Merck Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for KEYTRUDA® (pembrolizumab) in Advanced Colorectal Cancer
November 2, 2015 8:00 am ET
Designation Based on Results in Patients with Metastatic Colorectal Cancer with High Levels of Microsatellite Instability
Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
granted Breakthrough Therapy Designation to KEYTRUDA®
(pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of
patients with microsatellite instability high (MSI-H) metastatic
colorectal cancer. This is the third Breakthrough Therapy Designation
granted for KEYTRUDA.
“We are committed to understanding the full potential of KEYTRUDA to
help patients with a broad range of difficult-to-treat cancers,” said
Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “The
data investigating the use of KEYTRUDA in patients with advanced
colorectal cancer whose tumors have substantial evidence of mismatch DNA
repair defects have been encouraging, and we appreciate the opportunity
that this FDA Breakthrough Therapy Designation provides us to accelerate
our effort to bring KEYTRUDA to these patients.”
The FDA’s Breakthrough Therapy Designation is intended to expedite the
development and review of a candidate that is planned for use, alone or
in combination, to treat a serious or life-threatening disease or
condition when preliminary clinical evidence indicates that the drug may
demonstrate substantial improvement over existing therapies on one or
more clinically significant endpoints. KEYTRUDA was previously granted
breakthrough status for advanced melanoma and advanced non-small cell
lung cancer (NSCLC).
The Breakthrough Therapy Designation in advanced colorectal cancer is
based on data from a Phase 2 study evaluating the activity of KEYTRUDA
in cancers with microsatellite instability, a well-established feature
seen in cells with certain types of DNA repair defects. Findings from
the study, led by researchers from Johns Hopkins Kimmel Cancer Center,
were presented at the 2015 American Society of Clinical Oncology
(ASCO) annual meeting and were published simultaneously in the New
England Journal of Medicine.
Testing tumors for microsatellite instability can identify patients with
defective DNA mismatch repair (MMR) systems. DNA MMR is a process that
permits cells to recognize and repair genetic mismatches generated
during DNA replication. A defective MMR system allows mismatch mutations
to persist. The average tumor has dozens of mutations; however tumors
with DNA MMR deficiency may harbor thousands, especially in regions of
repetitive DNA known as microsatellites. Tumors that are found to have
mutations in select microsatellite sequences, called microsatellite
instability (MSI), are considered DNA MMR-deficient. These tumors are
referred to as being “MSI high.” Overall, DNA MMR-deficiency is present
in approximately 15-20 percent in Stage II disease, 10 percent in Stage
III disease and approximately 5 percent or less in Stage IV disease. In
colorectal cancers, MMR-deficiency is seen in approximately 15-20
percent of non-hereditary colorectal cancers and in most hereditary
colorectal cancers associated with Lynch Syndrome.
Merck is conducting a Phase 2 registration study (KEYNOTE-164) to
evaluate the efficacy and safety of KEYTRUDA based on microsatellite
instability status in patients with previously treated advanced
colorectal cancers, and is also planning a Phase 3 study (KEYNOTE-177)
in a treatment naïve patient population.
The KEYTRUDA clinical development program includes patients with more
than 30 tumor types in more than 160 clinical trials, including more
than 80 trials that combine KEYTRUDA with other cancer treatments.
Registration-enabling trials of KEYTRUDA are currently enrolling
patients in melanoma, NSCLC, head and neck cancer, bladder cancer,
gastric cancer, colorectal cancer, esophageal cancer, breast cancer,
Hodgkin lymphoma, multiple myeloma and other tumors, with further trials
in planning for other cancers.
About KEYTRUDA® (pembrolizumab) Injection
KEYTRUDA is a humanized monoclonal antibody that works by increasing the
ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA 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.
KEYTRUDA is indicated in the United States at a dose of 2 mg/kg
administered as an intravenous infusion over 30 minutes every three
weeks for the treatment of patients with metastatic non-small cell lung
cancer (NSCLC) whose tumors express PD-L1 as determined by an
FDA-approved test with disease progression on or after
platinum-containing chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is
also indicated at the same dosing for the treatment of patients with
unresectable or metastatic melanoma and disease progression following
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. These
indications are approved under accelerated approval based on tumor
response rate and durability of response. An improvement in survival or
disease-related symptoms has not yet been established. Continued
approval for these indications may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
Selected Important Safety Information for KEYTRUDA (pembrolizumab)
Pneumonitis, including fatal cases, occurred in patients receiving
KEYTRUDA. Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients,
including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients,
respectively, receiving KEYTRUDA. Pneumonitis occurred in 19 (3.5%) of
550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%),
or 5 (0.2%) pneumonitis in patients, receiving KEYTRUDA. 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
Colitis (including microscopic colitis) occurred in 4 (1%) of 411
patients with melanoma, including Grade 2 or 3 cases in 1 (0.2%) and 2
(0.5%) patients, respectively, receiving KEYTRUDA.
Colitis occurred in 4 (0.7 %) of 550 patients with NSCLC, including
Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA.
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.
Hepatitis occurred in patients receiving KEYTRUDA. Hepatitis (including
autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients with
melanoma, including a Grade 4 case in 1 (0.2%) patient, receiving
KEYTRUDA. 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.
Hypophysitis occurred in 2 (0.5%) of 411 patients with melanoma,
including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each)
patient, receiving KEYTRUDA. Hypophysitis occurred in 1 (0.2 %) of 550
patients with NSCLC, which was Grade 3 in severity. Monitor patients for
signs and symptoms of hypophysitis (including hypopituitarism and
adrenal insufficiency). Administer corticosteroids and hormone
replacement as indicated. Withhold KEYTRUDA for Grade 2 and withhold or
discontinue for Grade 3 or Grade 4 hypophysitis.
Hyperthyroidism occurred in 5 (1.2%) of 411 patients with melanoma,
including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients,
respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%)
of 411 patients with melanoma, including a Grade 3 case in 1 (0.2%)
patient, receiving KEYTRUDA. Hyperthyroidism occurred in 10 (1.8%) of
550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%).
Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC,
including Grade 2 (5.5%) or 3 (0.2%). Thyroid disorders can occur at any
time during treatment. Monitor patients for changes in thyroid function
(at the start of treatment, periodically during treatment, and as
indicated based on clinical evaluation) and for clinical signs and
symptoms of thyroid disorders. Administer replacement hormones for
hypothyroidism and manage hyperthyroidism with thionamides and
beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade
3 or Grade 4 hyperthyroidism.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred
in patients receiving KEYTRUDA. Monitor patients for hyperglycemia or
other signs and symptoms of diabetes. Administer insulin for type 1
diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in
patients with severe hyperglycemia.
Nephritis occurred in patients receiving KEYTRUDA. Nephritis occurred in
3 (0.7%) patients with melanoma, consisting of one case of Grade 2
autoimmune nephritis (0.2%) and two cases of interstitial nephritis with
renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for
changes in renal function. Administer corticosteroids for Grade 2 or
greater nephritis. Withhold KEYTRUDA for Grade 2; permanently
discontinue KEYTRUDA for Grade 3 or 4 nephritis.
Other clinically important immune-mediated adverse reactions can occur.
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 of the adverse reaction to Grade 1 or
less, initiate corticosteroid taper and continue to taper over at least
1 month. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or
less following steroid taper. Permanently discontinue KEYTRUDA for any
severe or Grade 3 immune-mediated adverse reaction that recurs and for
any life-threatening immune-mediated adverse reaction.
Across clinical studies with KEYTRUDA, the following clinically
significant, immune-mediated adverse reactions have occurred: bullous
pemphigoid and Guillain-Barré syndrome. The following clinically
significant, immune-mediated adverse reactions occurred in less than 1%
of patients with melanoma treated with KEYTRUDA: exfoliative dermatitis,
uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, and
partial seizures arising in a patient with inflammatory foci in brain
parenchyma. The following clinically significant, immune-mediated
adverse reactions occurred in less than 1% of 550 patients with NSCLC
treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum
sickness, and myasthenia gravis.
Infusion-related reactions, including severe and life-threatening
reactions, have occurred in patients receiving KEYTRUDA. Monitor
patients for signs and symptoms of infusion related reactions including
rigors, chills, wheezing, pruritus, flushing, rash, hypotension,
hypoxemia, and fever. For severe or life-threatening reactions, stop
infusion and permanently discontinue KEYTRUDA.
Based on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. If used during pregnancy, or if the
patient becomes pregnant during treatment, apprise the patient of the
potential hazard to a fetus. Advise females of reproductive potential to
use highly effective contraception during treatment and for 4 months
after the last dose of KEYTRUDA.
Among the 411 patients with metastatic melanoma, KEYTRUDA was
discontinued for adverse reactions in 9% of 411 patients. Adverse
reactions, reported in at least two patients, that led to
discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain.
Serious adverse reactions occurred in 36% of patients. The most frequent
serious adverse reactions, reported in 2% or more of patients, were
renal failure, dyspnea, pneumonia, and cellulitis. The most common
adverse reactions (reported in at least 20% of patients) were fatigue
(47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased
appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).
Among the 550 patients with metastatic NSCLC, KEYTRUDA was discontinued
due to adverse reactions in 14% of patients. Serious adverse reactions
occurred in 38% of patients. The most frequent serious adverse reactions
reported in 2% or more of patients were pleural effusion, pneumonia,
dyspnea, pulmonary embolism, and pneumonitis. The most common adverse
reactions (reported in at least 20% of patients) were fatigue (44%),
decreased appetite (25%), dyspnea (23%), and cough (29%).
No formal pharmacokinetic drug interaction studies have been conducted
It is not known whether KEYTRUDA is excreted in human milk. Because many
drugs are excreted in human milk, instruct women to discontinue nursing
during treatment with KEYTRUDA and for 4 months after the final dose.
Safety and effectiveness of KEYTRUDA have not been established in
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Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and the Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf
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