KEYTRUDA is the First Anti-PD-1 Therapy
Approved in Europe for the First-Line Treatment of Head and Neck
Cancer as Monotherapy or in Combination with Chemotherapy, in
Patients Whose Tumors Express PD-L1 (CPS ≥1)
Approval Based on Significant Overall
Survival Findings from Phase 3 KEYNOTE-048 Trial
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced that the European Commission has approved
KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy or in
combination with platinum and 5-fluorouracil (5-FU) chemotherapy,
for the first-line treatment of patients with metastatic or
unresectable recurrent head and neck squamous cell carcinoma
(HNSCC) whose tumors express PD-L1 (combined positive score [CPS]
≥1). This approval is based on findings from the pivotal Phase 3
KEYNOTE-048 trial, in which KEYTRUDA, compared with standard
treatment (cetuximab with carboplatin or cisplatin plus 5-FU),
demonstrated a significant improvement in overall survival (OS) as
monotherapy (HR = 0.74 [95% CI, (0.61-0.90); p=0.00133] and in
combination with chemotherapy (HR=0.65 [95% CI, 0.53-0.80];
p=0.00002), in patients whose tumors expressed PD-L1 (CPS ≥1).
“This disease is especially debilitating since it can be highly
visible and affect a patient’s appearance and their daily
functions, such as eating and speaking,” said Professor Kevin
Harrington, investigator for KEYNOTE-048, professor of biological
cancer therapies at The Institute of Cancer Research, London, and
consultant clinical oncologist at The Royal Marsden NHS Foundation
Trust. “Considering the great need for new treatment options, we
are encouraged by today’s KEYTRUDA approval in Europe, which will
allow certain patients to be treated with immunotherapy earlier in
the course of their treatment.”
This approval allows marketing of the KEYTRUDA monotherapy and
combination regimen in all 28 EU member states plus Iceland,
Lichtenstein and Norway.
“KEYTRUDA is now the first anti-PD-1 treatment option in the
first-line setting for metastatic or unresectable recurrent head
and neck cancer, a disease that has been treated the same way in
the EU for more than a decade,” said Dr. Jonathan Cheng, vice
president, clinical research, Merck Research Laboratories. “The
European Commission approval underscores our commitment to
transforming the way cancer is treated around the world.”
Data Supporting the European Approval
This approval is based on data from the Phase 3 KEYNOTE-048
trial, a multi-center, randomized, open-label, active-controlled
trial conducted in 882 patients with histologically confirmed
metastatic or recurrent HNSCC of the oral cavity, pharynx or
larynx, who had not previously received systemic therapy for
recurrent or metastatic disease and who were considered incurable
by local therapies. Randomization was stratified by tumor PD-L1
expression (Tumor Proportion Score [TPS] ≥50% or <50%), HPV
status (positive or negative), and ECOG Performance Status (PS) (0
vs. 1). The dual primary endpoints were OS and progression-free
survival (PFS). Patients were randomized 1:1:1 to one of the
following treatment arms:
- KEYTRUDA 200 mg intravenously every three weeks;
- KEYTRUDA 200 mg intravenously every three weeks, carboplatin
AUC 5 mg/mL/min intravenously every three weeks or cisplatin 100
mg/m2 intravenously every three weeks and 5-FU 1000 mg/m2/day as a
continuous intravenous infusion over 96 hours every three weeks
(maximum of six cycles of platinum and 5-FU);
- Cetuximab 400 mg/m2 intravenously as the initial dose then 250
mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min
intravenously every three weeks or cisplatin 100 mg/m2
intravenously every three weeks and 5-FU 1000 mg/m2/day as a
continuous intravenous infusion over 96 hours every three weeks
(maximum of six cycles of platinum and 5-FU).
Treatment with KEYTRUDA continued until RECIST v1.1-defined
progression of disease as determined by the investigator,
unacceptable toxicity or a maximum of 24 months.
Efficacy Results for KEYTRUDA as
Monotherapy in KEYNOTE-048 with PD-L1 Expression (CPS ≥1)
Endpoint
KEYTRUDA
n=257
Standard
Treatment*
n=255
OS
Number (%) of patients with event
197 (77%)
229 (90%)
Median in months (95% CI)
12.3 (10.8, 14.3)
10.3 (9.0, 11.5)
Hazard ratio† (95% CI)
0.74 (0.61, 0.90)
p-Value‡
0.00133
PFS
Number (%) of patients with event
228 (89%)
237 (93%)
Median in months (95% CI)
3.2 (2.2, 3.4)
5.0 (4.8, 6.0)
Hazard ratio† (95% CI)
1.13 (0.94, 1.36)
p-Value‡
0.89580
ORR
Objective response rate§ (95% CI)
19.1% (14.5, 24.4)
35% (29.1, 41.1)
Complete response
5%
3%
Partial response
14%
32%
p-Value
1.0000
Duration of Response
Median in months (range)
23.4 (1.5+, 43.0+)
4.5 (1.2+, 38.7+)
% with duration ≥6 months
81%
36%
*
Cetuximab, platinum, and 5-FU
†
Based on the stratified Cox proportional
hazard model
‡
Based on stratified log-rank test
§
Response: Best objective response as
confirmed complete response or partial response
Based on Miettinen and Nurminen method
stratified by ECOG (0 vs. 1), HPV status (positive vs. negative)
and PD-L1 status (strongly positive vs. not strongly positive)
Efficacy Results for KEYTRUDA
plus Chemotherapy in KEYNOTE-048 with PD-L1 Expression (CPS
≥1)
Endpoint
KEYTRUDA +
Platinum Chemotherapy
+
5-FU
n=242
Standard
Treatment*
n=235
OS
Number (%) of patients with event
177 (73%)
213 (91%)
Median in months (95% CI)
13.6 (10.7, 15.5)
10.4 (9.1, 11.7)
Hazard ratio† (95% CI)
0.65 (0.53, 0.80)
p-Value‡
0.00002
PFS
Number (%) of patients with event
212 (88%)
221 (94%)
Median in months (95% CI)
5.1 (4.7, 6.2)
5.0 (4.8, 6.0)
Hazard ratio† (95% CI)
0.84 (0.69, 1.02)
p-Value‡
0.03697
ORR
Objective response rate§ (95% CI)
36% (30.3, 42.8)
36% (29.6, 42.2)
Complete response
7%
3%
Partial response
30%
33%
p-Value
0.4586
Duration of Response
Median in months (range)
6.7 (1.6+, 39.0+)
4.3 (1.2+, 31.5+)
% with duration ≥6 months
54%
34%
*
Cetuximab, platinum, and 5-FU
†
Based on the stratified Cox proportional
hazard model
‡
Based on stratified log-rank test
§
Response: Best objective response as
confirmed complete response or partial response
Based on Miettinen and Nurminen method
stratified by ECOG (0 vs. 1), HPV status (positive vs. negative)
and PD-L1 status (strongly positive vs. not strongly positive
The safety of KEYTRUDA as monotherapy has been evaluated in
5,884 patients with advanced melanoma, resected Stage III melanoma
(adjuvant therapy), non-small cell lung cancer (NSCLC), classical
Hodgkin lymphoma, urothelial carcinoma, or HNSCC across four doses
(2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2
or 3 weeks) in clinical studies. In this patient population, the
median observation time was 7.3 months (range: 1 day to 31 months)
and the most frequent adverse reactions with KEYTRUDA were fatigue
(32%), nausea (20%), and diarrhea (20%). The majority of adverse
reactions reported for monotherapy were of Grades 1 or 2 severity.
The most serious adverse reactions were immune-related adverse
reactions and severe infusion-related reactions.
The safety of KEYTRUDA in combination with chemotherapy has been
evaluated in 1,067 patients with NSCLC or HNSCC receiving 200 mg, 2
mg/kg or 10 mg/kg KEYTRUDA every 3 weeks, in clinical studies. In
this patient population, the most frequent adverse reactions were
anemia (50%), nausea (50%), fatigue (37%), constipation (35%),
diarrhea (30%), neutropenia (30%), decreased appetite (28%) and
vomiting (25%). Incidences of Grades 3-5 adverse reactions in
patients with NSCLC were 67% for KEYTRUDA combination therapy and
66% for chemotherapy alone and in patients with HNSCC were 85% for
KEYTRUDA combination therapy and 84% for chemotherapy plus
cetuximab.
About Head and Neck Cancer
Head and neck cancer describes a number of different tumors that
develop in or around the throat, larynx, nose, sinuses and mouth.
Most head and neck cancers are squamous cell carcinomas that begin
in the flat, squamous cells that make up the thin surface layer of
the structures in the head and neck. Two substances that greatly
increase the risk of developing head and neck cancer are tobacco
and alcohol. It is estimated that there were more than 705,000 new
cases of head and neck cancer diagnosed and over 358,000 deaths
from the disease worldwide in 2018. In Europe, it is estimated that
there were more than 146,000 newly diagnosed cases of head and neck
cancer and around 66,000 deaths from the disease in 2018.
About KEYTRUDA® (pembrolizumab) Injection
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.
Selected Indications for KEYTRUDA® (pembrolizumab) in the
U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of 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 Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is
indicated for the first-line treatment of patients with metastatic
or with unresectable, recurrent head and neck squamous cell
carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with metastatic or with unresectable,
recurrent HNSCC whose tumors express PD-L1 [combined positive score
(CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic HNSCC with disease
progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult 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%).
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. For
more information, visit www.merck.com and connect with us on
Twitter, Facebook, Instagram, YouTube and LinkedIn.
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.
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).
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.
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Media: Pamela Eisele (267) 305-3558
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Investor: Peter Dannenbaum (908) 740-1037
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