Download IV placebo

Where we are with targeted
therapies for cholangiocarcinoma
Professor Juan W Valle
Professor & Honorary Consultant in Medical Oncology
The Christie NHS Foundation Trust
University of Manchester
11th May 2017
AMMF Conference, Radisson Blu Hotel, Stansted
Signalling pathways | Highly complex
Specific drug targets | The hallmarks of cancer
Hanahan & Weinberg 2011. Cell 144(5):646
Bringing cholangiocarcinoma into the era of precision medicine
https://pct.mdanderson.org/#/
EGFR
Epidermal growth factor receptor
EGFR inhibition | Rationale
• EGFR-expression is increased in the majority of gall bladder and bile duct cancers 1
• The TGF-ligand is frequently
increased in gall bladder
cancers 1
• Bile acids activate EGFR and
cellular proliferation via a
TGF-dependent mechanism
in human CC cells 2
• Sustained EGFR activation
has been demonstrated in CC
cells 3
• Blockade of the EGFR
tyrosine kinase activity
reduced the proliferation of
CC cells in vitro 3
1
Nyati et al 2006. Nature Reviews Cancer 6, 876-885
Lee Pathol Res Pract 1995, 2 Werneburg Am J Physiol Gastrointest Liver Physiol 2003, 3 Yoon J Hepatol 2004
Early EGFR inhibition data | Promising
• Cetuximab 500 mg/m² in 150 min IV – D1 +
Trial
design
• Gemcitabine 1000 mg/m² in 100 min IV – D1 +
• Oxaliplatin 100 mg/m² in 120 min IV – D2
• Every 2 weeks
Results
• N=30
• Median age 68
Response
%
CR
10
PR
53.3
SD
16.7
PD
20
Response
Rate 63%
• Median PFS: 8.8 months (95% CI 5.1-12.5)
• Median OS: 15.2 months (95% CI 9.9-20.5)
• N=9 patients (30%) underwent secondary curative resection after major response to
therapy
Gruenberger et al 2010. Lancet Oncol 11(12):1142
BINGO study (randomised phase II) | Negative
Promising •
start1
•
High (63%) response rate, including 10% CR, 9 patients (30%) underwent salvage surgery
Median PFS 8.8 months (95% CI 5.1-12.5), median OS 15.2 months (95% CI 9.9-20.5)
BINGO2
Eligible
patients 
n=150
#
Gemcitabine 1000mg/m² (10mg/m²/min) IV – D1
Advanced BTC (1st line)
• Stratification
• Stage (LA vs. M+)
• Type (GB vs. other)
• Center
• Previous treatments (Y/N)
Arm
A
Oxaliplatin 100 mg/m² in 120 min IV – D2
Every 2 weeks
R
Arm
B
For full eligibility criteria, see protocol
Gemcitabine 1000mg/m² (10mg/m²/min) IV – D1
Oxaliplatin 100 mg/m² in 120 min IV – D2
Cetuximab 500 mg/m² in 150 min IV – D1 or D2
Every 2 weeks
Until disease progression or limiting toxicity
1
4-month PFS
PFS (months)
RR
OS (months)
GemOx (n=74)
54%
5.5
23%
12.4
GemOx / CTX (n=76)
63%
6.1
23%
11.0
Gruenberger 2010 Lancet Oncol 11(12):1142 , 2 Malka 2014 Lancet Oncol 15(8):819
EGFR inhibition | 4 negative randomised studies
RR
(%)
1
Median PFS
(months)
Median OS
(months)
Phase
Chemo
alone
With
biological
Chemo
alone
With
biological
Chemo
alone
With
biological
GemOx +/- cetuximab
2
23
23
5.5
6.1
12.4
11.0
Chen2
GemOx +/- cetuximab
2
15
27
4
7.1
8.8
10.3
Lee3
GemOx +/- erlotinib
3
16
30
4.2
5.8
9.5
9.5
Leone4
Gem/Ox +/- panitumumab
2
18
27
4.4
5.3
10.2
9.9
ABC-025
CisGem (for reference)
Study
Regimens
Malka1
26
Malka 2014 Lancet Oncol, 2 Chen 2013 J Clin Oncol, 3 Lee 2012 Lancet Oncol, 4 Leone 2015 Cancer (ePub)
2010 N Engl J Med
5 Valle
8.0
11.7
Is EGFR inhibition still worth pursuing in BTC?
What have we learnt?
• Lessons from other tumour types
are not easily transferrable
– EGFR over-expression
– KRAS-status
• Low statistical power in BTC
• Chemotherapy partner may
matter
– Irinotecan preferable to
oxaliplatin?
– 5-FU preferable to
capecitabine?
• Remains investigational
• Scope for further study?
– Pooled analysis?
– Detailed evaluation of
“exceptional responders”?
Nyati et al 2006. Nature Reviews Cancer 6, 876-885
VEGFR
Vascular endothelial growth factor receptor
VEGF is over-expressed in 40-75% of
BTCs 1-3
•
VEGFR-1 and -2 are also overexpressed in adjacent endothelial
cells 4
•
VEGF expression associated with
•  metastases (IH-CC) 1
•  micro-vessel density 2,3
•  OS (EH-CC) 5
•
Cediranib is a pan-VEGF receptor TKI
(with some activity against PDGF
receptors and c-Kit) 6
1
4
Yoshikawa BJC 2008, 2 Tang Oncol Rep 2006, 3 Giatromanolaki EJSO 2003,
Benckert, Cancer Res 2003, 5 Hida Anticancer Res 1999, 6 Wedge Cancer Res 2005
VEGF expression in
CC tumour cells 4
•
VEGF expression in
Gallbladder carcinoma 3
Targeting VEGF | Rationale
ABC-03 | Study schema
n=124
Eligible
patients
Placebo
+ Cisplatin + Gemcitabine
20mg once daily
25 mg/m2 1000 mg/m2
Days 1 & 8,
21 day cycle
+ Cisplatin + Gemcitabine
Cediranib
20mg once daily
25 mg/m2 1000 mg/m2
Days 1 & 8,
21 day cycle
R
•
•
•
•
Histo-/cytologically confirmed ABC
Age ≥ 18 years (no upper limit)
Resolved biliary obstruction / sepsis
Adequate haem, renal & liver function
Valle et al 2015. Lancet Oncol. 16(8):967
•
•
•
•
ECOG PS 0-1
Chemo-naïve
Life expectancy >12 weeks
Informed consent
ABC-03 Results | Response rate, PFS & OS
Median time on cediranib:
4.6 months
100
75
HR = 0.93 [95%CI 0.65-1.35]
P = 0.72
50
25
0
100
cediranib
placebo
% of patients alive
% of patients progression-free
Did not meet its primary endpoint (PFS); however cediranib improved response rate (44% v 19% p=0.004)
75
3
6
12
18
24
25
30
Time since randomization (months)
Number at risk
Placebo 62
Cediranib 62
46
52
38
42
19
23
10
13
8
5
4
4
3
4
2
1
1
0
0
0
Events
n (%)
Median PFS
(months)
6-month PFS
(%)
Cediranib
59 (95)
8
71
Placebo
57 (92)
7.4
61
Valle et al 2015. Lancet Oncol. 16(8):967
HR = 0.86 [95%CI 0.58 - 1.27]
P = 0.44
50
0
0
cediranib
placebo
0
Number at risk
Placebo 62
Cediranib 62
6
12
18
24
30
Time since randomization (months)
58
57
49
51
41
39
30
34
21
27
14
20
5
13
5
11
2
3
1
1
Events
n (%)
Median OS
(months)
1 year survival
(%)
Cediranib
50 (81)
14.1
58
Placebo
50 (81)
11.9
48
Ramucirumab or Merestinib or placebo + Cisplatin & Gemcitabine
in patients with advanced or metastatic biliary tract cancer I3O-MC-JSBF Study
•
Locally-advanced or metastatic BTC
•
First line treatment
•
ECOG PS 0/1
•
Double-blind
N= 300 Patients
Chief Investigator | Valle
R
R
2:1
2:1
Ramucirumab +
IV placebo +
Merestinib +
Oral placebo +
Gemcitabine + Cisplatin
Gemcitabine + Cisplatin
Gemcitabine + Cisplatin
Gemcitabine + Cisplatin
Ramucirumab
8mg/kg D1 & 8 3qw
Cisplatin
25mg/m2 IV D1 & 8 3qw
Gemcitabine
1000mg/m2 IV D1 & 8 3qw
IV placebo
IV D1 & 8 3qw
Cisplatin
25mg/m2 IV D1 & 8 3qw
Gemcitabine
1000mg/m2 IV D1 & 8 3qw
Merestinib
80mg oral, daily with food
Cisplatin
25mg/m2 IV D1 & 8 3qw
Gemcitabine
1000mg/m2 IV D1 & 8 3qw
Oral placebo
Daily with food
Cisplatin
25mg/m2 IV D1 & 8 3qw
Gemcitabine
1000mg/m2 IV D1 & 8 3qw
Arm A1 | N=100
Arm B1 | N=100
Arm A2 | N=50
Arm B2 | N=50
Stratification factors
Primary
tumour site
Gall bladder
Intrahepatic cholangiocarcinoma
Extrahepatic cholangiocarcinoma
Ampulla of Vater
Geographic
region
Europe or North America
Rest of the world
Metastatic
status
Yes
No
•
CisGem treatment will be capped @ 8 cycles
•
Ramucirumab/Merestinib/placebo will not be capped
•
Crossover is not permitted
•
Appropriate best supportive care will be offered to all
•
After n=75 patients complete Cycle 1, an interim safety
analysis will be performed
Genetic targeting
In BTC
Improving our understanding of the genetic environment of BTC
Molecular heterogeneity reflects the heterogeneous group of biliary tract diseases
•
Intrahepatic cholangiocarcinoma has a different profile to extrahepatic CC or GBC1,2
Table adapted from 1
•
Opisthorchis viverrini (liver-fluke)- associated (TP53 mutations) is different from non-liver fluke
associated (BAP1, IDH1 and IDH2 mutations)3
•
Inflammatory subclass is different from proliferative subclass4
•
Up to 70% of IH-CCA patients have an actionable mutation4
1Ross
(ASCO GI) J Clin Oncol 33, 2015 (suppl 3; abstr 231); 2Borger 2011 Oncologist 17(1):72; 3Chan-on 2013 Nat
Genet 45(12):1474; 4Sia 2015 Nat Commun 6:6087
Improving our understanding of the genetic environment of BTC
Molecular heterogeneity reflects the heterogeneous group of biliary tract diseases
•
Intrahepatic cholangiocarcinoma has a different profile to extrahepatic CC or GBC1,2
Table adapted from 1
•
Opisthorchis viverrini (liver-fluke)- associated (TP53 mutations) is different from non-liver fluke
associated (BAP1, IDH1 and IDH2 mutations)3
•
Inflammatory subclass is different from proliferative subclass4
•
Up to 70% of IH-CCA patients have an actionable mutation4
1Ross
(ASCO GI) J Clin Oncol 33, 2015 (suppl 3; abstr 231); 2Borger 2011 Oncologist 17(1):72; 3Chan-on 2013 Nat
Genet 45(12):1474; 4Sia 2015 Nat Commun 6:6087
IDH1 & IDH2 mutations | Specifically in intra-hepatic CC
Intra-hepatic CC
Extra-hepatic CC
Blechacz et al 2011. Nat Rev
Gastroenterol Hepatol. (9):512
Slide c/o Professor Andrew Zhu, Borger et al 2012. Oncologist. 17(1):72
IDH1
Isocitrate dehydrogenase 1
IDH Isocitrate dehydrogenase
Krebs cycle or tricarboxylic acid (TCA) cycle
• IDH exists as 3 isoforms
• IDH1 & 2 have cancer-associated mutations which happen early in tumour development
• These mutations result in novel gain-of-function enzyme activity which;
− Block normal cell differentiation
− Promotes tumorigenesis
Cairns et al 2011. Nat Rev Cancer. 11(2):85. 2-HG; 2-hydroxyglutarate, αKG; α-ketoglutarate
IDH1 mutations ID in a variety of solid tumour types
70%
50%
20%
Intra-hepatic CC
• IDH1 mutations are not associated with prognosis in CC (but are associated with better
outcomes in glioma)
Zhang et al 2016. Data Brief. 6:948
ClarIDHy AG-120 in patients with advanced CC, with IDH1 mutations
Opening soon in UK
N=186 patients
AG-120
N=124
R
2:1
Placebo
N=62
Cross-over to AG-120
At disease progression
• Phase 3, 2nd-line, double-blind study
• AG-120 is an oral inhibitor of the IDH1 mutant protein
• Patients must have a histologically-confirmed diagnosis of IDH1 gene-mutation
• Opened in December 2016, aims to complete recruitment in 2020
• Currently recruiting in 3 US hospitals, plan to open in 45 sites globally
• Primary endpoint is progression-free survival
NCT02989857
FGFR
Fibroblast growth factor receptor
FGFR signalling in cancer
Activating mutation
FGFR3
• Bladder (60%)
FGFR2
• Endometrial (14%)
FGFR4
Rhabdomyosarcoma (8%)
Amplification
FGFR1
• NSCLC (20%)
• SCLC (6%)
• Breast (4%)
FGFR2
• Gastric (9%)
• TNBC (4%)
Fusion
FGFR2
• IHCCA (16%)
FGFR3
• GBM (3-7%)
• Bladder (3-6%)
Slide c/o Dr Elizabeth Smyth, figure adapted from Turner & Gross 2010. Rev Cancer 10(2):116
Angiogenesis
Paracrine loop
Altered splicing
Autocrine loop
FGFR2 translocations in Intrahepatic Cholangiocarcinoma
FGFR2
Fusion Partner
BICC1
References
Wu Cancer Discovery 2013
2 reported cases of FGFR2-BICC1
TACC3
Borad PLoS Genetics 2014
3 reported cases of FGFR2-BICC1, FGFR2TACC3, FGFR2-MGEA5 (3/6)
KIAA1598
MGEA5
Arai Hepatology 2013
translocations occur in 13.6% of 9/66 IHCCs
reported FGFR2-AHCYL1, FGFR2-BICC1
AHCYL1
Ross Oncologist 2014
FGFR2-KIAA1598, FGFR2-BICC1, FGFR2TACC3 (3/28 samples)
PPHLN1
Sia Nat Commun 2015
Translocations occur in ~45% of IHCCs
FGFR2-PPHLN1 (16%)
5′ FGFR2
3’ FGFR2
FGFR dysregulation in BTC (USA)
FGFR dysregulation is prognostic | No FGFR directed therapy
FGFR dysregulation positive
Median OS 36 months
FGFR normal
Median OS 22m
Jain et al 2016 ASCO General Meeting
BJG398 Phase II trial
Key inclusion criteria
• Advanced or metastatic CC
• FGFR2 fusion or other genetic
alterations in FGFR
• Progression following prior
cytotoxic therapy
BGJ398 125 mg daily
Days 1-21, every 28 days
Treatment until disease progression,
unacceptable toxicity, withdrawal of informed
consent, or death
Primary endpoint | RR (RECIST v1.1)
Secondary endpoints | PFS, OS, best
overall response (BOR), disease
control rate (DCR), safety, and
pharmacokinetics.
Javle et al 2016 ASCO GI meeting, NCT02150967
Update (ASCO-GI 2016)
• 47 patients treated
• Majority of patients had ≥2 prior
therapies and 11% had at ≥ 4 prior
regimens
• FGFR2 fusions/rearrangements
were present in 38 patients
• Other FGFR genetic alterations
were present in 9 patients;
− FGFR2 mutations (n=3)
− FGFR2 amplifications (n=4)
− FGFR3 amplifications (n=2)
BJG398 trial results
• Median duration of exposure was 188 days (6.2 months)
All 8 patients with a partial
response had an FGFR2 fusion
Javle et al 2016 ASCO GI meeting, NCT02150967
Ongoing targeted trials
Target
IDH1
IDH2
FGFR2
Drug
Phase
Line of treatment
NCT number
AG-120
I
2nd & beyond
NCT02073994
IDH305
I
2nd & beyond
NCT02381886
AG-221
I/II
2nd & beyond
NCT02273739
BAY1187982
I
2nd & beyond
NCT02368951
ARQ087
I
2nd & beyond
NCT01752920
BAY1179470
I
Any
NCT01881217
AZD4547
I
Any
NCT00979134
BGJ398
II
2nd & beyond
NCT02150967
Ponatinib Hydrochloride
II
2nd & beyond
NCT02265341
Selumetinib
II
1st/2nd
NCT00553332
Any
NCT01242605
MEK
Selumetinib + Gem + Cis
mTOR
AKT
I/II
Everolimus
I
2nd & beyond
NCT00949949
MK2206
II
2nd
NCT01425879
Ongoing targeted trials
Image c/o Dr Jorge Barriuso – Manuscript under review
Take-home messages
- Despite a shaky start, the search for targeted therapies is
warranted
- Progress will only be made with improved understanding of
biology
- We are likely to be dealing with lots of different
“cholangiocarcinomas”
- Clinical trials are underway to identify impact targeting specific
mutations
- This needs to go along-side the “pillars” of therapy (surgery,
chemotherapy, radiotherapy)
None of this would be possible without participation from patients,
their supporting families and patient advocates
Thank you