Based on a subgroup analysis, improvement in
event-free survival (EFS) with the KEYTRUDA-based regimen was
consistent across all PD-L1 expression subgroups, histology and
stage
Exploratory subgroup analysis showed a
reduction in EFS events with the KEYTRUDA perioperative regimen for
patients with or without pathological complete response (pCR)
compared with the chemotherapy-placebo regimen
KEYNOTE-671 is the eighth positive pivotal
study evaluating a KEYTRUDA-based regimen in earlier stages of
cancer and the seventh positive pivotal study in lung
cancer
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced positive results from the pivotal Phase 3
KEYNOTE-671 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy,
as a perioperative treatment regimen, which includes treatment
before surgery (neoadjuvant) and after surgery (adjuvant), for
patients with resectable stage II, IIIA or IIIB non-small cell lung
cancer (NSCLC). After a median follow-up of 25.2 months,
neoadjuvant KEYTRUDA plus chemotherapy followed by resection and
adjuvant single-agent KEYTRUDA significantly improved EFS, reducing
the risk of disease recurrence, progression or death by 42%
(HR=0.58 [95% CI, 0.46-0.72]; p<0.00001) for patients with
resectable stage II, IIIA or IIIB NSCLC versus neoadjuvant placebo
plus chemotherapy followed by adjuvant placebo. For patients who
received the KEYTRUDA-based regimen, median EFS was not reached
(95% CI, 34.1-NR) versus 17 months (95% CI, 14.3-22) for patients
who received chemotherapy alone.
The trial is continuing to allow for additional follow-up of
overall survival (OS), the other dual primary endpoint. A favorable
trend in OS was observed for the KEYTRUDA regimen versus
pre-operative chemotherapy (HR 0.73 [95% CI, 0.54-0.99];
p=0.02124); with only 177 events, these OS data are not mature and
did not reach statistical significance at the time of this interim
analysis. The safety profile of the KEYTRUDA regimen was consistent
with the safety profile in earlier stages and metastatic NSCLC,
with no new safety concerns identified. These results are being
presented today during a clinical science symposium, The Promise of
Neoadjuvant Immunotherapy Across Solid Tumors, at the 2023 American
Society of Clinical Oncology (ASCO) Annual Meeting (abstract
#LBA100) and are also being simultaneously published in the New
England Journal of Medicine.
In a subgroup analysis, improvement in EFS with the KEYTRUDA
regimen was consistent across PD-L1 expression subgroups, histology
and stage. Treatment with the KEYTRUDA-based regimen reduced the
risk of EFS events regardless of PD-L1 expression versus the
chemotherapy-placebo regimen (tumor proportion score [TPS] ≥50%
[n=266] HR=0.42 [95% CI, 0.28-0.65]; TPS 1-49% [n=242] HR=0.51 [95%
CI, 0.34-0.75]; TPS <1% [n=289] HR=0.77 [95% CI, 0.55-1.07]).
The KEYTRUDA-based regimen also improved EFS compared with the
chemotherapy-placebo regimen regardless of histology (nonsquamous
[n=453] HR=0.58 [95% CI, 0.43-0.78]; squamous [n=344] HR=0.57 [95%
CI, 0.41-0.77]) and stage (stage II [n=239] HR=0.65 [95% CI,
0.42-1.01]; stage IIIA [n=442] HR=0.54 [95% CI, 0.41-0.72]; stage
IIIB [n=116] HR=0.52 [95% CI, 0.31-0.88]).
While achieving pCR is a predictor of better outcomes, an
exploratory subgroup analysis showed the reduction in EFS events
with the KEYTRUDA perioperative regimen was observed for patients
with or without pCR (with pCR: HR=0.33 [95% CI, 0.09-1.22]; without
pCR: HR=0.69 [95% CI, 0.55-0.86]).
“Historically, more than half of people with earlier stages of
non-small cell lung cancer that has been surgically removed will
experience recurrence,” said Dr. Heather Wakelee, thoracic medical
oncologist and professor of medicine at Stanford Medicine,
president of the International Association for the Study of Lung
Cancer and principal investigator for KEYNOTE-671. “Results showed
that a pembrolizumab-based regimen before and after surgery
significantly reduced the risk of recurrence, progression or death
by 42 percent versus pre-operative chemotherapy, regardless of
PD-L1 expression and with or without a pathological complete
response. These event-free survival data are very encouraging and
support the potential of this perioperative approach for patients
with resectable stage II, IIIA or IIIB non-small cell lung
cancer.”
“These compelling new results build on previous studies of
KEYTRUDA in earlier stages of disease across certain types of
cancer, including non-small cell lung cancer,” said Dr. Marjorie
Green, senior vice president and head of late-stage oncology,
global clinical development, Merck Research Laboratories.
“KEYNOTE-671 demonstrated statistically significant and clinically
meaningful improvements in event-free survival for patients with
stage II, IIIA or IIIB non-small cell lung cancer treated with the
KEYTRUDA perioperative regimen compared with chemotherapy and
surgery alone. We are working with the FDA and other global
authorities to bring this new option to patients as quickly as
possible.”
“These results are meaningful for the community of thoracic
surgeons given the need for additional treatment options that can
improve event-free survival for patients with resectable stage II,
IIIA or IIIB non-small cell lung cancer,” said Dr. Jonathan Spicer,
associate professor of surgery, McGill University, attending
surgeon, division of thoracic and upper gastrointestinal surgery,
Montreal General Hospital, McGill University Health Centre and
KEYNOTE-671 investigator. “Notably, the results showed that the
KEYTRUDA-based perioperative regimen did not impact the opportunity
for a complete resection and improvements were seen regardless of
if they achieved a pathological complete response or not.”
Merck previously announced that, based on these results, the
U.S. Food and Drug Administration (FDA) has accepted a new
supplemental Biologics License Application (sBLA) for KEYTRUDA for
the treatment of patients with resectable stage II, IIIA, or IIIB
(T3-4N2) NSCLC in combination with platinum-containing chemotherapy
as neoadjuvant treatment, and then continued as a single agent as
adjuvant treatment. The FDA has set a Prescription Drug User Fee
Act, or target action, date of October 16, 2023.
In addition to KEYNOTE-671, seven other pivotal trials
evaluating a KEYTRUDA-based regimen in patients with earlier stages
of cancer met their primary endpoint(s). These trials included:
KEYNOTE-057 in Bacillus Calmette-Guerin (BCG)-unresponsive,
high-risk, non-muscle invasive bladder cancer; KEYNOTE-629 in
cutaneous squamous cell carcinoma; KEYNOTE-716 in stage IIB and IIC
melanoma; KEYNOTE-054 in stage III melanoma; KEYNOTE-091 in stage
IB, II or IIIA NSCLC; KEYNOTE-564 in renal cell carcinoma; and
KEYNOTE-522 in triple-negative breast cancer.
The seven positive pivotal studies in lung cancer include:
KEYNOTE-189, KEYNOTE-407, KEYNOTE-042, KEYNOTE-024, KEYNOTE-010,
KEYNOTE-091 and KEYNOTE-671.
Merck has an extensive clinical development program in lung
cancer and is advancing multiple registration-enabling studies,
with research directed at earlier stages of disease and novel
combinations. Key studies in earlier stages of NSCLC and small cell
lung cancer (SCLC) include KEYNOTE-671, KEYNOTE-091, KEYNOTE-867,
KEYLYNK-012, KEYVIBE-006 and KEYLYNK-013.
As announced, data spanning more than 25 different types of
cancer are being presented from Merck’s broad oncology portfolio
and investigational pipeline at the 2023 ASCO Annual Meeting. A
compendium of Merck’s presentations and posters is available
here.
Study design and additional data from KEYNOTE-671
KEYNOTE-671 is a randomized, double-blind Phase 3 trial
(ClinicalTrials.gov, NCT03425643) evaluating neoadjuvant KEYTRUDA
plus chemotherapy, followed by resection and adjuvant KEYTRUDA as a
single agent, versus placebo plus neoadjuvant chemotherapy,
followed by resection and adjuvant placebo, in patients with
resectable stage II, IIIA or IIIB (T3-4N2) NSCLC. The trial’s dual
primary endpoints are EFS and OS. Key secondary endpoints include
pCR and major pathological response (mPR). The study enrolled 797
patients who were randomly assigned (1:1) to receive either:
- KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W] for
up to four cycles) plus chemotherapy (cisplatin [75 mg/m2, IV;
given on Day 1 of each cycle] and either gemcitabine [1000 mg/m2,
IV; given on Days 1 and 8 of each cycle or pemetrexed [500 mg/m2,
IV; given on Day 1 of each cycle]) as neoadjuvant therapy prior to
surgery, followed by KEYTRUDA (200 mg IV Q3W for up to 13 cycles)
as adjuvant therapy post-surgery (n=397) for up to 13 cycles,
or;
- Placebo (saline IV Q3W for up to four cycles) plus chemotherapy
(cisplatin [75 mg/m2, IV; given on Day 1 of each cycle] and either
gemcitabine [1000 mg/m2, IV; given on Days 1 and 8 of each cycle]
or pemetrexed [500 mg/m2, IV; given on Day 1 of each cycle]) as
neoadjuvant therapy prior to surgery, followed by placebo (saline
IV Q3W for up to 13 cycles) as adjuvant therapy post-surgery
(n=400) for up to 13 cycles.
As previously announced, KEYNOTE-671 met the dual primary
endpoint of EFS at the first interim analysis. At two years, 62.4%
of patients treated with the KEYTRUDA regimen were alive and did
not experience an EFS event compared to 40.6% of patients treated
with the chemotherapy-placebo regimen.
The KEYTRUDA-based perioperative treatment regimen also
demonstrated statistically significant and clinically meaningful
improvements in key secondary endpoints of pCR and mPR. In the
study, 18.1% of patients treated with the KEYTRUDA plus
chemotherapy regimen achieved pCR versus 4% of patients treated
with pre-operative chemotherapy (difference: 14.2% (95% CI:
10.1-18.7); p<0.00001). Additionally, treatment with the
KEYTRUDA plus chemotherapy regimen resulted in a 30.2% mPR rate,
meaning 10% or less or their tumor cells remained after receiving
perioperative treatment, versus 11% with chemotherapy alone
(difference: 19.2% [95% CI: 13.9-24.7]; p<0.00001).
Among patients treated with pre-operative KEYTRUDA plus
chemotherapy, 80.6% underwent definitive surgery compared to 75.5%
who received chemotherapy alone. Of these patients, 92% and 84% had
a complete resection (R0 resection), respectively.
Treatment-related adverse events (TRAEs) occurred in 96.7% of
patients receiving the KEYTRUDA regimen (n=396) and 95% of patients
receiving the chemotherapy-placebo regimen (n=399); Grade 3-5 TRAEs
occurred in 44.9% versus 37.3%, respectively. Treatment-related
adverse events led to discontinuation of all study treatment in
12.6% of patients treated with the KEYTRUDA regimen and 5.3%
treated with the chemotherapy-placebo regimen. Treatment-related
adverse events led to death in 1.0% of patients receiving the
KEYTRUDA regimen (n=4) and 0.8% of patients receiving the
chemotherapy-placebo regimen (n=3). No new safety concerns were
identified.
Immune-mediated adverse events (AEs) and infusion reactions of
any grade occurred in 25.3% of patients receiving the KEYTRUDA
regimen and 10.5% of patients receiving the chemotherapy-placebo
regimen. Grade 3-5 immune-mediated AEs and infusion reactions
occurred in 5.8% versus 1.5%, respectively. The most common of
these events (occurring in ≥10% of patients) was hypothyroidism
(11.1%) in patients receiving the KEYTRUDA regimen. Immune-mediated
AEs and infusion reactions led to death in 0.3% of patients
receiving the KEYTRUDA regimen (n=1) and no patients receiving the
chemotherapy-placebo regimen. Immune-mediated AEs and infusion
reactions that led to discontinuation of all study treatment
occurred in 5.1% of patients receiving the KEYTRUDA regimen and
0.8% of patients receiving the chemotherapy-placebo regimen.
About lung cancer
Lung cancer is the leading cause of cancer death worldwide. In
2020 alone, there were more than 2.2 million new cases and 1.8
million deaths from lung cancer globally. Non-small cell lung
cancer is the most common type of lung cancer, accounting for about
81% of all cases. In the U.S., the overall five-year survival rate
for patients diagnosed with lung cancer is 25%, which is a 21%
improvement over the last five years. Improved survival rates are
due, in part, to reduction in smoking, advances in diagnostic and
surgical procedures, as well as the introduction of new therapies.
However, screening, early detection and improving treatment rates
remain an important unmet need, as 44% of lung cancer cases are not
found until they are advanced. Only 5.8% of people in the U.S. who
are eligible were screened for lung cancer in 2021.
About Merck’s research in lung cancer
Merck is advancing research aimed at transforming the way lung
cancer is treated, with a goal of improving outcomes for patients
affected by this deadly disease. Through nearly 200 clinical trials
evaluating more than 36,000 patients around the world, Merck is at
the forefront of lung cancer research. In NSCLC, KEYTRUDA has five
approved U.S. indications (see indications below) and is approved
for advanced disease in more than 95 countries. Among Merck’s
research efforts are trials focused on evaluating KEYTRUDA in
earlier stages of lung cancer as well as identifying new
combinations and coformulations with KEYTRUDA.
About Merck’s early-stage cancer clinical program
Finding cancer at an earlier stage may give patients a greater
chance of long-term survival. Many cancers are considered most
treatable and potentially curable in their earliest stage of
disease. Building on the strong understanding of the role of
KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in
earlier disease states, with approximately 20 ongoing
registrational studies across multiple types of cancer.
About KEYTRUDA® (pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy
that works by increasing the ability of the body’s immune system to
help detect and fight tumor cells. KEYTRUDA is a humanized
monoclonal antibody that blocks the interaction between PD-1 and
its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes
which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical
research program. There are currently more than 1,600 trials
studying KEYTRUDA across a wide variety of cancers and treatment
settings. The KEYTRUDA clinical program seeks to understand the
role of KEYTRUDA across cancers and the factors that may predict a
patient's likelihood of benefitting from treatment with KEYTRUDA,
including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications in the
U.S.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum
chemotherapy, is indicated for the first-line treatment of patients
with metastatic nonsquamous non-small cell lung cancer (NSCLC),
with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel
or paclitaxel protein-bound, is indicated for the first-line
treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with NSCLC expressing PD-L1 [tumor proportion
score (TPS) ≥1%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations, and is:
- stage III where patients are not candidates for surgical
resection or definitive chemoradiation, or
- metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%)
as determined by an FDA-approved test, with disease progression on
or after platinum-containing chemotherapy. Patients with EGFR or
ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
KEYTRUDA.
KEYTRUDA, as a single agent, is indicated as adjuvant treatment
following resection and platinum-based chemotherapy for adult
patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
See additional selected indications for KEYTRUDA in the U.S.
after the Selected Important Safety Information
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of
drugs that bind to either the PD-1 or the PD-L1, blocking the
PD-1/PD-L1 pathway, thereby removing inhibition of the immune
response, potentially breaking peripheral tolerance and inducing
immune-mediated adverse reactions. Immune-mediated adverse
reactions, which may be severe or fatal, can occur in any organ
system or tissue, can affect more than one body system
simultaneously, and can occur at any time after starting treatment
or after discontinuation of treatment. Important immune-mediated
adverse reactions listed here may not include all possible severe
and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be
clinical manifestations of underlying immune-mediated adverse
reactions. Early identification and management are essential to
ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver
enzymes, creatinine, and thyroid function at baseline and
periodically during treatment. For patients with TNBC treated with
KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at
baseline, prior to surgery, and as clinically indicated. In cases
of suspected immune-mediated adverse reactions, initiate
appropriate workup to exclude alternative etiologies, including
infection. Institute medical management promptly, including
specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on
severity of the immune-mediated adverse reaction. In general, if
KEYTRUDA requires interruption or discontinuation, administer
systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or
equivalent) until improvement to Grade 1 or less. Upon improvement
to Grade 1 or less, initiate corticosteroid taper and continue to
taper over at least 1 month. Consider administration of other
systemic immunosuppressants in patients whose adverse reactions are
not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is
higher in patients who have received prior thoracic radiation.
Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients
receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3
(0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were
required in 67% (63/94) of patients. Pneumonitis led to permanent
discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9%
(26) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 23% had recurrence.
Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL
receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3%
of patients. Patients received high-dose corticosteroids for a
median duration of 10 days (range: 2 days to 53 months).
Pneumonitis rates were similar in patients with and without prior
thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA
in 5.4% (21) of patients. Of the patients who developed
pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA,
and 77% had resolution.
Pneumonitis occurred in 7% (41/580) of adult patients with
resected NSCLC who received KEYTRUDA as a single agent for adjuvant
treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and
Grade 3 (1%) adverse reactions. Patients received high-dose
corticosteroids for a median duration of 10 days (range: 1 day to
2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26
(4.5%) of patients. Of the patients who developed pneumonitis, 54%
interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had
resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present
with diarrhea. Cytomegalovirus infection/reactivation has been
reported in patients with corticosteroid-refractory immune-mediated
colitis. In cases of corticosteroid-refractory colitis, consider
repeating infectious workup to exclude alternative etiologies.
Immune-mediated colitis occurred in 1.7% (48/2799) of patients
receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%),
and Grade 2 (0.4%) reactions. Systemic corticosteroids were
required in 69% (33/48); additional immunosuppressant therapy was
required in 4.2% of patients. Colitis led to permanent
discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5%
(13) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 23% had recurrence.
Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated
Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated
hepatitis occurred in 0.7% (19/2799) of patients receiving
KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2
(0.1%) reactions. Systemic corticosteroids were required in 68%
(13/19) of patients; additional immunosuppressant therapy was
required in 11% of patients. Hepatitis led to permanent
discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9)
of patients. All patients who were withheld reinitiated KEYTRUDA
after symptom improvement; of these, none had recurrence. Hepatitis
resolved in 79% of the 19 patients.
KEYTRUDA With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic
toxicity. Monitor liver enzymes before initiation of and
periodically throughout treatment. Consider monitoring more
frequently as compared to when the drugs are administered as single
agents. For elevated liver enzymes, interrupt KEYTRUDA and
axitinib, and consider administering corticosteroids as needed.
With the combination of KEYTRUDA and axitinib, Grades 3 and 4
increased alanine aminotransferase (ALT) (20%) and increased
aspartate aminotransferase (AST) (13%) were seen at a higher
frequency compared to KEYTRUDA alone. Fifty-nine percent of the
patients with increased ALT received systemic corticosteroids. In
patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4,
n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients
who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34)
administered as a single agent or with both (n=55), recurrence of
ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16
patients receiving axitinib, and 24 patients receiving both. All
patients with a recurrence of ALT ≥3 ULN subsequently recovered
from the event.
Immune-Mediated
Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency.
For Grade 2 or higher, initiate symptomatic treatment, including
hormone replacement as clinically indicated. Withhold KEYTRUDA
depending on severity. Adrenal insufficiency occurred in 0.8%
(22/2799) of patients receiving KEYTRUDA, including Grade 4
(<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic
corticosteroids were required in 77% (17/22) of patients; of these,
the majority remained on systemic corticosteroids. Adrenal
insufficiency led to permanent discontinuation of KEYTRUDA in
<0.1% (1) and withholding in 0.3% (8) of patients. All patients
who were withheld reinitiated KEYTRUDA after symptom
improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis
can present with acute symptoms associated with mass effect such as
headache, photophobia, or visual field defects. Hypophysitis can
cause hypopituitarism. Initiate hormone replacement as indicated.
Withhold or permanently discontinue KEYTRUDA depending on severity.
Hypophysitis occurred in 0.6% (17/2799) of patients receiving
KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2
(0.2%) reactions. Systemic corticosteroids were required in 94%
(16/17) of patients; of these, the majority remained on systemic
corticosteroids. Hypophysitis led to permanent discontinuation of
KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All
patients who were withheld reinitiated KEYTRUDA after symptom
improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders.
Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism. Initiate hormone
replacement for hypothyroidism or institute medical management of
hyperthyroidism as clinically indicated. Withhold or permanently
discontinue KEYTRUDA depending on severity. Thyroiditis occurred in
0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2
(0.3%). None discontinued, but KEYTRUDA was withheld in <0.1%
(1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving
KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to
permanent discontinuation of KEYTRUDA in <0.1% (2) and
withholding in 0.3% (7) of patients. All patients who were withheld
reinitiated KEYTRUDA after symptom improvement. Hypothyroidism
occurred in 8% (237/2799) of patients receiving KEYTRUDA, including
Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent
discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5%
(14) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement. The majority of patients with
hypothyroidism required long-term thyroid hormone replacement. The
incidence of new or worsening hypothyroidism was higher in 1185
patients with HNSCC, occurring in 16% of patients receiving
KEYTRUDA as a single agent or in combination with platinum and FU,
including Grade 3 (0.3%) hypothyroidism. The incidence of new or
worsening hypothyroidism was higher in 389 adult patients with cHL
(17%) receiving KEYTRUDA as a single agent, including Grade 1
(6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or
worsening hyperthyroidism was higher in 580 patients with resected
NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single
agent as adjuvant treatment, including Grade 3 (0.2%)
hyperthyroidism. The incidence of new or worsening hypothyroidism
was higher in 580 patients with resected NSCLC, occurring in 22% of
patients receiving KEYTRUDA as a single agent as adjuvant treatment
(KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.
Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic
Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms
of diabetes. Initiate treatment with insulin as clinically
indicated. Withhold KEYTRUDA depending on severity. Type 1 DM
occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to
permanent discontinuation in <0.1% (1) and withholding of
KEYTRUDA in <0.1% (1) of patients. All patients who were
withheld reinitiated KEYTRUDA after symptom improvement.
Immune-Mediated Nephritis With Renal
Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Immune-mediated
nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA,
including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%)
reactions. Systemic corticosteroids were required in 89% (8/9) of
patients. Nephritis led to permanent discontinuation of KEYTRUDA in
0.1% (3) and withholding in 0.1% (3) of patients. All patients who
were withheld reinitiated KEYTRUDA after symptom improvement; of
these, none had recurrence. Nephritis resolved in 56% of the 9
patients.
Immune-Mediated Dermatologic Adverse
Reactions
KEYTRUDA can cause immune-mediated rash or dermatitis.
Exfoliative dermatitis, including Stevens-Johnson syndrome, drug
rash with eosinophilia and systemic symptoms, and toxic epidermal
necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical
emollients and/or topical corticosteroids may be adequate to treat
mild to moderate nonexfoliative rashes. Withhold or permanently
discontinue KEYTRUDA depending on severity. Immune-mediated
dermatologic adverse reactions occurred in 1.4% (38/2799) of
patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2
(0.1%) reactions. Systemic corticosteroids were required in 40%
(15/38) of patients. These reactions led to permanent
discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6%
(16) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 6% had recurrence.
The reactions resolved in 79% of the 38 patients.
Other Immune-Mediated Adverse
Reactions
The following clinically significant immune-mediated adverse
reactions occurred at an incidence of <1% (unless otherwise
noted) in patients who received KEYTRUDA or were reported with the
use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have
been reported for some of these adverse reactions.
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous
System: Meningitis, encephalitis, myelitis and demyelination,
myasthenic syndrome/myasthenia gravis (including exacerbation),
Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy;
Ocular: Uveitis, iritis and other ocular inflammatory toxicities
can occur. Some cases can be associated with retinal detachment.
Various grades of visual impairment, including blindness, can
occur. If uveitis occurs in combination with other immune-mediated
adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome,
as this may require treatment with systemic steroids to reduce the
risk of permanent vision loss; Gastrointestinal: Pancreatitis, to
include increases in serum amylase and lipase levels, gastritis,
duodenitis; Musculoskeletal and Connective Tissue:
Myositis/polymyositis, rhabdomyolysis (and associated sequelae,
including renal failure), arthritis (1.5%), polymyalgia rheumatica;
Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic
anemia, aplastic anemia, hemophagocytic lymphohistiocytosis,
systemic inflammatory response syndrome, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune
thrombocytopenic purpura, solid organ transplant rejection.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have
been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor
for signs and symptoms of infusion-related reactions. Interrupt or
slow the rate of infusion for Grade 1 or Grade 2 reactions. For
Grade 3 or Grade 4 reactions, stop infusion and permanently
discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
Fatal and other serious complications can occur in patients who
receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments.
Transplant-related complications include hyperacute
graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic
veno-occlusive disease after reduced intensity conditioning, and
steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between anti–PD-1/PD-L1 treatment and
allogeneic HSCT. Follow patients closely for evidence of these
complications and intervene promptly. Consider the benefit vs risks
of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic
HSCT.
Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of
KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in
increased mortality. Treatment of these patients with an
anti–PD-1/PD-L1 treatment in this combination is not recommended
outside of controlled trials.
Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm
when administered to a pregnant woman. Advise women of this
potential risk. In females of reproductive potential, verify
pregnancy status prior to initiating KEYTRUDA and advise them to
use effective contraception during treatment and for 4 months after
the last dose.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse
reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to permanent discontinuation in more than one
patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic
reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%).
The most common adverse reactions (≥20%) with KEYTRUDA were fatigue
(28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-054, when KEYTRUDA was administered as a single agent
to patients with stage III melanoma, KEYTRUDA was permanently
discontinued due to adverse reactions in 14% of 509 patients; the
most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and
diarrhea (1%). Serious adverse reactions occurred in 25% of
patients receiving KEYTRUDA. The most common adverse reaction
(≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when
KEYTRUDA was administered as a single agent to patients with stage
IIB or IIC melanoma, adverse reactions occurring in patients with
stage IIB or IIC melanoma were similar to those occurring in 1011
patients with stage III melanoma from KEYNOTE-054.
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed
and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA
was discontinued due to adverse reactions in 20% of 405 patients.
The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney
injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA
were nausea (56%), fatigue (56%), constipation (35%), diarrhea
(31%), decreased appetite (28%), rash (25%), vomiting (24%), cough
(21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin
and either paclitaxel or paclitaxel protein-bound in metastatic
squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions
in 15% of 101 patients. The most frequent serious adverse reactions
reported in at least 2% of patients were febrile neutropenia,
pneumonia, and urinary tract infection. Adverse reactions observed
in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with
the exception that increased incidences of alopecia (47% vs 36%)
and peripheral neuropathy (31% vs 25%) were observed in the
KEYTRUDA and chemotherapy arm compared to the placebo and
chemotherapy arm in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse
reactions in 19% of 636 patients with advanced NSCLC; the most
common were pneumonitis (3%), death due to unknown cause (1.6%),
and pneumonia (1.4%). The most frequent serious adverse reactions
reported in at least 2% of patients were pneumonia (7%),
pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion
(2.2%). The most common adverse reaction (≥20%) was fatigue
(25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC; the
most common was pneumonitis (1.8%). The most common adverse
reactions (≥20%) were decreased appetite (25%), fatigue (25%),
dyspnea (23%), and nausea (20%).
Adverse reactions observed in KEYNOTE-091 were generally similar
to those occurring in other patients with NSCLC receiving KEYTRUDA
as a single agent, with the exception of hypothyroidism (22%),
hyperthyroidism (11%), and pneumonitis (7%). Two fatal reactions of
myocarditis occurred.
In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to
adverse events in 12% of 300 patients with HNSCC; the most common
adverse reactions leading to permanent discontinuation were sepsis
(1.7%) and pneumonia (1.3%). The most common adverse reactions
(≥20%) were fatigue (33%), constipation (20%), and rash (20%).
In KEYNOTE-048, when KEYTRUDA was administered in combination
with platinum (cisplatin or carboplatin) and FU chemotherapy,
KEYTRUDA was discontinued due to adverse reactions in 16% of 276
patients with HNSCC. The most common adverse reactions resulting in
permanent discontinuation of KEYTRUDA were pneumonia (2.5%),
pneumonitis (1.8%), and septic shock (1.4%). The most common
adverse reactions (≥20%) were nausea (51%), fatigue (49%),
constipation (37%), vomiting (32%), mucosal inflammation (31%),
diarrhea (29%), decreased appetite (29%), stomatitis (26%), and
cough (22%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse
reactions in 17% of 192 patients with HNSCC. Serious adverse
reactions occurred in 45% of patients. The most frequent serious
adverse reactions reported in at least 2% of patients were
pneumonia, dyspnea, confusional state, vomiting, pleural effusion,
and respiratory failure. The most common adverse reactions (≥20%)
were fatigue, decreased appetite, and dyspnea. Adverse reactions
occurring in patients with HNSCC were generally similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy, with the exception of increased incidences of
facial edema and new or worsening hypothyroidism.
In KEYNOTE-204, KEYTRUDA was discontinued due to adverse
reactions in 14% of 148 patients with cHL. Serious adverse
reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1%
were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney
injury, febrile neutropenia, and sepsis. Three patients died from
causes other than disease progression: 2 from complications after
allogeneic HSCT and 1 from unknown cause. The most common adverse
reactions (≥20%) were upper respiratory tract infection (41%),
musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue,
rash, and cough (20% each).
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse
reactions in 5% of 210 patients with cHL. Serious adverse reactions
occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis,
pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from
causes other than disease progression: 1 from GVHD after subsequent
allogeneic HSCT and 1 from septic shock. The most common adverse
reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse
reactions in 8% of 53 patients with PMBCL. Serious adverse
reactions occurred in 26% of patients and included arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial
effusion (2%), and pericarditis (2%). Six (11%) patients died
within 30 days of start of treatment. The most common adverse
reactions (≥20%) were musculoskeletal pain (30%), upper respiratory
tract infection and pyrexia (28% each), cough (26%), fatigue (23%),
and dyspnea (21%).
In KEYNOTE-869, when KEYTRUDA was administered in combination
with enfortumab vedotin to patients with locally advanced or mUC
and who are not eligible for cisplatin-based chemotherapy (n=121),
fatal adverse reactions occurred in 5% of patients, including
sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%),
and pneumonitis (0.8%). Serious adverse reactions occurred in 50%
of patients receiving KEYTRUDA in combination with enfortumab
vedotin; the serious adverse reactions in ≥2% of patients were
acute kidney injury (7%), urinary tract infection (7%), urosepsis
(5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%),
sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%),
myasthenia gravis (2.5%), myositis (2.5%), and urinary retention
(2.5%). Permanent discontinuation of KEYTRUDA occurred in 32% of
patients. The most common adverse reactions (≥2%) resulting in
permanent discontinuation of KEYTRUDA were pneumonitis (5%),
peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis
(2.5%). The most common adverse reactions (≥20%) occurring in
patients treated with KEYTRUDA in combination with enfortumab
vedotin were rash (71%), peripheral neuropathy (65%), fatigue
(60%), alopecia (52%), weight loss (48%), diarrhea (45%), pruritus
(40%), decreased appetite (38%), nausea (36%), dysgeusia (35%),
urinary tract infection (30%), constipation (27%), peripheral edema
(26%), dry eye (25%), dizziness (23%), arthralgia (23%), and dry
skin (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or mUC.
Serious adverse reactions occurred in 42% of patients; those ≥2%
were urinary tract infection, hematuria, acute kidney injury,
pneumonia, and urosepsis. The most common adverse reactions (≥20%)
were fatigue (38%), musculoskeletal pain (24%), decreased appetite
(22%), constipation (21%), rash (21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse
reactions in 8% of 266 patients with locally advanced or mUC. The
most common adverse reaction resulting in permanent discontinuation
of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions
occurred in 39% of KEYTRUDA-treated patients; those ≥2% were
urinary tract infection, pneumonia, anemia, and pneumonitis. The
most common adverse reactions (≥20%) in patients who received
KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus
(23%), decreased appetite (21%), nausea (21%), and rash (20%).
In KEYNOTE-057, KEYTRUDA was discontinued due to adverse
reactions in 11% of 148 patients with high-risk NMIBC. The most
common adverse reaction resulting in permanent discontinuation of
KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred
in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia
(2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and
urinary tract infection (2%). The most common adverse reactions
(≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).
Adverse reactions occurring in patients with MSI-H or dMMR CRC
were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in
patients with MSI-H or dMMR cancer were similar to those occurring
in patients with other solid tumors who received KEYTRUDA as a
single agent.
In KEYNOTE-811, when KEYTRUDA was administered in combination
with trastuzumab, fluoropyrimidine- and platinum-containing
chemotherapy, KEYTRUDA was discontinued due to adverse reactions in
6% of 217 patients with locally advanced unresectable or metastatic
HER2+ gastric or GEJ adenocarcinoma. The most common adverse
reaction resulting in permanent discontinuation was pneumonitis
(1.4%). In the KEYTRUDA arm versus placebo, there was a difference
of ≥5% incidence between patients treated with KEYTRUDA versus
standard of care for diarrhea (53% vs 44%) and nausea (49% vs
44%).
The most common adverse reactions (reported in ≥20%) in patients
receiving KEYTRUDA in combination with chemotherapy were
fatigue/asthenia, nausea, constipation, diarrhea, decreased
appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia,
peripheral neuropathy, mucosal inflammation, stomatitis, headache,
weight loss, abdominal pain, arthralgia, myalgia, and insomnia.
In KEYNOTE-590, when KEYTRUDA was administered with cisplatin
and fluorouracil to patients with metastatic or locally advanced
esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above
the GEJ) carcinoma who were not candidates for surgical resection
or definitive chemoradiation, KEYTRUDA was discontinued due to
adverse reactions in 15% of 370 patients. The most common adverse
reactions resulting in permanent discontinuation of KEYTRUDA (≥1%)
were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia
(1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in
combination with chemotherapy were nausea (67%), fatigue (57%),
decreased appetite (44%), constipation (40%), diarrhea (36%),
vomiting (34%), stomatitis (27%), and weight loss (24%).
Adverse reactions occurring in patients with esophageal cancer
who received KEYTRUDA as a monotherapy were similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy.
In KEYNOTE-826, when KEYTRUDA was administered in combination
with paclitaxel and cisplatin or paclitaxel and carboplatin, with
or without bevacizumab (n=307), to patients with persistent,
recurrent, or first-line metastatic cervical cancer regardless of
tumor PD-L1 expression who had not been treated with chemotherapy
except when used concurrently as a radio-sensitizing agent, fatal
adverse reactions occurred in 4.6% of patients, including 3 cases
of hemorrhage, 2 cases each of sepsis and due to unknown causes,
and 1 case each of acute myocardial infarction, autoimmune
encephalitis, cardiac arrest, cerebrovascular accident, femur
fracture with perioperative pulmonary embolus, intestinal
perforation, and pelvic infection. Serious adverse reactions
occurred in 50% of patients receiving KEYTRUDA in combination with
chemotherapy with or without bevacizumab; those ≥3% were febrile
neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%),
and acute kidney injury and sepsis (3.3% each).
KEYTRUDA was discontinued in 15% of patients due to adverse
reactions. The most common adverse reaction resulting in permanent
discontinuation (≥1%) was colitis (1%).
For patients treated with KEYTRUDA, chemotherapy, and
bevacizumab (n=196), the most common adverse reactions (≥20%) were
peripheral neuropathy (62%), alopecia (58%), anemia (55%),
fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea
(39%), hypertension and thrombocytopenia (35% each), constipation
and arthralgia (31% each), vomiting (30%), urinary tract infection
(27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and
decreased appetite (21%).
For patients treated with KEYTRUDA in combination with
chemotherapy with or without bevacizumab, the most common adverse
reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%),
fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%),
arthralgia (27%), vomiting (26%), hypertension and urinary tract
infection (24% each), and rash (22%).
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with previously treated recurrent or
metastatic cervical cancer. Serious adverse reactions occurred in
39% of patients receiving KEYTRUDA; the most frequent included
anemia (7%), fistula, hemorrhage, and infections [except urinary
tract infections] (4.1% each). The most common adverse reactions
(≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea
(23%), pain and abdominal pain (22% each), and decreased appetite
(21%).
Adverse reactions occurring in patients with HCC were generally
similar to those in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy, with the exception of increased
incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis
(2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a
higher incidence were elevated AST (20%), ALT (9%), and
hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017,
adverse reactions occurring in patients with MCC were generally
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy. Laboratory abnormalities
(Grades 3-4) that occurred at a higher incidence were elevated AST
(11%) and hyperglycemia (19%).
In KEYNOTE-426, when KEYTRUDA was administered in combination
with axitinib, fatal adverse reactions occurred in 3.3% of 429
patients. Serious adverse reactions occurred in 40% of patients,
the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%),
acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).
Permanent discontinuation due to an adverse reaction occurred in
31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the
combination (8%); the most common were hepatotoxicity (13%),
diarrhea/colitis (1.9%), acute kidney injury (1.6%), and
cerebrovascular accident (1.2%). The most common adverse reactions
(≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension
(48%), hepatotoxicity (39%), hypothyroidism (35%), decreased
appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea
(28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash
(25%), cough (21%), and constipation (21%).
In KEYNOTE-564, when KEYTRUDA was administered as a single agent
for the adjuvant treatment of renal cell carcinoma, serious adverse
reactions occurred in 20% of patients receiving KEYTRUDA; the
serious adverse reactions (≥1%) were acute kidney injury, adrenal
insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1%
each). Fatal adverse reactions occurred in 0.2% including 1 case of
pneumonia. Discontinuation of KEYTRUDA due to adverse reactions
occurred in 21% of 488 patients; the most common (≥1%) were
increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%).
The most common adverse reactions (≥20%) were musculoskeletal pain
(41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%),
and hypothyroidism (21%).
Adverse reactions occurring in patients with MSI-H or dMMR
endometrial carcinoma who received KEYTRUDA as a single agent were
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with TMB-H cancer were
similar to those occurring in patients with other solid tumors who
received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with recurrent or
metastatic cSCC or locally advanced cSCC were similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy.
In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant
chemotherapy (carboplatin and paclitaxel followed by doxorubicin or
epirubicin and cyclophosphamide) followed by surgery and continued
adjuvant treatment with KEYTRUDA as a single agent (n=778) to
patients with newly diagnosed, previously untreated, high-risk
early-stage TNBC, fatal adverse reactions occurred in 0.9% of
patients, including 1 each of adrenal crisis, autoimmune
encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary
embolism, and sepsis in association with multiple organ dysfunction
syndrome and myocardial infarction. Serious adverse reactions
occurred in 44% of patients receiving KEYTRUDA; those ≥2% were
febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and
neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients
due to adverse reactions. The most common reactions (≥1%) resulting
in permanent discontinuation were increased ALT (2.7%), increased
AST (1.5%), and rash (1%). The most common adverse reactions (≥20%)
in patients receiving KEYTRUDA were fatigue (70%), nausea (67%),
alopecia (61%), rash (52%), constipation (42%), diarrhea and
peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%),
headache (30%), arthralgia (29%), pyrexia (28%), cough (26%),
abdominal pain (24%), decreased appetite (23%), insomnia (21%), and
myalgia (20%).
In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel,
paclitaxel protein-bound, or gemcitabine and carboplatin) were
administered to patients with locally recurrent unresectable or
metastatic TNBC who had not been previously treated with
chemotherapy in the metastatic setting (n=596), fatal adverse
reactions occurred in 2.5% of patients, including
cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious
adverse reactions occurred in 30% of patients receiving KEYTRUDA in
combination with chemotherapy; the serious reactions in ≥2% were
pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).
KEYTRUDA was discontinued in 11% of patients due to adverse
reactions. The most common reactions resulting in permanent
discontinuation (≥1%) were increased ALT (2.2%), increased AST
(1.5%), and pneumonitis (1.2%). The most common adverse reactions
(≥20%) in patients receiving KEYTRUDA in combination with
chemotherapy were fatigue (48%), nausea (44%), alopecia (34%),
diarrhea and constipation (28% each), vomiting and rash (26% each),
cough (23%), decreased appetite (21%), and headache (20%).
Lactation
Because of the potential for serious adverse reactions in
breastfed children, advise women not to breastfeed during treatment
and for 4 months after the last dose.
Pediatric Use
In KEYNOTE-051, 173 pediatric patients (65 pediatric patients
aged 6 months to younger than 12 years and 108 pediatric patients
aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every
3 weeks. The median duration of exposure was 2.1 months (range: 1
day to 25 months).
Adverse reactions that occurred at a ≥10% higher rate in
pediatric patients when compared to adults were pyrexia (33%),
leukopenia (31%), vomiting (29%), neutropenia (28%), headache
(25%), abdominal pain (23%), thrombocytopenia (22%), anemia (17%),
decreased lymphocyte count (13%), and decreased white blood cell
count (11%).
Additional Indications for KEYTRUDA in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and
pediatric (12 years and older) patients with stage IIB, IIC, or III
melanoma following complete resection.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is
indicated for the first-line treatment of patients with metastatic
or with unresectable, recurrent head and neck squamous cell
carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with metastatic or with unresectable,
recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score
(CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic HNSCC with disease
progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with
relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients
with refractory cHL, or cHL that has relapsed after 2 or more lines
of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with refractory primary mediastinal large B-cell lymphoma
(PMBCL), or who have relapsed after 2 or more prior lines of
therapy. KEYTRUDA is not recommended for treatment of patients with
PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA, in combination with enfortumab vedotin, is indicated
for the treatment of adult patients with locally advanced or
metastatic urothelial carcinoma (mUC) who are not eligible for
cisplatin-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.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with locally advanced or metastatic urothelial carcinoma
(mUC):
- who are not eligible for any platinum-containing chemotherapy,
or
- who have disease progression during or following
platinum-containing chemotherapy or within 12 months of neoadjuvant
or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with Bacillus Calmette-Guerin (BCG)-unresponsive,
high-risk, non-muscle invasive bladder cancer (NMIBC) with
carcinoma in situ (CIS) with or without papillary tumors who are
ineligible for or have elected not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient
Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with unresectable or metastatic microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR) solid
tumors, as determined by an FDA-approved test, that have progressed
following prior treatment and who have no satisfactory alternative
treatment options.
Microsatellite Instability-High or Mismatch Repair Deficient
Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as
determined by an FDA-approved test.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and
platinum-containing chemotherapy, is indicated for the first-line
treatment of patients with locally advanced unresectable or
metastatic HER2-positive gastric or gastroesophageal junction (GEJ)
adenocarcinoma.
This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic esophageal or gastroesophageal junction
(GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ)
carcinoma that is not amenable to surgical resection or definitive
chemoradiation either:
- in combination with platinum- and fluoropyrimidine-based
chemotherapy, or
- as a single agent after one or more prior lines of systemic
therapy for patients with tumors of squamous cell histology that
express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA, in combination with chemotherapy, with or without
bevacizumab, is indicated for the treatment of patients with
persistent, recurrent, or metastatic cervical cancer whose tumors
express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic cervical cancer with disease
progression on or after chemotherapy whose tumors express PD-L1
(CPS ≥1) as determined by an FDA-approved test.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with recurrent locally advanced or metastatic Merkel cell
carcinoma (MCC). This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the
first-line treatment of adult patients with advanced renal cell
carcinoma (RCC).
KEYTRUDA is indicated for the adjuvant treatment of patients
with RCC at intermediate-high or high risk of recurrence following
nephrectomy, or following nephrectomy and resection of metastatic
lesions.
Endometrial Carcinoma
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with advanced endometrial carcinoma that is MSI-H or dMMR,
as determined by an FDA-approved test, who have disease progression
following prior systemic therapy in any setting and are not
candidates for curative surgery or radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with unresectable or metastatic tumor mutational
burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as
determined by an FDA-approved test, that have progressed following
prior treatment and who have no satisfactory alternative treatment
options. This indication is approved under accelerated approval
based on tumor response rate and durability of response. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials. The
safety and effectiveness of KEYTRUDA in pediatric patients with
TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with
recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or
locally advanced cSCC that is not curable by surgery or
radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with
high-risk early-stage triple-negative breast cancer (TNBC) in
combination with chemotherapy as neoadjuvant treatment, and then
continued as a single agent as adjuvant treatment after
surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the
treatment of patients with locally recurrent unresectable or
metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined
by an FDA-approved test.
Merck’s focus on cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
the potential to bring new hope to people with cancer drives our
purpose and supporting accessibility to our cancer medicines is our
commitment. As part of our focus on cancer, Merck is committed to
exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor
types. We also continue to strengthen our portfolio through
strategic acquisitions and are prioritizing the development of
several promising oncology candidates with the potential to improve
the treatment of advanced cancers. For more information about our
oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
At Merck, known as MSD outside of the United States and Canada,
we are unified around our purpose: We use the power of leading-edge
science to save and improve lives around the world. For more than
130 years, we have brought hope to humanity through the development
of important medicines and vaccines. We aspire to be the premier
research-intensive biopharmaceutical company in the world – and
today, we are at the forefront of research to deliver innovative
health solutions that advance the prevention and treatment of
diseases in people and animals. We foster a diverse and inclusive
global workforce and operate responsibly every day to enable a
safe, sustainable and healthy future for all people and
communities. For more information, visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc., Rahway,
N.J., USA
This news release of Merck & Co., Inc., Rahway, N.J., USA
(the “company”) includes “forward-looking statements” within the
meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline candidates that
the candidates will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of the global outbreak of novel coronavirus disease
(COVID-19); the impact of pharmaceutical industry regulation and
health care legislation in the United States and internationally;
global trends toward health care cost containment; technological
advances, new products and patents attained by competitors;
challenges inherent in new product development, including obtaining
regulatory approval; the company’s ability to accurately predict
future market conditions; manufacturing difficulties or delays;
financial instability of international economies and sovereign
risk; dependence on the effectiveness of the company’s patents and
other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s Annual
Report on Form 10-K for the year ended December 31, 2022 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
(pembrolizumab) at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and Medication Guide for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20230603005003/en/
Media: Julie Cunningham (617) 519-6264 Nikki Sullivan (718)
644-0730 Investor: Peter Dannenbaum (732) 594-1579 Damini Chokshi
(732) 594-1577
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