Merck Announces Positive Study Investigating the Use of KEYTRUDA® (pembrolizumab) Compared to Chemotherapy in Patients with Ipilimumab-Refractory Advanced Melanoma


November 16, 2014 4:25 am ET

KEYTRUDA Demonstrated Superiority to Chemotherapy for Primary Endpoint of Progression-Free Survival

Findings Presented for First Time at Society of Melanoma Research (SMR) 2014 International Congress

ZURICH–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
announced today that a pre-specified analysis of investigational data
from a pivotal Phase 2 study (KEYNOTE-002) showed KEYTRUDA®
(pembrolizumab), the company’s anti-PD-1 therapy, substantially improved
the primary endpoint of progression-free survival (PFS, as assessed by
RECIST 1.1, independent central review) (HR 0.57 and 0.50 for 2 mg/kg
and 10 mg/kg every three week doses, respectively), compared to
chemotherapy (P<0.0001 for both comparisons) in patients with
ipilimumab-refractory advanced melanoma (n=540). At six months, the PFS
rates for KEYTRUDA were 34 percent at the 2 mg/kg dose (95% CI, 27-41)
(n=180) and 38 percent at the 10 mg/kg dose (95% CI, 31-45) (n=181),
compared to 16 percent for chemotherapy (95% CI, 10-22) (n=179). The
median duration of follow-up at the interim analysis was 10 months.

These findings, including pre-specified analyses of overall response
rate (ORR), duration of response, safety and health-related quality of
life (HRQoL), were presented today in an oral session by Dr. Antoni
Ribas, professor, Hematology/Oncology and Surgery, and director of the
Tumor Immunology Program at the Jonsson Comprehensive Cancer Center,
University of California, Los Angeles at the Society of Melanoma
Research (SMR) 2014 International Congress in Zurich, Switzerland.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg every
three weeks for the treatment of patients with unresectable or
metastatic melanoma and disease progression following ipilimumab and, if
BRAF V600 mutation positive, a BRAF inhibitor. This indication is
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 this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials.

“These findings demonstrate KEYTRUDA was superior to chemotherapy in
helping more patients with ipilimumab-refractory advanced melanoma
achieve progression-free survival,” said Dr. Eric Rubin, vice president,
global clinical development for oncology, Merck Research Laboratories.
“The comparative efficacy and safety data from the pivotal KEYNOTE-002
study validate and extend the findings from our earlier study in these
difficult-to-treat patients, and we look forward to sharing data on
overall survival at a future congress.”

For the pre-specified analysis of PFS, no significant differences were
observed between KEYTRUDA doses (HR 0.91, range 0.71-1.16) (P<0.44). An
assessment of PFS by investigator review was shown to be consistent with
the central review findings. In addition, the PFS effect in favor of
KEYTRUDA was consistent across all pre-specified sub-groups.

The objective of the pre-specified analysis was to evaluate the
superiority of either dose of KEYTRUDA over chemotherapy for PFS
(conducted after ≥ 270 PFS events at a 0.25% significance level)
(one-sided) (estimated HR, 0.66). The study was designed with co-primary
endpoints of PFS and overall survival. An evaluation of overall survival
is planned at the pre-specified final analysis in 2015.

Additional Efficacy Data and Safety from the KEYNOTE-002 Study

Overall response rates (confirmed) for KEYTRUDA were five to six times
higher compared to chemotherapy. For KEYTRUDA, ORR was 21 percent at 2
mg/kg dose (95% CI, 15-28) and 25 percent at 10 mg/kg dose (95% CI,
19-32), compared to 4 percent for chemotherapy (95% CI, 2-9) (P<0.0001
for both comparisons). At the time of pre-specified analysis, the median
duration of response for KEYTRUDA was not reached, and confirmed
responses were ongoing in 92 percent of patients receiving 2 mg/kg dose
(range 6+ to 50+) and 87 percent receiving 10 mg/kg dose (range 5+ to
48+), respectively. The median duration of response was 37 weeks for
chemotherapy arm and 63 percent of responses were ongoing (range 7+ to
41). There was no significant difference in ORR or duration of response
between the doses of KEYTRUDA (P=0.21).

In a pre-specified exploratory analysis for HRQoL, patients treated with
KEYTRUDA reported a significantly smaller decrement in health
status/quality of life score compared to those treated with chemotherapy
(based on European Organization for Research and Treatment of Cancer
(EORTC) Core Quality of Life Questionnaire or “EORTC QLQ-C30”). The mean
change from baseline at week 12 (difference in least squares) for
KEYTRUDA compared to chemotherapy was 6.52 (P=0.011) at 2 mg/kg dose and
6.57 (p=0.009) at 10 mg/kg dose, respectively.

The incidence of adverse events was consistent with previously reported
data for KEYTRUDA. Despite longer median treatment duration, the
incidence of treatment-related, grade 3-5 adverse events was lower with
KEYTRUDA at 2 mg/kg dose (11%) and at 10 mg/kg dose (14%) compared to
chemotherapy (26%). Serious treatment-related adverse events were
observed for KEYTRUDA at 2 mg/kg dose (8%) and 10 mg/kg dose (11%), and
for chemotherapy (10%). Immune-related grade 3 adverse events observed
for KEYTRUDA across doses included hepatitis (n=3), colitis (n=2),
pneumonitis (n=3), hypophysitis (n=1) and iritis or uveitis (n=1). No
grade 4/5 immune-related adverse events were reported. Three percent of
patients receiving KEYTRUDA at 2 mg/kg dose and 7 percent at the 10
mg/kg dose, as well as 6 percent receiving chemotherapy discontinued
treatment due to investigator assessed, treatment-related adverse
events. One treatment-related death was reported for KEYTRUDA and none
in the chemotherapy arm.

About the KEYNOTE-002 Study

KEYNOTE-002 is a global, randomized pivotal Phase 2 study (n=540)
evaluating KEYTRUDA at doses of 2 mg/kg every three weeks (n=180) and
10mg/kg every three weeks (n=181) compared to investigator’s choice
chemotherapy (n=179) (paclitaxel plus carboplatin, paclitaxel,
carboplatin, dacarbazine, or temozolomide) in patients with
ipilimumab-refractory advanced melanoma. In the study, 83 percent of
patients had the most advanced stage of disease (M1c) and 73 percent of
patients had received at least two prior systemic therapies including
ipilimumab. The co-primary endpoints were PFS and OS; secondary
endpoints were ORR, duration of response and safety; and HRQoL as a
pre-specified exploratory endpoint. Tumor response was assessed at week
12, then every 6 weeks through week 48, followed by every 12 weeks
thereafter by independent, central, blinded radiographic review per
RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). Patients on
chemotherapy with progressive disease as assessed by blinded central
review were able to cross over to KEYTRUDA arms after three months.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks
the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By
binding to the PD-1 receptor and blocking the interaction with the
receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition
of the immune response, including the anti-tumor immune response.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma
receiving KEYTRUDA (the approved indication in the United States),
including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients,
respectively. 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

Colitis (including microscopic colitis) occurred in 4 (1%) of 411
patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients
respectively, 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 (including autoimmune hepatitis) occurred in 2 (0.5%) of 411
patients, 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, including a Grade 2
case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving
KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer
corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA
for Grade 2; withhold or discontinue for Grade 3; and permanently
discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, 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.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, 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,
including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA.
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 corticosteroids for Grade 3 or greater hyperthyroidism.
Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for
Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with
replacement therapy without treatment interruption and without

Other clinically important immune-mediated adverse reactions can occur.
The following clinically significant, immune-mediated adverse reactions
occurred in less than 1% of patients treated with KEYTRUDA: exfoliative
dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic
anemia, partial seizures arising in a patient with inflammatory foci in
brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic
neuritis, and rhabdomyolysis.

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. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or
less. Permanently discontinue KEYTRUDA for any severe or Grade 3
immune-mediated adverse reaction that recurs and for any
life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may 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.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for
adverse reactions in 6% of 89 patients who received the recommended dose
of 2 mg/kg and 9% of 411 patients across all doses studied. Serious
adverse reactions occurred in 36% of patients receiving KEYTRUDA. The
most frequent serious adverse drug reactions reported in 2% or more of
patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were
fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%),
decreased appetite (26%), constipation (21%), arthralgia (20%), and
diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an
intravenous infusion over 30 minutes every three weeks until disease
progression or unacceptable toxicity. No formal pharmacokinetic drug
interaction studies have been conducted with KEYTRUDA.

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. Safety and effectiveness of KEYTRUDA
have not been established in pediatric patients.

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Please see Prescribing Information for KEYTRUDA (pembrolizumab) at
and the Medication Guide for KEYTRUDA at

KEYTRUDA® is a registered trademark of Merck
& Co., Inc., Whitehouse Station, N.J., USA

Lainie Keller, 908-236-5036
Claire Mulhearn, 908-236-1118
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