The programmed death 1 (PD-1) pathway is frequently altered in cancer, leading to inhibition of active T-cellâmediated
TPS504
Presented at the 2017 Gastrointestinal Cancers Symposium (ASCO-GI) January 19-21, 2017 San Francisco, California, USA
Zhu AX1; Knox J2; Kudo M3; Chan SL4; Finn RS5; Siegel AB6; Ma J6; Cheng A-L7
KEYNOTE-224: Phase 2 Study of Pembrolizumab in Patients With Previously Treated Advanced Hepatocellular Carcinoma 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
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
Assessments and follow-up
DESIGN Figure 1. Pembrolizumab and the PD-1 pathway.
•• Response will be assessed by imaging every 9 weeks per RECIST v1.1 by central imaging vendor and investigator review
•• Approximately 100 patients will be enrolled •• Patients will receive pembrolizumab 200 mg intravenously every 3 weeks (Figure 2)
•• 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
•• 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
•• 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
•• 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
•• After confirmed disease progression or start of new anticancer therapy, patients will be contacted by telephone every 12 weeks to monitor survival
Figure 2. Study design.
Analyses
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
Pembrolizumab 200 mg Q3W
Response assessed Q9W
Safety and survival follow-up
ECOG PS = Eastern Cooperative Oncology Group performance status; HCC = hepatocellular carcinoma; Q3W = every 3 weeks; Q9W = every 9 weeks.
MHC-1 = major histocompatibility complex 1; PD-1 = programmed death 1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2.
OBJECTIVES Primary
•• 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
Patient eligibility criteria Key Inclusion Criteria
Key Exclusion Criteria
•• Age ≥18 years
•• Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes of HCC
•• 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)
•• Sorafenib treatment within 2 weeks of first study dose
•• 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
