This paper reports phase II clinical data on galunisertib, a novel small molecule TGF-beta receptor inhibitor in patients with advanced non-operable hepatocellular carcinoma. This poster was presented at ASCO 2016 in Chicago. Results show activity and mild toxicity.

1. BACKGROUND ♦ Summary statistics provided for demographics and baseline characteristics
♦ Safety reported using CTCAE v4.0
♦ OS and TTP analyses carried out using the Kaplan-Meier method
• For all patients – OS and TTP
• By 2 sub-groups – OS only
‒ Categorizing by patients who had > 20% reduction from baseline in TGF-β1
concentrations at least once
‒ Categorizing by patients who had > 20% reduction from baseline in
E-cadherin concentrations at least once
‒ Additional longitudinal analyses are ongoing to investigate the correlation of
the timing and duration of reduction with overall survival
Patients: Inclusion/Exclusion Criteria – Part B
Table 1. Patient Baseline Characteristics
Plasma concentrations (90 total observations from 38 patients):
♦ Comparable with historical PK galunisertib data
♦ Mean exposure (AUC0-24,ss) 6.025 mg*h/L (box plot)
♦ Half-life approximately 8h
Figure 4. Overall Survival and Time-to-Tumor ProgressionFigure 2. Pharmacokinetics
Figure 1. Study Design for Part A and Part B
Figure 6. Maximum Reduction From Baseline in E-cadherin
Concentrations
A phase 2 study of galunisertib, a novel transforming growth factor-beta (TGF-β) receptor I kinase inhibitor, in patients with advanced
hepatocellular carcinoma (HCC) and low serum alpha fetoprotein (AFP)
Sandrine Faivre,1 Armando Santoro,2 Ed Gane,3 Robin K Kelley,4 Isabelle Ollivier Hourmand,5 Eric Assenat,6 Ivelina Gueorguieva,7 Ann Cleverly,7 Durisala Desaiah,8 Michael M Lahn,8 Eric Raymond,1 Karim A Benhadji,9 Gianluigi Giannelli10
1Medical Oncology, Beaujon University Hospital, Clichy, France; 2Istituto Clinico Humanitas, Milano, Italy; 3Auckland City Hospital, Auckland, NZ; 4University of California, San Francisco, CA, USA; 5Service d'Hépatogastroentérologie, CHU Côte de Nacre, Caen Cedex, France; 6Service d'Oncologie médicale, CHRU Saint ELOI, Montpellier Cedex, France; 7Eli Lilly and Company, Erl
Wood, UK; 8Eli Lilly and Company, Indianapolis, IN, USA; 9Eli Lilly and Company, Neuilly sur Seine, France; 10Internal Medicine, University of Bari Medical School, Bari, Italy
RESULTS
METHODS
CONCLUSIONS
♦ HCC patients with normal AFP treated with galunisertib had a manageable toxicity
profile
♦ Median overall survival is 16.8 months (90% CI:10.4, 24.1)
♦ HCC patients with normal AFP and with maximum TGF-β1 reduction >20%
showed improvement in OS compared to patients with non-TGF-β1 reduction.
♦ HCC patients with normal AFP and with E-cadherin reduction of >20% occurred in
46% of patients and the majority of these also had >20% reduction in TGF-β1
• The difference in OS seen with e-cadherin could be confounded with
changes in TGF-β1. Additional sensitivity analyses are ongoing to qualify
any potential prognostic effect on OS of these changes in biomarkers
♦ It should be noted that reductions in TGF-β1 may be a marker of effective
treatment in HCC and a randomized study is needed to determine whether the
reduction in TGF-β1 plasma levels is specific to treatment with galunisertib
Acknowledgements
References
Study Objectives
American Society of Clinical Oncology (ASCO), Chicago, IL June 3 – 7, 2016 Sponsored by Eli Lilly and Company
Statistical Analysis
62
♦ TGF-β signaling is associated with:
• Progression in HCC1,2
• Epithelial-mesenchymal transition (EMT) and cancer stem cells3
• Induction of T regulatory cells4
♦ Galunisertib is a TGF-β receptor I kinase inhibitor:
• Antitumor activity in various HCC models5-7
• Galunisertib has a favorable toxicity profile in patients with glioma8
♦ In this poster, we report the results of a cohort of patients with HCC and normal serum
AFP treated with galunisertib as part of a larger phase 2 study
♦ Primary objectives were time-to-progression (TTP) and evaluation of biomarker changes
(TGFβ1 and E-cadherin)
♦ Secondary objectives included overall survival (OS), toxicity (CTCAE, v 4.0) and
pharmacokinetics (PK)
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Screening
Patients
With
Child Pugh
A or B7
Galunisertib
160 mg/day
Galunisertib
300 mg/day
1st
Interim
Safety/PK
Final
Analysis
R
A
N
D
O
M
I
Z
E
Galunisertib
300 mg/day
Part A
AFP ≥1.5 ULN
Part B
AFP <1.5 ULN
Reporting in this
poster Part B
2nd
Interim
Dose
Determination
4th
Interim
Outcome
OS
3rd
Interim
Outcome
TTP
ULN, upper limit of normal.
♦ Inclusion criteria:
• Histological diagnosis of HCC
• Child-Pugh Stage A or B7
• AFP <1.5 the ULN (Part B) – study entry was based on local laboratory results
• Measurable disease (RECIST 1.1)
• Eastern Cooperative Oncology Group performance status of ≤1
• Have received sorafenib (progressed or intolerant) or are ineligible for sorafenib
treatment
♦ Exclusion criteria:
• Fibrolamellar or mixed histology
• Clinically relevant ascites
• Liver transplant requiring increased immunosuppressive therapy
• >1 line of systemic treatment
• Moderate or severe cardiac disease
Time after Dose (Hrs)
-5 0 5 10 15 20 25 30
PlasmaGalunisertib(ng/ml)
1
10
100
1000
10000
Plasma Galunisertib JBAK Pt B
Dose (mg)
300 (n=38)
PlasmaGalunisertibExposure(h*ng/ml)
0
2000
4000
6000
8000
10000
12000
14000
16000
Plasma galunisertib observations in patients
(Part B) following administration of 300 mg
total daily dose (n=38 patients)
Plasma exposure of galunisertib in patients
(Part B) AUC0-24hr. (Box Plot 5th/95th centiles)
Figure 3. Treatment-related TEAEs by SOC and Maximum Grade
Overall survival: median = 16.8 months TTP (RECIST v1.1): median = 4.1 months
Figure 5. Maximum Reduction from Baseline in TGF-β1
Concentrations
29 (74%) of patients had >20% reduction from baseline in TGF-β1
Figure is color coded by patients’ % reduction in e-cadherin concentrations: for
patients with a >20% reduction in TGF-β1 concentrations, only 50% also had a >20%
reduction in e-cadherin
18 (46%) of patients had >20% reduction from baseline in E-cadherin
Figure is color coded by patients’ % reduction in TGF- β1 concentrations:
the majority of patients with >20% reduction in e-cadherin also had a >20% reduction
in TGF-β1 concentrations
♦ We thank the patients and their caregivers for participating in this trial
♦ We thank the investigators and their support staff who generously participated in this work
Figure 7. Overall Survival (months) by Reduction in
Biomarkers
TGF-β1 pg/ml
(Reference range*: 741-3742 pg/ml)
E-cadherin ng/ml
(Reference range*: 1520-4900 g/ml)
n (%) Median 90% CI
TGFβ reduction 29 (74) 21.8 mo (15.4, -)
TGFβ non-reduction 10 (26) 7.9 mo (1.4, 13.8)
n (%) Median 90% CI
E-cad reduction 18 (46) 24.1 mo 24.1 (16.5, -)
E-cad non-reduction 21 (54) 10.4 mo (6.3, 16.8)
N Median Range
Baseline
Concentration
39 3389 1163, 37481
N Median Range
Baseline
Concentration
39 6330 1450, 18900
1. Giannelli G, et al. Biochim Biophys Acta 2011;1815(2):214-23.
2. Hoshida Y, et al. Cancer Res 2009;69(18):7385-92.
3. van Zijl F, et al. Future Oncol 2009;5(8):1169-79.
4. Yang P, et al. Cancer Cell 2012;22(3):291-303.
5. Fransvea E, et al. Cancer Chemother Pharmacol 2011;68(1):79-86.
6. Dituri F, et al. PLoS One 2013;8(6):e67109.
7. Serova M, et al. Cancer Res 2013;73(8 Suppl):abstr 2094.
8. Rodon J, et al. J Clin Oncol 2013;31(suppl):abstr 2016.
Note: A patient will only occur once for each term but may occur more than once across terms
Characteristic
Galunisertib
N = 40*
Age, years, median (range) 67.5 (46-89)
Gender, n (%)
Males 36 (90.0)
Females 4 (10.0)
Race, n (%)
White 35 (87.5)
Other 2 (5.0)
Missing 3 (7.5)
Prior sorafenib treatment, n (%)
Yes 34 (85.0)
No 6 (15.0)
ECOG, n (%)
0 24 (60.0)
1 16 (40.0)
Child Pugh, n (%)
5 23 (57.5)
6 7 (17.5)
7 10 (25.0)
Disease etiology, n (%)
Hepatitis B 6 (15.0)
Hepatitis C 7 (17.5)
Hepatic steatosis 5 (12.5)
Alcohol 9 (22.5)
Hemachromatosis 1 (2.50)
Other 8 (20.0)
Multiple 4 (10.0)
Portal vein thrombosis, n (%)
Yes 10 (25.0)
No 29 (72.5)
Missing 1 (2.5)
Tumor morphology, n (%)
Unimodular 5 (12.5)
Multinodular 28 (70.0)
Massive 6 (15.0)
Missing 1 (2.5)
BCLCCa, n (%)
Stage A 1 (2.5)
Stage B 12 (30.0)
Stage C 26 (65.0)
Missing 1 (2.5)
Prior systemic therapies, n (%)
Sorafenib 34 (85.0)
Investigational Drug 1 (2.5)
a Barcelona Clinic Liver Cancer Classification.*1 patient with missing data for portal vein thrombosis, tumor
morphology, BCLCC. Note: patients who had received more than 1 line of therapy were excluded from the study.
Number of Patients with Related Treatment Emergent Adverse Events