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 months 1-4 • 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 vivo 7 – PD-L1 is widely expressed by tumor cells in urothelial cancer 8,9 • In KEYNOTE-012, a phase 1b study, pembrolizumab exhibited antitumor activity in patients with PD-L1–positive advanced urothelial cancer 10 – 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% • This phase 3 study will investigate the efficacy and safety of pembrolizumab in the treatment of patients with recurrent/progressive metastatic urothelial cancer Figure 1. The role of the PD-1 pathway in tumor immunity. TUMOR CELL PD-L1 PD-L2 PD-1 MHC-I TUMOR- ASSOCIATED ANTIGEN T-CELL RECEPTOR Activation Inactivation T CELL 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 platinum- containing 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 http://bit.ly/1AxZZZu Figure 2. Study design. OS/SFU OS/SFU PD PD Pembrolizumab 200 mg Q3W Investigator’s choice from one of the following a • Paclitaxel b • 175 mg/m 2 Q3W • Docetaxel c • 75 mg/m 2 Q3W • Vinflunine d • 320 mg/m 2 Q3W R 1:1 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) ECOG = Eastern Cooperative Oncology Group; PD = progressive disease; Q3W = every 3 weeks; R = randomization; SFU = survival follow-up; ULN = upper limit of normal. a All therapies will be on day 1 of each cycle. b In the case of mild hepatic impairment (total bilirubin ≥1.25 × ULN), paclitaxel should be started at a dose of 135 mg/m 2 . c Docetaxel 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. d The 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). Patient Eligibility Criteria • Patient eligibility criteria are shown in Table 1 Table 1. Key Inclusion/Exclusion Criteria Key Inclusion Criteria Key Exclusion Criteria • Male/female patients aged ≥18 years • Histologically or cytologically confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra • 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 • 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 • 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) Patient Assessments and Follow-Up • Assessments are to be performed prior to day 1 and prior to dosing for each treatment cycle • 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 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 • PFS (RECIST v1.1) a • ORR (RECIST v1.1) a • Response duration (RECIST v1.1) a • PFS, OS, and ORR (RECIST v1.1) in subgroup of PD-L1– positive patients • Safety and tolerability a By independent radiologic review. Planned Statistical Analyses • Analysis will be employed in the intent-to-treat population • The all-patients-as-treated population will be employed for safety analyses REFERENCES 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. 4. Bellmunt J et al. J Clin Oncol. 2009;27(27):4454-4461. 5. KEYTRUDA ® (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc.; 2014. 6. Agata Y et al. Int Immunol. 1996;8(5):765-772. 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. Plimack 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. Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO ® and the author of this poster. KEYNOTE-045: Randomized Phase 3 Trial of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Previously Treated Metastatic Urothelial Cancer Joaquim Bellmunt, 1-3 Guru Sonpavde, 4 Ronald de Wit, 5 Toni K. Choueiri, 1 Arlene Seifker-Radtke, 6 Elizabeth R. Plimack, 7 Nicole M. Lewis, 8 Holly Brown, 8 Yabing Mai, 8 Christine Gause, 8 David Kaufman, 8 Dean Bajorin 9 1 Dana-Farber Cancer Institute, Boston, MA, USA; 2 Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA; 3 Harvard Medical School, Boston, MA, USA; 4 University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, Birmingham, AL, USA; 5 Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 6 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7 Fox Chase Cancer Center, Philadelphia, PA, USA; 8 Merck & Co., Inc., Kenilworth, NJ, USA; 9 Memorial Sloan Kettering Cancer Center, New York, NY, USA TPS4571 Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA. Presented at the 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, Illinois, USA
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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%
• This phase 3 study will investigate the efficacy and safety of pembrolizumab in the treatment of patients with recurrent/progressive metastatic urothelial cancer
Figure 1. The role of the PD-1 pathway in tumor immunity.
TUMORCELL
PD-L1PD-L2
PD-1MHC-I
TUMOR-ASSOCIATED
ANTIGENT-CELL
RECEPTOR
Activation
Inactivation
T CELL
LEGEND FOR SELECTED TERMS
MHC = major histocompatibility complex.PD = programmed death.
METHODSStudy 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 platinum-containing 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
http://bit.ly/1AxZZZu
Figure 2. Study design.
OS/SFU
OS/SFU
PD
PD
Pembrolizumab200 mg Q3W
Investigator’s choice from one of the followinga • Paclitaxelb • 175 mg/m2 Q3W• Docetaxelc • 75 mg/m2 Q3W• Vinflunined
• 320 mg/m2 Q3W
R1:1
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)
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.c Docetaxel 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.
d The 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).
Patient Eligibility Criteria • Patient eligibility criteria are shown in Table 1
Table 1. Key Inclusion/Exclusion CriteriaKey Inclusion Criteria Key Exclusion Criteria
• Male/female patients aged ≥18 years
• Histologically or cytologically confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra
• 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
• 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
• 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)
Patient Assessments and Follow-Up • Assessments are to be performed prior to day 1 and prior to dosing for each treatment cycle
• 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
End Points • End points are listed in Table 2
Table 2. Primary and Key Secondary End PointsPrimary End Points Key Secondary End Points
• OS
• PFS (RECIST v1.1)a
• ORR (RECIST v1.1)a
• Response duration (RECIST v1.1)a
• PFS, OS, and ORR (RECIST v1.1) in subgroup of PD-L1–positive patients
• Safety and tolerabilityaBy independent radiologic review.
Planned Statistical Analyses • Analysis will be employed in the intent-to-treat population
• The all-patients-as-treated population will be employed for safety analyses
REFERENCES1. 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. 4. Bellmunt J et al. J Clin Oncol. 2009;27(27):4454-4461.5. KEYTRUDA® (pembrolizumab) [prescribing information].
Whitehouse Station, NJ: Merck & Co., Inc.; 2014.6. Agata Y et al. Int Immunol. 1996;8(5):765-772. 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. Plimack E, et al. Presented at the American Society of Clinical Oncology 2015 Annual Meeting; May 28-June 2, 2015, Chicago, IL, USA. Abstr 4502.
ACKNOWLEDGMENTSEditorial assistance was provided by the APO Group (Yardley, PA, USA) and was funded by Merck & Co., Inc.
Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster.
KEYNOTE-045: Randomized Phase 3 Trial of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Previously Treated Metastatic Urothelial CancerJoaquim Bellmunt,1-3 Guru Sonpavde,4 Ronald de Wit,5 Toni K. Choueiri,1 Arlene Seifker-Radtke,6 Elizabeth R. Plimack,7 Nicole M. Lewis,8 Holly Brown,8 Yabing Mai,8 Christine Gause,8 David Kaufman,8 Dean Bajorin9 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
TPS4571
Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA.Presented at the 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, Illinois, USA
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