Pembrolizumab 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
MSD, known as Merck in the United States and Canada, announced
today that a pre-specified analysis of investigational data from a
pivotal Phase 2 study (KEYNOTE-002) showed 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).1 At six months,
the PFS rates for pembrolizumab 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.1
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.
“These findings demonstrate pembrolizumab 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 pembrolizumab 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 favour of pembrolizumab was
consistent across all pre-specified sub-groups.1
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 pembrolizumab were five
to six times higher compared to chemotherapy. For pembrolizumab,
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 pembrolizumab 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 pembrolizumab (P=0.21).
In a pre-specified exploratory analysis for HRQoL, patients
treated with pembrolizumab 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 pembrolizumab compared to
chemotherapy was 6.52 (P=0.011) at 2 mg/kg dose and 6.57 (p=0.009)
at the 10 mg/kg dose, respectively.
The incidence of adverse events was consistent with previously
reported data for pembrolizumab. Despite longer median treatment
duration, the incidence of treatment-related, grade 3-5 adverse
events was lower with pembrolizumab 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 pembrolizumab at
2 mg/kg dose (8%) and 10 mg/kg dose (11%), and for chemotherapy
(10%). Immune-related grade 3 adverse events observed for
pembrolizumab 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 pembrolizumab 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 pembrolizumab and none in the chemotherapy arm.
About the KEYNOTE-002 Study
KEYNOTE-002 is a global, randomized pivotal Phase 2 study
(n=540) evaluating pembrolizumab 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. Co-primary endpoints
were PFS and OS; secondary endpoints were ORR, duration of response
and safety; and HRQoL as a pre-specified exploratory endpoint.
Tumour 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 Tumours). Patients on chemotherapy
with progressive disease as assessed by blinded central review were
able to cross over to pembrolizumab arms after three months.
About Pembrolizumab
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, pembrolizumab releases the PD-1 pathway-mediated
inhibition of the immune response, including the anti-tumour immune
response.
Our Focus on Cancer
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helping people fight cancer is our passion, supporting
accessibility to our cancer medicines is our commitment, and
pursuing research in immuno-oncology is our focus to potentially
bring new hope to people with cancer. For more information about
our oncology clinical trials, visit
www.merck.com/clinicaltrials.
About MSD
Today's MSD is a global healthcare leader working to help the
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Reference 1. A Randomized Controlled Comparison of
Pembrolizumab and Chemotherapy in Patients With
Ipilimumab-Refractory Melanoma. Ribas, A, Puzanov, I, Dummer, R et
al. Presented at Society for Melanoma Research 2014 International
Congress, 13-16 November 2014, Zurich, Switzerland.
MSDMedia:Lainie Keller, +1-908-236-5036Claire Mulhearn,
+1-908-236-1118orInvestor:Joseph Romanelli, +1-908-423-5185Justin
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