administered at a dose of 2
mg/kg (up to a maximum of 200 mg) every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in patients
without disease progression.
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 [combined positive score
(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. The recommended dose of KEYTRUDA is a fixed dose of
200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease progression.
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. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every
three weeks until disease progression, unacceptable toxicity, or up to
24 months in patients without disease progression.
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. The recommended dose of
KEYTRUDA is a fixed dose of 200 mg every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression.
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. The recommended dose of
KEYTRUDA in adults is 200 mg administered as an intravenous infusion
over 30 minutes every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without disease
progression. The recommended dose of KEYTRUDA in pediatric patients is 2
mg/kg (up to a maximum of 200 mg), administered as an intravenous
infusion over 30 minutes every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.
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 receiving KEYTRUDA,
including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%),
and occurred more frequently in patients with a history of prior
thoracic radiation (6.9%) compared to those without (2.9%). Monitor
patients for signs and symptoms of pneumonitis. Evaluate suspected
pneumonitis with radiographic imaging. Administer corticosteroids for
Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2;
permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2
pneumonitis.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7%
(48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3
(1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of
colitis. Administer corticosteroids for Grade 2 or greater colitis.
Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for
Grade 4 colitis.
Immune-Mediated Hepatitis
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7%
(19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.4%), and 4 (<0.1%). Monitor patients for changes in liver function.
Administer corticosteroids for Grade 2 or greater hepatitis and, based
on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Immune-Mediated Endocrinopathies
KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes
mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including
Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5%
(237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The
incidence of new or worsening hypothyroidism was higher in patients with
HNSCC, occurring in 15% (28/192) of patients. 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 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
developed graft-versus-host disease (GVHD) (1 fatal case) and 2
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-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 nab-paclitaxel 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-010, KEYTRUDA monotherapy was discontinued due to adverse
reactions in 8% of 682 patients with metastatic NSCLC. The most common
adverse event resulting in permanent discontinuation of KEYTRUDA was
pneumonitis (1.8%). The most common adverse reactions (≥20%) were
decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).
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.
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%).
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, in 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%).
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 click here
for complete Prescribing Information, including Patient Information
(Medication Guide).
About the AstraZeneca and Merck Strategic Oncology Collaboration
In July 2017, AstraZeneca and Merck, 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.
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 2017 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).
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
.
Media:
Pamela Eisele
(267) 305-3558
Elizabeth H. Sell
(267) 305-3877
Investors:
Teri Loxam
(908) 740-1986
Peter Dannenbaum
(908) 740-1037
