120

100

80

60

40

20

0

–20

–40

–60

–80

–100

Cha

nge

from

bas

elin

e (%

)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Time (months)

Figure 2. Tumor Size Change from Baseline (As-treated Population)*

*Assessed by investigator according to RECIST 1.1**New lesion appeared on first post-dose scan and was present on subsequent scans, while target lesions decreased over time (maximum of 39% reduction)

Background• Approximately 80% of HCC cases are associated with chronic hepatitis B

virus (HBV) or hepatitis C virus (HCV) infections.1

• Treatment options for advanced HCC are limited; tyrosine kinase inhibitors are the mainstay of systemic treatment but have limited survival benefits.2–5

There is a clear unmet need for additional and more effective treatment options.

• Programmed cell death ligand-1 (PD-L1) is a cell-surface protein that binds to programmed cell death-1 (PD-1), a receptor expressed on activated T cells, and CD80, a receptor expressed on activated T cells and antigen-presenting cells (APCs).6

• PD-L1 binding interferes with T-cell proliferation and inhibits immune responses; PD-L1 overexpression thus allows cancer cells to avoid immune detection and elimination.7,8

• Several anti-PD-1 and anti-PD-L1 agents have demonstrated encouraging clinical activity in various solid tumor types;9–15 however, current evidence on their efficacy and safety in HCC is limited16

Conclusions• Durvalumab 10 mg/kg Q2W demonstrated a tolerable and manageable

safety profile and promising antitumor activity and OS in an HCC population in which a majority (58%) had ECOG performance status of 1.– Any-grade treatment-related AEs occurred in 80.0% of patients; grade 3/4

AEs in 20.0% of patients.– ORR was 10.0% in the total patient population; median OS was

13.2 months.

• Results of a Phase 1/2 study of durvalumab in combination with the anti-CTLA-4 antibody tremelimumab for the treatment of unresectable HCC are being presented on Poster Board #65 (Kelley et al. Abstract #4073) at ASCO 2017.

MethodsStudy Design • This global, multicenter, open-label study (ClinicalTrials.gov identifier:

NCT01693562) was initiated in October 2012.

• The study comprised a standard 3 + 3 dose-escalation phase (now completed), followed by a dose-expansion phase (still ongoing).

• The dose-expansion phase included patients with 15 different solid tumortypes, including HCC.

• Preliminary data from the HCC cohort were previously presented (data cutoff August 21, 2014).17

• Patients received durvalumab 10 mg/kg i.v. once every 2 weeks (Q2W) for up to 12 months or until confirmed progressive disease, initiation of another anticancer therapy, unacceptable toxicity, consent withdrawal, or another reason for treatment discontinuation.

• Patients must have failed, be intolerant to, be ineligible for, or have refused first-line standard therapy. Key inclusion and exclusion criteria are listed in Table 1.

• HBV and HCV status were determined using viral titers at the screening stage.Figure 1. Mechanism of Action of Durvalumab

4071

Poster presented at the American Society of Clinical Oncology (ASCO) Annual Meeting; Chicago, IL, USA; June 2–6, 2017

Objective• The objectives of this Phase 1/2, first-in-human study were to evaluate the

safety and clinical activity of durvalumab in patients with advanced solid tumors.

• Here we present interim data from the HCC cohort in the dose-expansion part of the study (data cutoff as of October 24, 2016).

Table 1. Key Inclusion and Exclusion Criteria of the HCC Cohort

AcknowledgmentsOn behalf of the study team, the authors thank the patients and their families and caregivers for their participation in this study. This study was funded by MedImmune. Medical writing support was provided by Lietta Nicolaides at CircleScience (London, UK), an Ashfield company, part of UDG Healthcare plc, which was funded by MedImmune.

DisclaimerThe use of durvalumab described herein is currently investigational.

Copies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster.Contact email: ZWainberg@mednet.ucla.edu

Zev A. Wainberg1, Neil H. Segal2, Dirk Jaeger3, Kyung-Hun Lee4, John Marshall5, Scott Antonia6, Marcus Butler7, Rachel E. Sanborn8, John Nemunaitis9, Cheryl Carlson10, Richard S. Finn1, Xiaoping Jin11, Joyce Antal11, Ashok Gupta11, Christophe Massard12

1David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 2Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; 4Seoul National University Hospital, Seoul, Korea; 5Georgetown University Medical Center, Washington, DC, USA;6H. Lee Moffitt Cancer Center, Tampa, FL, USA; 7Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 8Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA; 9Mary Crowley Cancer Research Centers, Dallas, TX, USA; 10University of North Carolina Hospitals, Chapel Hill, NC, USA; 11MedImmune, Gaithersburg, MD, USA; 12Institut Gustave Roussy Cancer Centre, Villejuif, France

Safety and Clinical Activity of Durvalumab Monotherapy in Patients with Hepatocellular Carcinoma (HCC)

MHC, major histocompatibility complex; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; TCR, T-cell receptor

• Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 (IC50 0.1 nM) and CD80 (IC50 0.04 nM)6

(Figure 1).– The interaction between PD-1 and PD-L2 is not blocked by durvalumab.6

• Durvalumab has an engineered triple mutation in the Fc domain to remove antibody-dependent cell mediated cytotoxicity and complement-dependent cytotoxicity.6

• Durvalumab has shown evidence of clinical activity across multiple tumortypes17–19 and has been approved in the US for post-platinum locally advanced or metastatic urothelial carcinoma.

Key inclusion criteria≥18 years of age

Histologically or cytologicallyconfirmed diagnosis of HCC• Child-Pugh class A HCC • Could be positive for HBV or HCV

– HBV+ patients must be receiving adequate antiviral therapy

ECOG PS 0–1

Adequate organ and marrow function

Available archived tumor sampleECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus;irAE, immune-related adverse event; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; PS, performance status

Study Endpoints and Assessments• The primary endpoint was the assessment of safety and tolerability.

– Adverse events (AEs) and serious AEs were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03).

• Secondary endpoints included antitumor activity and survival.– Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

ResultsBaseline Characteristics• As of October 24, 2016, 40 patients with HCC had received durvalumab

10 mg/kg Q2W (Table 2).– The majority of patients (90.0%) had Stage IV disease at study entry.– 92.5% of patients had been previously treated with sorafenib.– At baseline, 10 patients (25.0%) were positive for HBV and 8 (20.0%) were

positive for HCV.

CharacteristicHCC cohort (as-treated population)

(N=40)Age, years Median (min, max) 61.5 (20,77)Sex, n (%) Female / Male 8 (20.0) / 32 (80.0)Race, n (%) (n=34)a White

AsianBlack or African AmericanNative Hawaiian or other Pacific IslanderOther

19 (55.9)9 (26.5)3 (8.8)2 (5.9)1 (2.9)

ECOG performancestatus, n (%)

01

17 (42.5)23 (57.5)

HBV / HCV status HBV+HCV+Non-HBV / non-HCV

10 (25.0)8 (20.0)

22 (55.0)Stage at study entry, n (%)

34

4 (10)36 (90)

Prior treatments AnyBiologicChemotherapyRadiationSurgeryOther

38 (95.0)15 (37.5)33 (82.5)12 (30.0)18 (45.0)16 (40.0)

Prior treatment with sorafenib (%) 37 (92.5)Smoking history Current

FormerNever

3 (7.5)17 (42.5)20 (50.0)

Cirrhosis (underlying liver disease) (%) 11 (27.5)Fibrosis (underlying liver disease) (%) 7 (17.5)Current alcohol use (%) 10 (25.0)Ascites at baseline (Child-Pugh) (%) 2 (5.0)Encephalopathy at baseline (Child-Pugh) (%) 0

Treatment Exposure and Follow-up• Median duration of follow-up was 24.0 months (range: 2.4–34.7).

Safety• Treatment-related AEs of any grade occurred in 80% of patients (Table 3).

– The most common were fatigue (27.5%), pruritus (25.0%), and elevated aspartate aminotransferase (AST; 22.5%).

• Treatment-related grade 3/4 AEs occurred in 20.0% of patients (Table 3).– The most common were elevated AST (7.5%) and elevated ALT (5.0%).

• Seven patients (17.5%) discontinued treatment due to an AE; none were related to treatment.

• There were no treatment-related deaths.

Table 2. Demographic and Baseline Characteristics in the HCC Cohort

Table 3. Treatment-related AEsAEs in ≥5% of patients (for all-grade AEs)

As-treated population (N=40)All grades, n (%) Grade 3/4, n (%)

Any treatment-related AE 32 (80.0) 8 (20.0)Fatigue 11 (27.5) 1 (2.5)Pruritus 10 (25.0) 1 (2.5)Elevated AST 9 (22.5) 3 (7.5)Decreased appetite 5 (12.5) 1 (2.5)Elevated ALT 4 (10.0) 2 (5.0)Diarrhea 4 (10.0) 0Nausea 4 (10.0) 0Constipation 3 (7.5) 0Vomiting 3 (7.5) 0Rash 3 (7.5) 0Asthenia 2 (5.0) 0Leukopenia 2 (5.0) 1 (2.5)Hypothyroidism 2 (5.0) 0Dry mouth 2 (5.0) 0Influenza-like illness 2 (5.0) 0Elevated blood alkaline phosphatase 2 (5.0) 1 (2.5)Myalgia 2 (5.0) 0Insomnia 2 (5.0) 0Dyspnea 2 (5.0) 0

ALT, alanine aminotransferase; AST, aspartate aminotransferase

Efficacy• At data cutoff, 4 patients (10.0%; 95% CI, 2.8–23.7) had achieved a partial

response (Table 4) and response was ongoing in 2/4 (50.0%).– None of the HBV+ patients had a response.

• Tumor responses occurred early and were durable (Figure 2).

• Median OS was 13.2 months (95% CI, 6.3–21.1) in the total population (Table 5 Figure 3).

Table 4. Antitumor Activity in the HCC Cohort

*All responses were confirmed.CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease

HBV+ HCV+Non-HBV / non-HCV All

Antitumor activity (IA) n=10 n=8 n=22 N=40ORR (CR + PR), % (95% CI)*

0 (0–30.8)

25.0 (3.2–65.1)

9.1 (1.1–29.2)

10.0 (2.8–23.7)

CR + PR + SD ≥24 weeks, % (95% CI)

10.0(0.3–44.5)

62.5 (24.5–91.5)

31.8(13.9–54.9)

32.5 (18.6–49.1)

El-Serag HB. Gastroenterology 2012;142:1264–73. Frenette C, Gish R. World J Gastroenterol 2012;18:498–506. Sanoff HK, et al. Oncologist 2016;21:1113–20. Llovet JM, et al. N Engl J Med 2008;359:378–90. Bruix J, et al. Lancet 2017;389(10064):56–66. Stewart R, et al. Cancer Immunol Res 2015;3:1052–62. Sznol M, Chen L. Clin Cancer Res 2013;19:1021–34. Creelan BC. Cancer Control 2014;21:80–9. Borghaei H, et al. N Engl J Med 2015;373:1627–39. Ferris RL, et al. N Engl J Med 2016;375:1856–67.

Reck M, et al. N Engl J Med 2016;375:1823–33.Sharma P, et al. Lancet Oncol 2016;17:1590–8. Herbst RS, et al. Lancet 2016;387(10027):1540–50. Rosenberg JE, et al. Lancet 2016;387(10031):1909–20. Fehrenbacher L, et al. Lancet 2016;387(10030):1837–46. El-Khoueiry AB, et al. Lancet 2017; pii: S0140–6736(17):31046-2. Segal HN, et al. Poster presented at ESMO 2014 (Abstract 1058PD). Antonia S, et al. Poster presented at ESMO 2016 (Abstract 1216PD). Massard C, et al. J Clin Oncol 2016;34:3119–25.

References1.

2.

3.4.5.6.

7.

8.9.

10.

11.

12.

13.

14.

15.

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17.

18.

19.

Figure 3. Kaplan-Meier Estimate of OS in the HCC cohort (As-treated Population)

Key exclusion criteriaActive or prior auto-immune disease in past 2 years

History of primary immunodeficiencies

History of bleeding from esophageal varices, unless treatment with active bleeding occurred >30 days prior to first dose of durvalumab

Any concurrent chemotherapy, immunotherapy (including anti-PD-1/ PD-L1 treatment), biologic or hormonal therapy for cancer treatment

Any prior immunotherapy in past 4 weeks (past 6 weeks for monoclonal antibodies)

Any prior grade ≥3 irAE while receiving immunotherapy

Any prior anti-PD-1 or anti-PD-L1 antibody treatment

*Information unavailable for 6 patients

**

Survival All (N=40) Median OS (95% CI), months 13.2 (6.3–21.1)

OS 6-month rate, % (95% CI) 76.5 (59.6–87.0)

OS 9-month rate, % (95% CI) 62.3 (44.7–75.8)

OS 12-month rate, % (95% CI) 56.1 (38.4–70.5)

Median PFS (95% CI), months 2.7 (1.4–5.3)

PFS 6-month rate, % (95% CI) 30.3 (16.8–45.1)

PFS 9-month rate, % (95% CI) 27.6 (14.6–42.2)

PFS 12-month rate, % (95% CI) 20.7 (9.2–35.3)CI, confidence interval;OS, overall survival; PFS, progression-free survival

Table 5. OS and PFS in the HCC Cohort

OS

rate

No. of subjects at risk

40 35 27 20 18 13 12 11 4 2 2

0.8

0.6

0.4

0.2

0.0

0

Time (months)

3 6 9 12 15 18 21 24 27 30 33

No. of subjects (no. of events)Median (months) (95% Cl) OS – 12 months, % (95% CI)

All subjects40 (27)

13.2 (6.3–21.1)56.1 (38.4‒70.5)

1.0