Download KEYNOTE-045: Randomized Phase 3 Trial of Pembrolizumab (MK

KEYNOTE-045: Randomized Phase 3 Trial of Pembrolizumab (MK-3475) Versus Paclitaxel,
Docetaxel, or Vinflunine for Previously Treated Metastatic Urothelial Cancer
Bellmunt,1-3
Sonpavde,4
Wit,5
Choueiri,1
Joaquim
Guru
Ronald de
Toni K.
Arlene
Holly Brown,8 Yabing Mai,8 Christine Gause,8 David Kaufman,8 Dean Bajorin9
Seifker-Radtke,6
Elizabeth R.
Plimack,7
Nicole M.
Lewis,8
TPS4571
1Dana-Farber
Cancer Institute, Boston, MA, USA; 2Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA; 3Harvard Medical School, Boston, MA, USA; 4University of Alabama at Birmingham (UAB) Comprehensive
Cancer Center, Birmingham, AL, USA; 5Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 6The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Fox Chase Cancer Center, Philadelphia, PA, USA;
8Merck & Co., Inc., Kenilworth, NJ, USA; 9Memorial Sloan Kettering Cancer Center, New York, NY, USA
Patient Assessments and Follow-Up
Figure 2. Study design.
INTRODUCTION
•• Urothelial cancer describes a range of tumors that arise from the urothelial
endothelium, which includes the bladder, renal pelvis, ureter, and urethra
–– Patients with metastatic urothelial cancer that has recurred or progressed
following platinum-based chemotherapy present a challenge
–– There are no approved therapies in the United States for recurrent/
progressive urothelial cancer
–– Paclitaxel, docetaxel, and vinflunine are commonly used as second-line
therapy for advanced urothelial cancer, but median overall survival (OS) is
only 7–9 months1-4
•• Pembrolizumab (MK-3475) is a humanized IgG4 kappa monoclonal antibody
that directly blocks the interaction between the programmed death 1 (PD-1)
receptor and its 2 ligands (PD-L1 and PD-L2)5
–– The PD-1 receptor is expressed on activated T cells,6 and activation of the
PD-1 receptor by its ligands results in inhibition of the active T-cell immune
surveillance of tumors (Figure 1)5
–– Preclinical data have demonstrated that blocking the interaction between
PD-1 and its ligands promotes effector T-cell infiltration of the tumor and
tumor rejection in vivo7
–– PD-L1 is widely expressed by tumor cells in urothelial cancer8,9
•• In KEYNOTE-012, a phase 1b study, pembrolizumab exhibited antitumor
activity in patients with PD-L1–positive advanced urothelial cancer10
–– Pembrolizumab was generally well tolerated in this patient population
–– Treatment of 28 patients with intravenous (IV) pembrolizumab 10 mg/kg
every 2 weeks resulted in an objective response rate (ORR) of 28%
(RECIST v1.1), including a complete response rate of 10.3%
Stratification by:
• ECOG status (0/1 or 2)
• Liver metastases (presence or
absence)
• Hemoglobin (<10 g/dL or ≥10 g/dL)
• Time from last dose of prior
chemotherapy (<90 days or ≥90 days)
Pembrolizumab
200 mg Q3W
PD
•• Assessments are to be performed prior to day 1 and
prior to dosing for each treatment cycle
OS/SFU
R
1:1
Investigator’s choice
from one of the
followinga
• Paclitaxelb
• 175 mg/m2 Q3W
• Docetaxelc
• 75 mg/m2 Q3W
• Vinflunined
• 320 mg/m2 Q3W
PD
OS/SFU
•• Radiographic imaging assessment will be performed
at 9 weeks after randomization and every 6 weeks for
the first year (12 months) followed by every 12 weeks
thereafter
•• Adverse events (AEs) will be graded and recorded
according to National Cancer Institute Common
Terminology Criteria for Adverse Events, Version 4.0
•• After the end of treatment, patients will be followed for
a minimum of 30 days for AE monitoring
•• Serious AEs will be collected for up to 90 days after
end of treatment, or until 30 days after the start of a
new anticancer treatment
•• Once a patient stops receiving treatment, the patient
will be contacted by telephone every 12 weeks to
assess for survival status until death or the end of the
study
ECOG = Eastern Cooperative Oncology Group; PD = progressive disease; Q3W = every 3 weeks; R = randomization; SFU = survival follow-up;
ULN = upper limit of normal.
aAll therapies will be on day 1 of each cycle.
bIn the case of mild hepatic impairment (total bilirubin ≥1.25 × ULN), paclitaxel should be started at a dose of 135 mg/m2.
cDocetaxel will only be a comparator option for patients with a total bilirubin ≤1 × ULN and an aspartate aminotransferase level ≤1.5 × ULN if alkaline phosphatase is also
>2.5 × ULN.
dThe overall proportion of patients receiving vinflunine is capped at approximately 35% and will only be a comparator option in countries where vinflunine is approved for
the treatment of metastatic urothelial cancer.
Figure 3. Countries with sites enrolling in the KEYNOTE-045 study (shown in green).
End Points
•• End points are listed in Table 2
Table 2. Primary and Key Secondary End Points
Primary End Points
Key Secondary End Points
•• OS
•• ORR (RECIST v1.1)a
•• PFS (RECIST v1.1)a
•• Response duration
(RECIST v1.1)a
•• This phase 3 study will investigate the efficacy and safety of pembrolizumab
in the treatment of patients with recurrent/progressive metastatic urothelial
cancer
•• PFS, OS, and ORR
(RECIST v1.1) in
subgroup of PD-L1–
positive patients
Figure 1. The role of the PD-1 pathway in tumor immunity.
•• Safety and tolerability
aBy
TUMOR
CELL
Planned Statistical Analyses
PD-L1
PD-L2
•• Analysis will be employed in the intent-to-treat
population
•• The all-patients-as-treated population will be employed
for safety analyses
PD-1
MHC-I
independent radiologic review.
REFERENCES
TUMORASSOCIATED
ANTIGEN
T-CELL
RECEPTOR
1. Vaughn DJ et al. J Clin Oncol. 2002;20(4):937-940.
2. McCaffrey JA et al. J Clin Oncol. 1997;15(5):1853-1857.
3. Joly F et al. Clin Genitourin Cancer. 2009;7(2):E28-E33.
Patient Eligibility Criteria
Inactivation
Activation
•• Patient eligibility criteria are shown in Table 1
•• Male/female patients aged ≥18 years
•• Histologically or cytologically confirmed diagnosis of
urothelial cancer of the renal pelvis, ureter, bladder,
or urethra
LEGEND FOR
SELECTED TERMS
MHC = major histocompatibility complex.
PD = programmed death.
METHODS
Study Design
•• Multicenter, randomized, active-controlled, open-label, adaptively designed
phase 3 KEYNOTE-045 clinical trial (ClinicalTrials.gov, NCT02256436) of
pembrolizumab in patients with metastatic or locally advanced/unresectable
urothelial cancer that has recurred or progressed following platinumcontaining chemotherapy (Figures 2 and 3)
•• Patients eligible for inclusion will be randomized centrally using an
interactive voice/integrated Web response system in a 1:1 ratio to either the
investigational treatment or an active comparator in an unblinded fashion
using centrally randomized blocks
•• Pembrolizumab will be given for up to 24 months or until confirmed disease
progression, unacceptable toxicity, or investigator decision; treatment may be
discontinued following complete response
Presented at the 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, Illinois, USA
5. KEYTRUDA® (pembrolizumab) [prescribing information].
Whitehouse Station, NJ: Merck & Co., Inc.; 2014.
Table 1. Key Inclusion/Exclusion Criteria
Key Inclusion Criteria
T CELL
4. Bellmunt J et al. J Clin Oncol. 2009;27(27):4454-4461.
•• Provided written informed consent
•• Prior platinum failure: disease progression or
recurrence of urothelial cancer following receipt of
a first-line platinum-containing regimen (cisplatin or
carboplatin)
•• Received no more than 2 prior lines of systemic
chemotherapy for urothelial cancer
•• Tissue available for biomarker analysis from an
archival tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously
irradiated
•• Measurable disease based on RECIST v1.1
•• ECOG performance status: 0, 1, or 2; patients with
an ECOG of 2 must have hemoglobin ≥10 g/dL,
must not have liver metastases, and must have
received the last dose of their prior chemotherapy
regimens ≥90 days prior to enrollment
6. Agata Y et al. Int Immunol. 1996;8(5):765-772.
Key Exclusion Criteria
•• Prior anticancer monoclonal antibody treatment
within 4 weeks prior to study
•• Prior chemotherapy, targeted small-molecule therapy,
or radiation therapy within 2 weeks prior to study
•• Active central nervous system metastases and/or
carcinomatous meningitis
•• Active cardiac disease, active noninfectious
pneumonitis, or evidence of an interstitial lung
disease, or has an active infection requiring systemic
therapy
7. Duraiswamy J et al. Cancer Res. 2013;73(12):3591-3603.
8. Bellmunt J et al. Ann Oncol. 2015;26(4):812-817.
9. Inman BA et al. Cancer. 2007;109(8):1499-1505.
10. P
limack E, et al. Presented at the American Society of Clinical
Oncology 2015 Annual Meeting; May 28-June 2, 2015, Chicago,
IL, USA. Abstr 4502.
ACKNOWLEDGMENTS
Editorial assistance was provided by the APO Group (Yardley,
PA, USA) and was funded by Merck & Co., Inc.
•• History of severe hypersensitivity reaction to study
treatments
•• Ongoing therapy with a medication that is a strong
inhibitor of the CYP3A4 enzyme
•• Prior therapy with an anti–PD-1, anti–PD-L1, or
with an agent directed to another coinhibitory T-cell
receptor.
•• History of HIV; active hepatitis B or C
•• Prior chemotherapy for urothelial cancer with all
available study therapies in the control arm (or both
prior paclitaxel and docetaxel in regions where
vinflunine is not approved)
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Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA.