This document provides an overview of cholangiocarcinoma, a rare and deadly form of cancer. It discusses risk factors and increasing incidence rates. For localized disease, surgical resection is standard but outcomes remain poor. For advanced disease, gemcitabine-based chemotherapy is the standard first-line treatment based on results from the ABC-02 trial showing improved survival with gemcitabine and cisplatin. Retrospective data on second-line therapies and combination of pazopanib and trametinib show some benefit. Adding radiation therapy may also improve outcomes based on another retrospective review. Next generation sequencing is helping identify molecular alterations to guide targeted therapy trials. Ongoing clinical trials at MD Anderson include testing new

1. A U B H O 2 0 1 5 , B A N G K O K , T H A I L A N D
R A C H N A T . S H R O F F , M D , M S
A S S I S T A N T P R O F E S S O R ,
D E P T O F G I M E D I C A L O N C O L O G Y
M . D . A N D E R S O N C A N C E R C E N T E R
R S H R O F F @ M D A N D E R S O N . O R G
Cholangiocarcinoma:
Changing the landscape for a rare
disease

2. Outline
 Overview of the disease
 Second-line therapy
 Retrospective data
 Phase Ib of pazopanib and trametinib
 The role of radiation
 Retrospective data
 Next steps
 Next generation sequencing for cholangiocarcinoma
 Profiling data
 Clinical trials at MD Anderson

3. The Magnitude of the Problem: U.S. Data
 >7,000 cases annually in 2009
 5-year survival is <15%
 Most patients present with locally advanced or metastatic
disease
 Treatment commonly administered in the community,
at low-volume centers.

4. Risk factors
 Obesity, Metabolic Syndrome
 Chronic inflammation (hepatitis, ETOH, smoking,
occupational)
 Parasitic infections
 Primary sclerosing cholangitis, Crohns disease
 Cysts, anomalous pancreatobiliary ducts
 Biliary polyps (>10 mm)

5. Rising incidence
J Hepatol. 2004;40(3):472-7

6. Cholangiocarcinoma: Site of Disease
Hilar Intrahepatic

7. Localized Cholangiocarcinoma
 Surgical resection is the standard of care
 Post operative radiation/ chemoradiation therapy improves
recurrence-free survival in R1 disease
 Role of adjuvant therapy in R0 resection is debatable
 Role of liver transplantation in unresectable hilar
cholangiocarcinoma.
NCCN Guidelines

8. Advanced biliary tract cancers
 Disease-related factors
 Uncommon malignancies
 Unwell, elderly population, infection/obstruction
 Histological / cytological confirmation difficult
 Lack of evidence
 Disease often not measurable
 Primarily small phase II and one phase III study of
gemcitabine-based combinations

9. ABC-02 - Study schema
Eligible patients (n=400*)
Arm A
Gem 1000 mg/m2 D1,8,15 q
28d, 24 weeks (6 cycles)
Arm B
Cisplatin 25 mg/m2
+ Gem 1000 mg/m2
24 weeks (8 cycles)
Randomized 1:1
(stratified by centre, primary site, PS, prior
therapy and locally advanced vs. metastatic)
Upon disease progression, management will be on clinician’s
discretion (mostly best supportive care)
D1,8 q 21d
+ QoL

10. Result
Gem
n (%)
Gem + Cis
n (%)
Not assessed * 74 (36%) 56 (27%)
Assessed * 132 (64%) 148 (73%)
Complete Response 1 (0.8%) 1 (0.7%)
Partial Response 20 (15.2%) 37 (25.0%)
Stable Disease 73 (55.3%) 79 (53.4%)
Progressive Disease 33 (25.0%) 28 (18.9%)
CR + PR + SD 94 (71.2%) 117 (79.1%)
p-value 0.256
* Patients not required to have measurable disease at study entry,
some patients still in follow-up
Radiologic Response

11. ABC-02 - Results:
Overall Survival (ITT)
Treatment arm Gem Gem + Cis
Number of patients n=206 n=204
Deaths n(%) 141 (68.5) 122 (59.8)
Median survival (mo) 8.3 11.7
Log rank p value 0.002
Hazard ratio (95% CI) 0.70 (0.54, 0.89)

12. ABC-02 Conclusions
 Cisplatin and gemcitabine significantly improves overall
survival compared with gemcitabine monotherapy (11.7
vs. 8.3 months)
 Benefit gained with no clinically significant added toxicity
 CisGem is recommended as a worldwide standard of care
and the backbone for further studies
 Caution required in patients with PS > 2

13. Agents Target Patients RR PFS Author
Combination Regimens First line therapy
GEMOX-
cetuximab
EGFR 51 - 61% (4 mths) Malka
GEMOX-
bevacizumab
VEGF 35 40
7 months
(median)
Zhu
Single Agent Regimens First or Second line
AZD6244
MEK1/2 22 14
5.4 months
(median)
Bekaii-Saab
Erlotinib
EGFR 43 7
2.6 months
(median)
Philip et al
Lapatinib
EGFR/HER2 17 0
1.8 months
(median)
Ramanathan
Sorafenib
BRAF/VEGFR 36 6
2 months
(median)
El-Khoueiry
Sorafenib
BRAF/VEGFR 46 2
2.3 months
(median)
Bengala
Zhu et al, JCO, 2009

14. Phase III GEMOX + Erlotinib
268 pts randomized: GEMOX +
Erlotinib
PR higher in erlotinib group (40
vs. 21, p=0.005)
Higher PFS with erlotinib (5·9
months vs 3·0 months) (p=0·049)
Median overall survival was the
same in both groups
Lancet Oncol. 2012;13(2):181-8.

15. Gastrointest Cancer Res. 2011;4(5-6):155-60.
First line regimens at MD Anderson

16. Second-line therapy
 Retrospective review of MD Anderson experience:
 Patients with advanced cholangiocarcinoma who received 2nd
line therapy from 2009-2012
 56 patients evaluated, majority were intrahepatic
cholangiocarcinoma
 Primary objective: PFS with second-line therapy
 Secondary objectives: OS, disease control rate
 80% received gemcitabine-based first-line therapy
 Majority of patients received 5-fluorouracil in the second-line
setting

17. Second-line therapy
Rogers JE, et al. J Gastrointest Oncol 2014
Median PFS: 2.7 months
Median OS: 13.8 months
DCR: 50%

18. Pazopanib and trametinib – a phase Ib study
 Collaboration between MD Anderson and Johns
Hopkins
 Phase I showed one prolonged PR and one SD with
cholangiocarcinoma
 Expansion to 25 patients (MD Anderson n = 18)
 Primary endpoint: PFS
 Secondary endpoints: OS, RR, DCR
 Highly refractory population (median # prior
therapies: 2)
 Median follow-up: 8.9 months
Shroff RT, et al, ASCO Annual Meeting 2015

19. Pazopanib and trametinib – a phase Ib study
 Overall response rate – 5%
 Disease control rate – 75% (15/20 patients)
 Median PFS 4.3 months
 4-month PFS – 56%
 p<0.002 compared with a pre-specified null hypothesis rate of
25%
 Median OS was 6.7 mths
 Next steps: In development

20. The role of radiation
 Retrospective review of MD Anderson experience
 114 patients from 2009-2013, majority intrahepatic
 Primary objectives
 Determine first-line therapy given to unresectable
cholangiocarcinoma (uCC) patients
 Determine the percentage of patients that received chemoradiation
(CRT)
 Secondary objectives
 Disease response with first-line therapy
 Evaluate the median number of chemotherapy cycles received prior
to CRT
 Duration of CRT control
 Progression-free survival (PFS) with or without CRT
 Overall survival (OS) with or without CRT
Rogers JE, et al, Cholangiocarcinoma Foundation Annual Meeting 2015

21. The role of radiation
 66% received gemcitabine plus platinum (cisplatin or
oxaliplatin)
First-Line Therapy Percentage
Gemcitabine + Cisplatin 63.2 %
Gemcitabine + Cisplatin +
Erlotinib
5.3%
Gemcitabine monotherapy 3.5%
Others (Gemcitabine +
capecitabine; Gemcitabine +
Oxaliplatin, etc)
11.4%
CRT 16.7%
Shroff RT, et al, Cholangiocarcinoma Foundation Annual Meeting 2015

22. The role of radiation
Patient group Median PFS (95% CI) Median OS (95% CI)
No CRT
(N= 40)
11.4 months (9.1-15.3) 22.4 months (12.6-37.5)
CRT
(N =74)
14.5 months (12.1-16.6) 29.4 months (23.8-38.2)
CRT with disease control
on first-line treatment
(N= 62)
15.7 months (13.5-19.0) 32.0 months (24.0-44.1)
CRT with progression on
first-line treatment
(N=12)
4.2 months (2.3-9.0) 6.9 months (7.0-30.2)
Rogers JE, et al, Cholangiocarcinoma Foundation Annual Meeting 2015

23. The role of radiation - PFS
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48 60 72 84 96
Months
No CRT
CRT
p = 0.105
Progression-free Survival
0.00
0.25
0.50
0.75
1.00
ProportionProgression-free
0 12 24 36 48 60 72 84 96
Months
No CRT
CRT with First-line Treatment Disease Control
CRT with First-line Treatment Progression
p < 0.001
Progression-free Survival
CRT vs. No CRT: 14.5 vs. 11.4 mths
CRT (DC) vs. CRT (PD): 15.7 vs. 4.2 mths
Rogers JE, et al, Cholangiocarcinoma Foundation Annual Meeting 2015

24. The role of radiation - OS
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48 60 72 84 96
Months
No CRT
CRT
p = 0.005
Overall Survival
0.00
0.25
0.50
0.75
1.00
ProportionSurviving
0 12 24 36 48 60 72 84 96
Months
No CRT
CRT with First-line Treatment Disease Control
CRT with First-line Treatment Progression
p = 0.001
Overall Survival
CRT vs. No CRT: 29.4 vs. 22.4 mths
CRT (DC) vs. CRT (PD): 32 vs. 6.9 mths
Rogers JE, et al, Cholangiocarcinoma Foundation Annual Meeting 2015

25. The role of radiation
Rogers JE, et al, Cholangiocarcinoma Foundation Annual Meeting 2015

26. Unresectable
Cholangiocarcinoma
-liver confined
-no cirrhosis or CPC A
-up to 2 satellite lesions
-12 cm or less
Stratify:
Largest tumor > 6 cm
-satellite y/n
Gem/Cis x 4
Liver Directed Radiation
Therapy
Followed by maintenance
Gem/Cis x 4
Gem/Cis x 4
Re-staging
AND
Randomization
after cycle 3
Radiation
Planning
during cycle 4
NRG GI-001 Phase III Trial
Hong, PI, Activated 8/2014

27. Next generation sequencing (NGS)
 NGS on all cholangiocarcinoma patients with
available tissue
 Standard practice at MD Anderson since 2013
 Important differences between intrahepatic and
extrahepatic cholangiocarcinoma
 75 patients
Churi CR, et al. PLoS One 2014.

28. Next generation sequencing (NGS)
Churi CR, et al. PLoS One 2014.

29. Next generation sequencing (NGS)
Churi CR, et al. PLoS One 2014.

30. Next generation sequencing (NGS) –
BRAF inhibition
Churi CR, et al. PLoS One 2014.

31. MD Anderson Approach
Unresectable Cholangiocarcinoma
Localized
Induction Chemo
followed by
ChemoRT
Disseminated
Systemic
Chemotherapy
NGS
Add targeted agents
based on molecular
phenotype
Clinical trials:
GAP
FGFR Inhibitor
Radiation Therapy
Select cases
with SD/PR> 6
mos on chemo,
consider OLT
(investigational)

32. Clinical Trials at MD Anderson
 First-line therapy
 GAP trial – multicenter, phase II study of Nab-Paclitaxel with
gemcitabine and cisplatin in advanced, untreated biliary cancers
 15 of 50 patients enrolled thus far and all remain on study
 Therapy for refractory disease
 Ramucirumab for advanced biliary cancers
 FGFR inhibitor for patients with known FGFR alterations
 IDH inhibitors for IDH1 and IDH2 mutations
 Pilot study with anti-PD-1 planned
 Radiation therapy
 NRG-GI001
 Pre-clinical work
 PDX models
 BAP1, KRAS mutant models

33. Q U E S T I O N S ?
Thank you!