19W

CGIC

Poster presented at:

72-PToshihiko Doi DOI: 10.3252/pso.eu.19wcgic.2017

Clinical Esophageal Cancer

Analyses • Efficacy

– The intention-to-treat population (all randomized patients) will serve as the population for primary efficacy analysis

– OS and PFS will be estimated using the Kaplan-Meier method, and treatment differences will be assessed using the stratified log-rank test

– Treatment differences in ORR will be assessed using the stratified Miettinen and Nurminen method, and 95% CIs will be provided

• Safety – The all-subjects-as-treated population (all

randomized patients who received at least 1 dose of study treatment) will be used for analysis of safety data

– Descriptive summary statistics will be provided

STATUS • Enrollment in KEYNOTE-181 is ongoing at 160 sites in 31 countries in Asia, Australia, Europe, North America, and South America (Figure 3)

Figure 3. Countries With Sites of Enrollment for KEYNOTE-181 (shown in green)

References1. Pardoll DM. Nat Rev Cancer. 2012;12:252-264.2. The Cancer Genome Atlas Research Network. Nature.

2014;513:202-209.3. Chen L et al. Int J Clin Exp Pathol. 2014;7:6015-6023.4. Ohigashi Y et al. Clin Cancer Res. 2005;11:2947-2953.5. Doi T et al. J Clin Oncol. 2016;34(suppl 4S). Abstract 7.6. Ribas A et al. J Clin Oncol. 2015;33(suppl). Abstract 3001.7. Seiwert T et al. J Clin Oncol. 2015;33(suppl). Abstract 6017.8. Shankaran V et al. J Clin Oncol. 2015;33(suppl). Abstract 3026.

Acknowledgments

The authors thank the patients and their families and all investigators and site personnel. Medical writing and/or editorial assistance was provided by Sarita S. Shaevitz, PhD, of the ApotheCom oncology team (Yardley, Pennsylvania, USA). This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA.

Please contact Dr. Doi at tdoi@east.ncc.go.jp for questions or comments.

DESIGN • In KEYNOTE-181, ~600 patients will be randomly assigned in a 1:1 ratio to receive 1 of the following (Figure 2):

– Pembrolizumab 200 mg every 3 weeks (Q3W) – Investigator’s choice of 1 of 3 standard chemotherapy regimens, determined before randomization: • Paclitaxel 80-100 mg/m2 on days 1, 8, and 15 every 4 weeks (Q4W) • Docetaxel 75 mg/m2 Q3W• Irinotecan 180 mg/m2 every 2 weeks (Q2W)

• Patients are to be stratified by tumor histology (squamous vs adenocarcinoma) and geographic region (Asia vs rest of world)

• Treatments are to continue until disease progression, unacceptable toxicity, patient withdrawal of consent, investigator decision to withdraw the patient, or completion of 35 cycles (pembrolizumab only)

• Patients in the pembrolizumab arm who experience an investigator-determined confirmed complete response (CR) may consider stopping trial treatment after receiving at least 8 treatments (~6 months) of pembrolizumab and having had at least 2 treatments with pembrolizumab beyond initial CR

• Patients who discontinue pembrolizumab because of CR or those who stop after receiving 35 treatments (~2 years) may be eligible for an additional 17 treatments (~1 year) after experiencing radiographic progressive disease if they meet the criteria for retreatment and the study is ongoing

Figure 2. Study Design

Patients• Advanced/metastatic adenocarcinoma or squamous cell carcinoma of the

esophagus or Siewert type I adenocarcinoma of the EGJ• Measurable disease per RECIST v1.1

• Progression on or after first-line therapy

• ECOG PS 0-1

Stratification by:• Tumor histology (squamous vs adenocarcinoma)• Geographic region (Asia vs rest of world)

Investigator’s choiceof 1 of the following:• Paclitaxel 80-100 mg/m2

on days 1, 8, and 15 Q4W • Docetaxel 75 mg/m2 Q3W• Irinotecan 180 mg/m2 Q2W

Continued for 35 cycles oruntil disease progression,

unacceptable toxicity,patient withdrawal, orinvestigator decision

Continued until disease progression, unacceptable toxicity,

patient withdrawal,or investigator decision

Pembrolizumab200 mg IV Q3W

Follow-up for safety(≤90 days)

Follow-up for survival(every 9 weeks)

Ran

dom

ize

1:1

N ≈

600

ECOG PS, Eastern Cooperative Oncology Group performance status; EGJ, esophagogastric junction; IV, intravenously; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks.

Patient Eligibility Criteria

Key Inclusion Criteria Key Exclusion Criteria

• Age ≥18 years • ECOG performance status 0-1 • Histologically or cytologically confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJa

• Patients with Siewert type I adenocarcinoma of the EGJ with HER2/neu-negative tumors are eligible

• For patients with HER2/neu-positive Siewert type I adenocarcinoma of the EGJ or unknown HER2/neu status:

– If HER2/neu positive, must have documented progression on treatment containing trastuzumab

– Patients with unknown status must have HER2/neu status determined locally. If negative, the patient will be eligible; if positive, the patient must have documented progression on treatment containing trastuzumab

• Measurable disease based on RECIST v1.1 by central imaging vendor review

• Documented disease progression on or after first-line therapy

• Tissue sample suitable for intratumoral immune-related gene expression profiling analysis

• Adequate organ function

• Active autoimmune disease requiring systemic treatment in the past 2 years

• Diagnosis of immunodeficiency or currently receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before study start

• Active CNS metastases and/or carcinomatous meningitis

• Prior anticancer monoclonal antibody, chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks before study start

• Prior anti–PD-1, anti–PD-L1, or anti–PD-L2 therapy • History of HIV, history of interstitial lung disease, or active, noninfectious pneumonitis

• Active hepatitis B or C

CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; EGJ, esophagogastric junction; HER2, human epidermal growth factor receptor 2; PD-1, programmed death 1; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2.aDefined as adenocarcinoma of the lower esophagus, with the center located within 1-5 cm above the anatomic EGJ.

Assessments and Follow-Up • Intratumoral expression levels of select immune-related genes will be analyzed using an analytically validated platform, such as the NanoString nCounter Analysis System

– Association between an immune-related expression profile and response to pembrolizumab has been established in melanoma and head and neck, bladder, gastric, ovarian, esophageal, and other cancers6-8

• Tumor imaging will be performed at baseline and every 9 weeks thereafter • Imaging will be performed by computed tomography (CT; strongly preferred) or by magnetic resonance imaging when CT is contraindicated or for imaging in the brain

• Response will be assessed per RECIST v1.1 by central imaging vendor review • Adverse events (AEs), including serious AEs and predefined AEs of clinical interest, will be monitored throughout the study and for 30 days thereafter (90 days for serious AEs) and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0

• After confirmed disease progression or start of new anticancer therapy, patients will be contacted by telephone every 9 weeks to monitor survival

BACKGROUND • The programmed death 1 (PD-1) pathway is commonly altered in cancer, leading to inhibition of active T-cell–mediated immune surveillance of tumors (Figure 1)1

• Programmed death ligand 1 (PD-L1) is frequently overexpressed in esophageal cancer,2,3 and its expression has been associated with poor prognosis3,4

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

– Pembrolizumab has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types and is currently approved in more than 60 countries for one or more advanced malignancies

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.

• In the phase 1b KEYNOTE-028 study, pembrolizumab demonstrated antitumor activity and was well tolerated in 23 patients with PD-L1–positive advanced esophageal cancer 5

– The objective response rate (ORR) was 30% (95% confidence interval [CI], 13%-53%)

– The median duration of response was not reached (range, 5.5-11.8+ months)

• KEYNOTE-181 (ClinicalTrials.gov, NCT02564263) is an open-label, randomized, multicenter, phase 3 study designed to compare the efficacy of pembrolizumab with that of physician’s choice of chemotherapy in previously treated patients with advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ)

OBJECTIVESPrimary • Compare progression-free survival (PFS) per RECIST v1.1 assessed by central imaging vendor review in patients with biomarker-positive (determined by intratumoral gene expression analysis) esophageal cancer and in all enrolled patients

• Compare overall survival (OS) in patients with biomarker-positive esophageal cancer and in all enrolled patients

Secondary • Evaluate ORR per RECIST v1.1 assessed by central imaging vendor review in patients with biomarker-positive esophageal cancer and in all enrolled patients

• Evaluate safety and tolerability of pembrolizumab in patients with biomarker-positive esophageal cancer and in all enrolled patients

Exploratory • Evaluate time to progression per RECIST v1.1 assessed by central imaging vendor review in patients with biomarker-positive esophageal cancer and in all enrolled patients

• Evaluate PFS per immune-related (ir)RECIST assessed by central imaging vendor review in patients with biomarker-positive esophageal cancer and in all enrolled patients

• Explore the relationship between PD-L1 expression by immunohistochemistry and response to treatment

• Explore the concordance of gene expression profiles in archival compared with newly obtained tumor tissue

• Explore the relationship between genetic variation and response to treatment

• Evaluate health-related quality of life assessed using the EORTC QLQ-C30 and EORTC QLQ-OES18 questionnaires

• Evaluate health outcome utilities assessed using the EuroQol EQ-5D questionnaire

Pembrolizumab Versus Investigator’s Choice Single-Agent Chemotherapy in Patients With Advanced/Metastatic Esophageal Adenocarcinoma That Progressed After First-Line Therapy: Phase 3 KEYNOTE-181 Study

T. Doi1; J. Bennouna2; L. Shen3; P.C. Enzinger4; R. Wang5; R. Dalal6; M. Koshiji6; M.A. Shah7

1National Cancer Center Hospital East, Chiba, Japan; 2Institut de Cancérologie de l’Ouest, Nantes, France; 3Peking University Cancer Hospital and Institute, Beijing, China; 4Dana-Farber Cancer Institute, Boston, MA, USA; 5MSD China, Beijing, China; 6Merck & Co., Inc., Kenilworth, NJ, USA; 7Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY, USA

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Copyright © 2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.Presented at the European Society for Medical Oncology (ESMO) 19th World Congress on Gastrointestinal Cancer; June 28-July 1, 2017; Barcelona, Spain