Presented at the 2017 Gastrointestinal Cancers Symposium (ASCO-GI) January 19-21, 2017 San Francisco, California, USA

KEYNOTE-224: Phase 2 Study of Pembrolizumab in Patients With Previously Treated Advanced Hepatocellular Carcinoma

Zhu AX1; Knox J2; Kudo M3; Chan SL4; Finn RS5; Siegel AB6; Ma J6; Cheng A-L7

1Massachusetts General Hospital, Boston, MA, USA; 2Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada; 3Kindai University Faculty of Medicine, Osaka, Japan; 4Prince of Wales Hospital, Shatin, Hong Kong; 5University of California, Los Angeles, Los Angeles, CA, USA; 6Merck & Co., Inc., Kenilworth, NJ, USA; 7National Taiwan University Hospital, Taipei, Taiwan

BACKGROUND • The tyrosine kinase inhibitor sorafenib is the standard of care for first-line treatment of patients with advanced hepatocellular carcinoma (HCC)1,2

– No therapy has yet been approved for patients with HCC following disease progression on sorafenib or for those with intolerance to sorafenib1

• HCC is often driven by inflammation,3 yet it is also associated with a suppressed immunoenvironment,4 providing a strong rationale to evaluate immunotherapy in patients with this type of cancer

• The programmed death 1 (PD-1) pathway is frequently altered in cancer, leading to inhibition of active T-cell–mediated immune surveillance of tumors (Figure 1)5

– Additionally, the PD-1 ligands, PD-L1 and PD-L2, are upregulated in HCC6

• Pembrolizumab is a highly selective, humanized, monoclonal, anti–PD-1 antibody designed to block the interaction between PD-1 and its ligands, allowing activation of an antitumor response (Figure 1)

– Pembrolizumab has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types and is currently approved in >60 countries for 1 or more advanced malignancies

• The single-arm, open-label, multisite, phase 2 KEYNOTE-224 study (ClinicalTrials.gov, NCT02702414) was designed to evaluate the efficacy and safety of pembrolizumab in patients with previously treated advanced HCC

OBJECTIVESPrimary • Evaluate objective response rate (ORR) per RECIST v1.1 by central imaging vendor review

Secondary • Evaluate duration of response (DOR), disease control rate (DCR), time to progression (TTP), and progression-free survival (PFS) per RECIST v1.1 by central imaging vendor review

• Evaluate overall survival (OS) • Evaluate safety and tolerability

Exploratory • Evaluate ORR, DCR, TTP, and PFS per RECIST v1.1 by investigator review • Evaluate ORR, DCR, TTP, and PFS per immune-related (ir)RECIST by central imaging vendor review • Identify molecular (genomic, metabolic, proteomic) determinants of response or resistance (eg, PD-L1 immunohistochemistry, gene expression profiling, genomic variation) to pembrolizumab

• Explore the relationship between cause of sorafenib discontinuation (intolerance to therapy vs radiographic progression of disease) and response to pembrolizumab

• Explore the response of underlying hepatitis B virus or hepatitis C virus (if present) to pembrolizumab as assessed by viral loads and viral serologies

DESIGN • Approximately 100 patients will be enrolled • Patients will receive pembrolizumab 200 mg intravenously every 3 weeks (Figure 2) • Treatment will continue for up to 35 cycles (~2 years) or until disease progression, unacceptable toxicity, patient withdrawal of consent, or investigator decision to discontinue treatment

• Patients who stop treatment after experiencing centrally confirmed complete response or after 35 cycles may be eligible for an additional 17 cycles (~1 year) of treatment after disease progression

Figure 2. Study design.

ECOG PS = Eastern Cooperative Oncology Group performance status; HCC = hepatocellular carcinoma; Q3W = every 3 weeks; Q9W = every 9 weeks.

Patient eligibility criteria

Key Inclusion Criteria Key Exclusion Criteria

• Age ≥18 years

• Histologically or cytologically confirmed diagnosis of HCC BCLC stage C disease, or BCLC stage B disease not amenable to or refractory to locoregional therapy, and not amenable to a curative treatment approach (eg, transplantation, surgery, or ablation)

• Child-Pugh class A liver score within 7 days of first study dose

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

• Documented objective radiographic progression during or after treatment with sorafenib or intolerance to sorafenib

• For patients with successfully treated HBV infection – Antiviral therapy for ≥12 weeks and HBV viral load

<100 IU/mL before first study dose • ECOG performance status 0 or 1

• Adequate organ function

• Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes of HCC

• Sorafenib treatment within 2 weeks of first study dose

• Esophageal or gastric variceal bleeding within the past 6 months

• Clinically apparent ascites on physical examination†

• Portal vein invasion at the main portal (Vp4) or the inferior vena cava or cardiac involvement of HCC based on imaging

• Clinically diagnosed hepatic encephalopathy within the past 6 months

• Previous solid organ or hematologic transplantation

• Previous systemic therapy for HCC other than sorafenib or intercurrent local therapy to the liver tumor between sorafenib and study drug

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

• Diagnosis of immunodeficiency or receiving systemic steroid therapy or other immunosuppressive therapy within 7 days before first study dose

• Previous locoregional therapy or major surgery to the liver within 6 weeks before first study dose

• Minor surgery to liver or other site within 1 week before first study dose

• Evidence of central nervous system metastases and/or carcinomatous meningitis

BCLC = Barcelona Clinic Liver Cancer; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; HCC = hepatocellular carcinoma.†Patients with ascites only detectable on imaging studies are eligible.

Response

assessed Q9W

Safety and

survival follow-up

Pembrolizumab

200 mg Q3W

Patients

• Confirmed diagnosis

of HCC

• Progression on or

intolerance to first-line

sorafenib treatment

• Measurable disease per

RECIST v1.1

• ECOG PS 0-1

• Child-Pugh class A score

Assessments and follow-up • Response will be assessed by imaging every 9 weeks per RECIST v1.1 by central imaging vendor and investigator review • After the first radiologic evidence of progressive disease by RECIST v1.1, treatment decisions may be made per irRECIST to accommodate for the tumor response patterns (eg, tumor flare) seen with pembrolizumab treatment

• Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and will be graded per NCI CTCAE v4.0

• After confirmed disease progression or start of new anticancer therapy, patients will be contacted by telephone every 12 weeks to monitor survival

Analyses • Efficacy

– The all-patients-as-treated population (all allocated patients who received ≥1 dose of study treatment) will serve as the population for analyses of ORR, DCR, TTP, PFS, and OS

– The analysis population for DOR will consist of responders (partial and complete) – For ORR and DCR, the exact binomial method will be used for the point estimate and the 95% confidence interval – The Kaplan-Meier method will be used to estimate PFS, OS, TTP, and DOR curves – Patients who have achieved complete or partial response and are alive, have not experienced disease progression, have not initiated new anticancer treatment, and have not been lost to follow-up are considered ongoing responders at the time of analysis

• Safety – The all-patients-as-treated population will also be used for safety analyses – Counts and percentages of patients with AEs will be provided

TPS504

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.

STATUS • As of January 2017, enrollment in KEYNOTE-224 is ongoing or planned in 10 countries in Asia, Australia, Europe, and North America (Figure 3)

Figure 3. Countries with sites of enrollment (shown in green) for KEYNOTE-224.

REFERENCES1. Chen K-W et al. World J Hepatol. 2015;7:1412-1420. 2. Raza A, Sood GK. World J Gastroenterol. 2014;20:4115-4127.3. Nakagawa H, Maeda S. World J Gastroenterol. 2012;18:4071-4081.4. Aerts M et al. World J Gastroenterol. 2016;22:253-261.5. Pardoll DM. Nat Rev Cancer. 2012;12:252-264.6. Wang BJ et al. World J Gastroenterol. 2011;17:3322-3329.

ACKNOWLEDGMENTSThe authors thank the patients and their families and all investigators and site personnel. Editorial assistance was provided by Payal Gandhi, PhD, of the ApotheCom 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 AZHU@mgh.harvard.edu for questions or comments.

Copyright © 2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All Rights Reserved.

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