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
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 pneumonitis.
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 corticosteroids.
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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bring new hope to people with cancer. For more information about
our oncology clinical trials, visit
www.merck.com/clinicaltrials.
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Forward-Looking Statement
This news release includes “forward-looking statements” within
the meaning of the safe harbor provisions of the United States
Private Securities Litigation Reform Act of 1995. These statements
are based upon the current beliefs and expectations of Merck’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
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Merck 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 Merck’s 2013 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
(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.
KEYTRUDA® is a registered trademark of Merck
& Co., Inc., Whitehouse Station, N.J., USA
MerckMedia:Lainie Keller, 908-236-5036Claire Mulhearn,
908-236-1118orInvestor:Joseph Romanelli, 908-423-5185Justin Holko,
908-423-5088
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