725PD

Presented at the European

Society for Medical Oncology
(ESMO) 2016 Congress
Pembrolizumab for Patients With Advanced Prostate Adenocarcinoma: Hansen A1; Massard C2; Ott PA3; Haas N4; Lopez J5; Ejadi S6; Wallmark J7; Keam B8; Delord J-P9; Aggarwal R10;
Gould M11; Qiu P11; Saraf S11; Keefe S11; Piha-Paul S12

Preliminary Results From the KEYNOTE-028 Study

1Princess Margaret Cancer Centre, Toronto, ON, Canada; 2Institut Gustave Roussy, Villejuif, France; 3Dana-Farber Cancer Institute, Boston, MA, USA; 4Hospital of the
October 7-11, 2016 University of Pennsylvania, Philadelphia, PA, USA; 5Institute of Cancer Research, London, UK; 6Virginia G. Piper Cancer Center, Scottsdale, AZ, USA; 7Associates in Oncology
& Hematology, Rockdale, MD, USA; 8Seoul National University Hospital, Seoul, Republic of Korea; 9Institut Claudius Régaud, Toulouse, France; 10UCSF Helen Diller Family
Copenhagen, Denmark Comprehensive Cancer Center, San Francisco, CA, USA; 11Merck & Co., Inc., Kenilworth, NJ, USA; 12The University of Texas MD Anderson Cancer Center, Houston, TX, USA

BACKGROUND Statistical considerations

•• The primary efficacy end point was overall response rate (ORR) per RECIST v1.1
Safety
•• Median follow-up duration was 33 weeks (range, 6-79 weeks) as of the
Figure 1. Best percentage change in the sum of the longest
diameters of target lesions from baseline as assessed per
•• Median PFS was 3.6 months (95% CI, 1.7-7.2 months) (Figure 4A)
–– 6-month and 12-month PFS rates were 39.1% and 14.7%, respectively
Figure 5. Heat map for final 18-gene expression signature based on
gene expression data from 2 clinical studies6 (N = 220).
•• Therapies currently available for advanced prostate cancer provide only modest by investigator review February 17, 2016, data cutoff RECIST v1.1 by investigator review (n = 20†). •• Median OS was 7.9 months (95% CI, 6.5-12.2 months) (Figure 4B) Color Key
clinical benefit1
•• Secondary end points included duration of response, progression-free survival •• 14 patients (61%) experienced ≥1 treatment-related AE of any grade, most –– 6-month and 12-month OS rates were 73.4% and 34.0%, respectively
•• Upregulation of the programmed death 1 (PD-1) receptor pathway leads to 100
(PFS), and overall survival (OS) commonly nausea, which occurred in 13% of patients (Table 2)
suppression of the immune response in many tumors2
•• Efficacy was assessed in all patients who received ≥1 dose of study treatment and •• 3 patients (13%) experienced grade 3 treatment-related AEs (asthenia, fatigue, and
80
Figure 4. Kaplan-Meier estimates of (A) progression-free survival per
–– Expression of PD-1 and its ligand, PD-L1, has been reported in prostate

Change From Baseline, %

had a baseline scan showing measurable disease per RECIST v1.1 peripheral neuropathy), and 1 patient (4%) experienced a grade 4 treatment-related 60 RECIST v1.1 by investigator review and (B) overall survival (N = 23).
cancer3-5 AE (increased lipase) −2 2
•• Safety was assessed in all patients who received ≥1 dose of study treatment
•• KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is a nonrandomized, phase 1b •• 5 patients (22%) experienced 6 total immune-mediated AEs:
40 A 100 Column Z−Score
trial designed to evaluate the safety and efficacy of pembrolizumab monotherapy –– Immune-mediated AEs were defined as events with potentially drug-related +20% tumor
in 20 PD-L1–positive advanced solid tumor cohorts immunologic causes, regardless of attribution to treatment or immune –– Face edema, grade 1 (1 patient) 20
increase
80 R
R
R
R
relatedness by the investigator

PFS, %
•• Preliminary results from the prostate adenocarcinoma cohort of this study are –– Hyperthyroidism, grades 1 and 2 (1 patient each) 0 60 R
reported •• All data were analyzed based on a database cutoff date of February 17, 2016 –– Hypothyroidism, grade 2 (1 patient) R
R
R
–20 40 R
–– Local swelling, grade 1 (1 patient) –30% tumor R

RESULTS 20
–40 reduction
OBJECTIVES
–– Pneumonitis, grade 1 (1 patient) R
R
R
R
•• There were no deaths or discontinuations due to treatment-related AEs –60 0 R
R
R
R
0 2 4 6 8 10 12 14 16 18
•• Assess the safety and tolerability of pembrolizumab in patients with PD-L1–positive PD-L1 screening and baseline characteristics Table 2. Treatment-Related Adverse Events Observed in ≥2 Patients –80
Months
R
R
advanced prostate adenocarcinoma
•• 245 patients with prostate cancer were screened, of whom 35 (14.3%) had (N = 23) –100 n at risk 23 14 9 8 4 3 3 3 2 0 R
R
R
•• Assess the antitumor activity of pembrolizumab in patients with PD-L1–positive PD-L1–positive tumors † R
R
3 patients were nonevaluable or had no assessment.
advanced prostate adenocarcinoma Event n (%)
•• 23 patients with PD-L1–positive tumors were enrolled and received ≥1 dose of R
R
R
•• Investigate the relationship between candidate efficacy/resistance biomarkers and B 100 R
pembrolizumab •• Decreases in tumor size over time are shown in Figure 2 R
R
R
R
R
antitumor activity of pembrolizumab in patients with PD-L1–positive advanced solid Nausea 3 (13) 80
•• Median age was 65 years, and the majority of patients had received multiple R
tumors
therapy types for prostate cancer (Table 1)
Figure 2. Percentage change from baseline in the sum of the longest R
Asthenia 2 (9) 60

OS, %
diameters of target lesions over time as assessed per RECIST v1.1 by R

METHODS Table 1. Patient Baseline Characteristics investigator review (n = 21†).

Decreased appetite 2 (9) 40

Total 20
Characteristic Decreased weight 2 (9)
Study design and patients
100
N = 23 0
Diarrhea 2 (9) Responder 0 2 4 6 8 10 12 14 16 18

Change From Baseline, %

80 R
•• Key eligibility criteria for the prostate adenocarcinoma cohort of KEYNOTE-028 Age, median (range), years 65 (46-83) Nonresponder R
include: Hyperthyroidism 2 (9) 60 Months
Male, n (%) 23 (100) n at risk 23 21 18 16 9 5 4 3 2 0
–– Age ≥18 years 40
Increased lipase 2 (9) +20% tumor R
–– Unresectable and/or metastatic prostate adenocarcinoma Race, n (%) 20 increase
R

Maculopapular rash 2 (9) Biomarker analysis

ID 0
C 1
C T

D 3

N 1
7
PS L5

.D 9
C A1

LA AT1
27

1)

M 6

ST 6

H 1
.E
(P D8A

27 L 2)
–– Failure of or inability to receive standard-of-care therapy Asian 3 (13)

B1

O
4 AG

R
KG

LA L
C CR

27

B
I
G

−L

LA
−L

H XC
D

R
KL
0

TI

D
M
C

.D
C

X
D

C
(P
–– Eastern Cooperative Oncology Group performance status of 0 or 1 Black or African American 1 (4) Pruritus 2 (9) •• Gene expression data combined from 2 studies (all 5 cohorts from KEYNOTE-012

H
2
–20

G
White 18 (78)

1L

D
–– Measurable disease per RECIST v1.1

C
–30% tumor [NCT01848834] and 5 cohorts from KEYNOTE-028 [NCT02054806]) in

D
C
–40
Not specified 1 (4)

PD
–– PD-L1–positive tumors (≥1% PD-L1 expression by immunohistochemistry) reduction
220 patients with 9 different cancer types were used to discover a final set of
•• Patients received pembrolizumab intravenously 10 mg/kg every 2 weeks for ECOG performance status, n (%)
Efficacy –60
18 genes and a scoring algorithm expected to be a useful tool for identifying Rows represent patients and columns signify genes. Expression levels have been standardized (centered and
24 months or until disease progression, intolerable toxicity, or patient or investigator 0 5 (22) •• 3 patients achieved a confirmed partial response (PR), for an ORR of 13% –80
patients likely to respond to anti–PD-1 therapy across multiple cancer types6 scaled) within columns for visualization. The “R” on the right-hand side indicates if the patient was a responder or
decision 1 17 (74) (95% confidence interval [CI], 3%-34%) (Table 3) –100 (Figure 5)
not (by investigator assessment in KEYNOTE-028 and by central review in KEYNOTE-012). The rows have been
grouped using unsupervised clustering.
•• Patients with radiographic progression who were clinically stable could remain on 2 1 (4) •• An additional 2 patients achieved an unconfirmed PR for an unconfirmed + 0 8 16 24 32 40 48 56 64 72
•• Exploratory assessment of the relationship between the gene expression profile
pembrolizumab until progression was confirmed on follow-up imaging performed Baseline lactate dehydrogenase, n (%) confirmed ORR of 22% (95% CI, 8%-44%) Weeks Since Treatment Initiation
score and clinical outcome in the prostate adenocarcinoma cohort is ongoing
≥4 weeks later Normal 12 (52) †2 patients were nonevaluable or had no assessment.
Elevated 8 (35) Table 3. Best Overall Response Assessed per RECIST v1.1 by
Assessments
•• Response was assessed every 8 weeks for the first 6 months, and every 12 weeks
Not specified
Baseline hemoglobin, mean (SD), g/L
3 (13)
114 (21)
Investigator Review (N = 23) •• Median response duration was 58.7 weeks at the data cutoff (range, 28.3-
61.7 weeks)
CONCLUSIONS
thereafter per RECIST v1.1 by investigator review Best Overall Response n % (95% CI)
•• At the data cutoff, 2 patients remained on treatment, 1 with an unconfirmed PR and •• Pembrolizumab monotherapy demonstrated antitumor activity in a subset of patients with advanced prostate adenocarcinoma that progressed on standard therapies
•• Adverse events (AEs) were assessed throughout the study and for 30 days Baseline alkaline phosphatase, mean (SD), µkat/L 3.3 (2.6) 1 with stable disease (Figure 3)
thereafter (90 days for serious AEs and AEs of clinical interest based on their Partial responses† 3 13 (3-34) •• Pembrolizumab was well tolerated, with no treatment-related discontinuations or deaths
immune etiology) and graded according to the National Cancer Institute Common Sum of target lesions measurable at baseline, mean (SD), mm 91 (117) •• The safety profile in this cohort was generally consistent with that previously observed for pembrolizumab in patients with advanced cancers
Figure 3. Duration of exposure to pembrolizumab and summary of
Terminology Criteria for Adverse Events, version 4.0 Metastatic staging, n (%) Stable disease 9 39 (20-62) •• Future analyses will confirm the relationship between the gene expression profile score and clinical outcome in advanced prostate cancer
best overall response assessed per RECIST v1.1 by investigator
•• For trial inclusion, PD-L1 expression was assessed in an archival or newly MX 1 (4) •• The clinical benefit of pembrolizumab in advanced prostate cancer will be further investigated as monotherapy in the phase 2 KEYNOTE-199 study
Progressive disease 8 35 (16-57) review (n = 21†).
obtained core or excisional biopsy using a prototype immunohistochemical assay M0 1 (4) (ClinicalTrials.gov, NCT02787005), and as combination therapy with olaparib, docetaxel plus prednisone, or enzalutamide in the multicohort phase 1
(Qualtek Molecular Laboratories, Goleta, CA, USA) and the 22C3 antibody M1 16 (70) Only confirmed responses are included. 3 patients were nonevaluable or had no assessment. KEYNOTE-365 study (ClinicalTrials.gov, NCT02861573)
(Merck & Co., Inc., Kenilworth, NJ, USA) M1B 1 (4)
†
There were no complete responses.
–– Analysis was performed at a central laboratory M1C 1 (4) •• 45% of evaluable patients had a decrease from baseline in the sum of longest
–– Positivity was defined as membrane staining of ≥1% of scorable cells, including Not specified 3 (13) diameters of target lesions (Figure 1)
both neoplastic cells and contiguous mononuclear inflammatory cells, or the
presence of a distinctive interface pattern
Type of prior therapy, n (%) REFERENCES ACKNOWLEDGMENTS
Chemotherapy 21 (91) The authors thank the patients and their families and all investigators and site
•• The NanoString nCounter platform (NanoString Technologies, Seattle, WA, USA) Hormonal therapy 22 (96) 1. Vaishampayan U. Curr Opin Oncol. 2014;26:265-273.
was used to assess baseline tumor tissue for the gene expression profile of an personnel, QualTek Molecular Laboratories for PD-L1 analyses, and Andrew Joe
Supportive therapy 12 (52) 2. Pardoll DM. Nat Rev Cancer. 2012;12:252-264.
18-gene panel hypothesized to be associated with a Th1-derived interferon-gamma Confirmed partial response and Jared Lunceford for biomarker analyses. Editorial assistance was provided by
Radiotherapy 1 (4) 3. Thoma C. Nat Rev Urol. 2016;13:5. Sarah Adai, MS, and Matthew Grzywacz, PhD, of the ApotheCom oncology team
immune response Unconfirmed partial response
4. Gevensleben H et al. Clin Cancer Res. 2016;22:1969-1977. (Yardley, Pennsylvania, USA) and was funded by Merck & Co., Inc., Kenilworth, New
Select prior therapies, n (%) Progressive disease
5. Massari F et al. Target Oncol. 2016;11:345-351. Jersey, USA. The study was funded by Merck & Co., Inc., Kenilworth, New Jersey, USA.
Taxane chemotherapy 21 (91) Ongoing response
Enzalutamide or abiraterone 20 (87) 6. Piha-Paul SA et al. J Clin Oncol. 2016;34(suppl): abstr 1536.
Enzalutamide + abiraterone 11 (48) 0 10 20 30 40 50 60 70 80
LHRH agonist or antagonist 18 (78) Weeks Since Treatment Initiation
ECOG = Eastern Cooperative Oncology Group; LHRH = luteinizing hormone-releasing hormone; SD = standard Copies of this poster obtained through QR (Quick Response)
deviation. †2 code are for personal use only and may not be reproduced
patients were nonevaluable or had no assessment.
without written permission of the authors.
http://bit.ly/2cFFq5D

Copyright © 2016 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All Rights Reserved