Assessments and follow-up • Tumors will be evaluated by cystoscopy and urine cytology every 12 weeks for the first 2 years, every 24 weeks for the next 2 years, and every 52 weeks thereafter

• The presence of extravesical disease will be evaluated using computed tomographic urography or magnetic resonance urography every 24 weeks for the first 2 years and every 52 weeks thereafter

• Computed tomography or magnetic resonance imaging will be used to assess for the presence of metastatic or nodal disease

• Patients with abnormal cystoscopy will undergo biopsy of the lesion • AEs will be monitored throughout the study and for 30 days (90 days for serious AEs and events of clinical interest) after treatment end and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0

• The disease status of patients who discontinue pembrolizumab for reasons other than high-risk recurrence or disease progression will continue to be assessed until disease progression, initiation of a new anticancer therapy, withdrawal of consent, or death

• All patients will be followed by telephone for survival until death or withdrawal of consent

Analyses • Efficacy

– All patients who receive ≥1 dose of pembrolizumab and who have a pre-enrollment cystoscopy and baseline computed tomographic/magnetic resonance image will serve as the primary population for efficacy analyses• Efficacy will be analyzed separately for the 2 cohorts

– The point estimates and 95% CIs for CR rates will be provided using the binomial exact method

– DFS, PFS, DOR, and OS will be estimated using the Kaplan-Meier method • Safety

– All patients who received ≥1 dose of pembrolizumab will serve as the population for safety analyses

– Descriptive summary statistics will be provided

STATUS • Enrollment in KEYNOTE-057 is ongoing in 8 countries, with additional sites in up to 15 countries anticipated to open (Figure 3)

Figure 3. Countries with currently open sites of enrollment for KEYNOTE-057 (shown in green).

REFERENCES1. Nielsen ME et al. Cancer. 2014;120:86-95.2. Aldousari S, Kassouf W. Can Urol Assoc J. 2010;4:56-64.3. Kamat AM et al. Eur Urol. 2013;63:4-15.4. Shelley MD et al. Cochrane Database Syst Rev. 2000;CD001986.5. Boorjian SA et al. Clin Cancer Res. 2008;14:4800-4808.6. Plimack E et al. Presented at the American Society of Clinical Oncology 2015 Annual Meeting;

May 29-June 2, 2015, Chicago, IL, USA. Abstract 4502.7. Kamat AM et al. J Clin Oncol. 2016;34:1935-1944.

ACKNOWLEDGMENTSThe authors thank the patients and their families and all investigators and site personnel. Editorial assistance was provided by Matt Grzywacz, PhD, and Dana Francis, PhD, of the ApotheCom Merck oncology team (Yardley, Pennsylvania, USA) and was funded by Merck & Co., Inc., Kenilworth, New Jersey, USA. The study is being funded by Merck & Co., Inc., Kenilworth, New Jersey, USA.

Contact the author at akamat@mdanderson.org for questions or comments.

DESIGN • Approximately 260 patients will be enrolled in KEYNOTE-057 and placed into 1 of 2 cohorts based on tissue pathology at screening:

– Cohort A: patients with CIS at baseline (CIS only, Ta + CIS, T1 + CIS) – Cohort B: patients without CIS at baseline (high-grade Ta or any grade T1)

• Patients in both cohorts will receive intravenous pembrolizumab 200 mg every 3 weeks for 24 months or until high-risk recurrence or disease progression, unacceptable toxicity, or investigator/patient decision (Figure 2)

– Patients with pathology-confirmed persistent high-risk disease at the first disease assessment or recurrence or progression at any assessment time point will be discontinued

– Patients with pathology-confirmed low-grade Ta will be permitted to undergo a repeat TURBT and remain on pembrolizumab; low-grade recurrence will not be considered treatment failure

– At 18 months, patients without evidence of disease in at least 2 preceding evaluations may stop pembrolizumab

Figure 2. Study design.

Patient population:• High-risk NMIBC refractory or intolerant to BCG• Cohort A: with CIS• Cohort B: without CIS

28-dayscreening

period

12weeks

24weeks

–Continue treatment

+Discontinue

treatment

Evaluation forhigh-grade disease on cystoscopy/

biopsy

and

Extravesicaldisease on

CT/MRI

• Continue assessment per protocol• Continue therapy until PD or 24 months of therapy

Survivalfollow-up

Pembrolizumab200 mg

Q3W

2nd diseaseassessment (cystoscopy,

cytology,biopsy)

1st diseaseassessment

(cystoscopy, cytology, biopsy)

BCG = Bacillus Calmette-Guérin; CIS = carcinoma in situ; CT = computed tomography; MRI = magnetic resonance imaging; NMIBC = non–muscle-invasive bladder cancer; PD = progressive disease; Q3W = every 3 weeks.

Patient eligibility criteria7

Key Inclusion Criteria Key Exclusion Criteria

• Age ≥18 years • Histologically confirmed NMIBC (high-grade Ta, T1, and/or CIS)

– Tumors must be predominantly of translational histology

• BCG-unresponsive disease: – Persistent high-risk NMIBC despite

6 months of therapy – Stage or grade progression after

3 months of therapy – Recurrent high-risk NMIBC within

6 months of last treatment • Underwent ≥2 cystoscopic procedures, with the most recent ≤8 weeks before study start, including complete TURBT (tissue sample must be available and sufficient for biomarker analyses)

• Ineligible for/elected not to undergo radical cystectomy

• ECOG performance status 0-2 • Adequate organ function

• Muscle invasive (T2, T3, T4) locally advanced nonresectable or metastatic urothelial carcinoma

• Concurrent extravesical (urethra, ureter, or renal pelvis) non–muscle-invasive translational cell carcinoma of the urothelium

• Underwent intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/TURBT to study start

• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks or unresolved AEs thereof

• Prior treatment with PD-L1–, PD-L2–, or coinhibitory T-cell receptor–directed therapy

• Additional progressing malignancy • Active autoimmune disease requiring systemic therapy in the past 2 years

• Active infection requiring systemic therapy, including active or intractable UTI in the last month

• Interstitial lung disease or active noninfectious pneumonitis

• History of HIV infection • Active hepatitis B or C infection

AE = adverse event; BCG = Bacillus Calmette-Guérin; CIS = carcinoma in situ; ECOG = Eastern Cooperative Oncology Group; NMIBC = non–muscle-invasive bladder cancer; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TURBT = transurethral resection of bladder tumor; UTI = urinary tract infection.

Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting June 3-7, 2016 Chicago, Illinois

KEYNOTE-057: Phase 2 Study of Pembrolizumab for Patients With Bacillus Calmette Guérin–Unresponsive, High-Risk Non–Muscle-Invasive Bladder Cancer

Kamat AM1; Bellmunt J2; Choueiri TK3; Nam K4; De Santis M5; Dreicer R6; Hahn NM7; Perini R4; Siefker-Radtke A1; Sonpavde G8; de Wit R9; Witjes JA10; Keefe S4; Bajorin D11

1The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 3Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA, USA; 4Merck & Co., Inc., Kenilworth, NJ, USA; 5University of Warwick, Coventry, United Kingdom; 6University of Virginia School of Medicine, Charlottesville, VA, USA; 7Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA; 8University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, USA; 9Erasmus MC Cancer Institute, Rotterdam, Netherlands; 10University Radboud, Nijmegen, Netherlands; 11Memorial Sloan Kettering Cancer Center, New York, NY, USA

BACKGROUND • The incidence of bladder cancer in the United States is increasing, with the majority of patients presenting with non–muscle-invasive bladder cancer (NMIBC)1,2

• High-risk NMIBC (T1, high grade and/or carcinoma in situ [CIS]) is characterized by frequent recurrence and progression to muscle-invasive disease despite standard therapy with transurethral resection of bladder tumor (TURBT) and intravesical Bacillus Calmette-Guérin (BCG) administration3,4

• The programmed death 1 (PD-1) pathway is a major pathway hijacked by tumors to evade immune surveillance (Figure 1)

• PD-1 is widely expressed in urothelial tumors, and studies have demonstrated markedly higher PD-1 expression in tumors that relapse after BCG treatment compared with BCG-naive tumors5

• Pembrolizumab, a highly selective, humanized monoclonal anti–PD-1 antibody, is designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2

• In the phase 1b KEYNOTE-012 (Clinicaltrials.gov, NCT01848834) study, pembrolizumab 10 mg/kg administered every 2 weeks demonstrated promising antitumor activity in patients with PD-L1–positive, recurrent/metastatic urothelial cancer6

– In these patients, overall response rate (ORR) was 25% (95% confidence interval [CI], 11%-45%), with 3 complete responses (CRs) and 4 partial responses

– Pembrolizumab was well tolerated in this patient population, with 15% experiencing grade 3/4 treatment-related adverse events (AEs)

• KEYNOTE-057 (ClinicalTrials.gov, NCT02625961) is a single-arm, open-label, phase 2 study to evaluate intravenous pembrolizumab in patients with high-risk NMIBC unresponsive to BCG who are ineligible for/or who have elected not to undergo radical cystectomy

OBJECTIVES • Except where noted, each primary, secondary, and exploratory objective will be evaluated in the following populations:

– Cohort A (patients with CIS at baseline [CIS only, Ta + CIS, T1 + CIS])• All patients• PD-L1–positive patients

– Cohort B (patients without CIS at baseline [high-grade Ta or any grade T1])• All patients• PD-L1–positive patients

Primary • Antitumor activity as evidenced by absence of high-risk NMIBC or progressive disease per cystoscopy, cytology, biopsy (if applicable), and radiologic imaging by central pathology and radiology review

– For cohort A, antitumor activity will be defined as the CR rate (ie, the proportion of patients whose tumors are in response to treatment and who are free of high risk NMIBC or worse)

– For cohort B, antitumor activity will be defined as the disease-free survival (DFS) rate

Secondary • CR rate of any disease (ie, the proportion of patients whose tumors are in response to treatment and who are free of any disease) (cohort A only)

• Duration of response (DOR) of high-risk NMIBC and any disease (cohort A only) • Time to CR (cohort A only) • Overall DFS and 3-month, 6-month, and 12-month DFS rates of high-risk NMIBC and any disease

– 12-month DFS of high-risk NMIBC is a secondary objective of cohort A only • Progression-free survival (PFS) to worsening of grade or stage or death • PFS to muscle invasive or metastatic disease or death • Overall survival (OS)

Exploratory • Association between candidate biomarkers and antitumor activity using pretreatment and on-treatment tumor biopsies and blood sampling

• Pharmacokinetic profile, including antidrug antibodies • Changes in health-related quality-of-life assessments from baseline using FACT-B1 and EuroQol EQ-5D

• Utilities using FACT-B1 and EuroQol EQ-5D • Rates of lower urinary tract symptoms, including irritative and obstructive symptoms and gross hematuria, pelvic pain, and culture-positive urinary tract infections

TPS4576

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Figure 1. Pembrolizumab and the PD-1 pathway.

MHC-1 = major histocompatibility complex 1; PD-1 = programmed death 1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2.

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