FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for the Treatment of Patients
with Hepatocellular Carcinoma (HCC) Who Have Been Previously Treated with Sorafenib
Approval Marks 14th Indication for KEYTRUDA
Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration
(FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, 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.
“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic
advancements, there are still limited treatment options for advanced recurrent disease,” said Dr. Andrew X. Zhu, lead investigator
and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School.
“Today’s approval of KEYTRUDA is important, as it provides a new treatment option for patients with hepatocellular carcinoma who
have been previously treated with sorafenib.”
Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis,
hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic
hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or
discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related
reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more
information, see “Selected Important Safety Information” below.
“The approval of KEYTRUDA for advanced hepatocellular carcinoma marks the second FDA approval for hepatocellular carcinoma in
Merck’s oncology portfolio this year, underscoring our commitment to help bring forward new treatment options for cancers that have
historically been very challenging to treat,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research
Laboratories. “We look forward to continuing to advance research for hepatocellular carcinoma across our portfolio with the goal to
help even more patients affected by this type of cancer.”
Data Supporting the Approval
The approval was based on data from KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating KEYTRUDA in 104 patients
with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib. Additional eligibility included having
measurable disease and Child-Pugh class A liver impairment. Patients with active and inactive hepatitis B virus (HBV) as well as
patients with past or ongoing hepatitis C virus (HCV) infection were eligible for the trial. Patients with active autoimmune
disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of
ascites by physical exam were ineligible for the trial.
Patients received KEYTRUDA 200 mg every three weeks until unacceptable toxicity or confirmed disease progression. Patients
without disease progression were treated for up to 24 months. Assessment of tumor status was performed every nine weeks. The major
efficacy outcome measures were objective response rate (ORR) and duration of response according to RECIST v1.1, modified to follow
a maximum of 10 target lesions and a maximum of five target lesions per organ, as assessed by blinded independent central review
(BICR).
Among the 104 patients treated, the baseline characteristics were: median age 68 years (67% age 65 or older); 83 percent were
male; 81 percent were White; 14 percent were Asian; ECOG PS of 0 (61%) or 1 (39%); Child Pugh class and score were A5 (72%), A6
(22%), B7 (5%), and B8 (1%); 21 percent were HBV seropositive and 25% HCV seropositive. Nine patients (9%) were seropositive for
both HBV and HCV. Sixty-four percent of patients had extrahepatic disease, 17 percent had vascular invasion, and 9 percent had
both, and 38 percent had alfa-fetoprotein (AFP) levels greater than 400 ug/mL. All patients received prior sorafenib; reasons for
discontinuation were intolerance in 20 percent of patients.
In KEYNOTE-224, the ORR was 17 percent (95% CI, 11-26), with a complete response rate of 1 percent and a partial response rate
of 16 percent. Among the responding patients (n=18), 89 percent experienced a DOR for six months or longer and 56 percent
experienced a DOR for 12 months or longer.
Among the 104 patients in KEYNOTE-224, the median duration of exposure to KEYTRUDA was 4.2 months (range, 1 day to 1.5 years).
Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or non-small cell lung
cancer, 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%).
About KEYTRUDA® (pembrolizumab) Injection, 100mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2,
thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 850 trials studying
KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of
KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA,
including exploring several different biomarkers.
KEYTRUDA® (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every
three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with
metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of
patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer
(NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ?50%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS
?1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with
EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to
receiving KEYTRUDA.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given
on the same day. See also the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, as
appropriate.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)
with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based
on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every
three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who
have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg
every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell
lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated
approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients
with PMBCL who require urgent cytoreductive therapy.
In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is
administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity,
or up to 24 months in patients without disease progression.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not
eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ?10] as determined by
an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This
indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for
this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have
disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment
with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks
until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Microsatellite Instability-High (MSI-H) Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR)
- solid tumors that have progressed following prior treatment and who have no satisfactory alternative
treatment options, or
- colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and
irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued
approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been
established.
In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer,
KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease progression.
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal
junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ?1] as determined by an FDA-approved test,
with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing
chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three
weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Cervical Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or
after chemotherapy whose tumors express PD-L1 (CPS ?1) as determined by an FDA-approved test. This indication is approved under
accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a
fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without
disease progression.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with
sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory
trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease progression.
Selected Important Safety Information for KEYTRUDA
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients
receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients
with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of
pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater
pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2
(0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or
greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
Immune-Mediated Hepatitis
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including
Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2
or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Immune-Mediated Endocrinopathies
KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of
patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including
Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 15%
(28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and
thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic
ketoacidosis, occurred in 0.2% (6/2799) of patients.
Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function
(prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone
replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis.
Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate.
Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA
and administer antihyperglycemics in patients with severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including
Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in
combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids
for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal
outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based
on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or
symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is
confirmed, permanently discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving
KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate
evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and
administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least
1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled
with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse
reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3
immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of
2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic
anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and
postmarketing use.
Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of
treatment vs the risk of possible organ rejection in these patients.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have
been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4
reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with
KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (1
fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases
of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1
receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications
such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic
veno-occlusive disease (VOD), and other immune-mediated adverse reactions.
In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with
KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider
the benefit of KEYTRUDA vs the risk of GVHD in these patients.
Increased Mortality in Patients With Multiple Myeloma
In clinical 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 clinical trials.
Embryofetal Toxicity
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.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic
reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (?20%) with KEYTRUDA were
fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC,
KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (?20%) with
KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting
(24%), cough (21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or nab-paclitaxel in metastatic squamous
NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions
reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in
KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and
peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm
in KEYNOTE-407.
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The
most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). The most common adverse
reactions (?20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions
occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia,
dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (?20%) were
fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of
facial edema and new or worsening hypothyroidism.
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions
occurred in 16% of patients; those ?1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients
died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most
common adverse reactions (?20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and
rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions
occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion
(2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (?20%)
were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea
(21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic
urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ?2% were urinary tract infection, hematuria,
acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (?20%) were fatigue (38%), musculoskeletal pain
(24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic
urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%).
Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ?2% were urinary tract infection, pneumonia, anemia,
and pneumonitis. The most common adverse reactions (?20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal
pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).
Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical
cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula,
hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (?20%) were fatigue
(43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).
Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy, with the exception of increased occurrences of elevated AST (14% Grade 3-4), ALT (7% Grade 3-4), blood
bilirubin (3.8% Grade 3-4), and ascites (7% Grade 3-4). Immune-mediated hepatitis occurred in 3 (2.9%) patients.
Lactation
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.
Pediatric Use
There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or
PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with
KEYTRUDA. Toxicities 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%), hypertransaminasemia (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.
About the Merck Access Program for KEYTRUDA
At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help ensure
that appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides
reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance
for eligible patients. Merck also offers free product through our patient assistance program to eligible patients, primarily the
uninsured, who, without our assistance, could not afford their medicine. More information is available by calling 855-257-3932 or
visiting
www.merckaccessprogram-keytruda.com.
About Merck’s Patient Support Program for KEYTRUDA
Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA. The
KEY+YOU Patient Support Program provides a range of resources and services. For further information and to sign up, patients and
physicians may call 85-KEYTRUDA (855-398-7832) or visit
www.keytruda.com.
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
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The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause results to differ materially from those described in the
forward-looking statements can be found in the company’s 2017 Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).
Please see Prescribing Information for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and
Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf
Media:
Pamela Eisele, 267-305-3558
or
Ann Bush, 908-740-6677
or
Investors:
Teri Loxam, 908-740-1986
or
Courtney Ronaldo, 908-740-6132
View source version on businesswire.com: https://www.businesswire.com/news/home/20181109005572/en/