1. AUBHO 2014Rachna T. Shroff, MD, MSAssistant Professor,Dept of GI Medical OncologyM.D. Anderson Cancer Centerrshroff@mdanderson.org

2. None with the subject matter to bepresentedResearch Funding:CelgeneClovis Oncology 3. >7,0000 cases annually in 20095-year survival is 10 mm) 5. J Hepatol. 2004;40(3):472-7 6. 180160140120100806040200New Cases2009201020112012Medical Oncology Referrals or New CasesCauses:Reclassification from CUPTrue increase: Obesity,Hepatitis, Better Detectionwith Imaging/ Pathology 7. Adenocarcinoma Nodular Sclerosing PapillarySquamous cell carcinomaMixed hepatocellular/cholangiocarcinomaIHC CK7+, CK20-, CA19.9+ 8. Al Jaffiry, WJG 2009 9. Extrahepatic Painless jaundice Weight loss FeverIntrahepatic Constitutional Symptoms Pain Hepatomegaly Abnormal Liver Chemistries 10. Hilar Intrahepatic 11. Hilar CholangioBiliary ObstructioncommonCholangitis lifethreateningLocal-directedtherapies (TACE, Y90,RFA) increased risk ofabscess/complicationsIntrahepaticCholangioCourse can berelatively indolentLocal therapies foradvanced diseasefeasible, particularlyradiation 12. Surgical resection is the standard of carePost operative radiation/ chemoradiation therapyimproves recurrence-free survival in R1 diseaseRole of adjuvant therapy in R0 resection is debatableRole of liver transplantation in unresectable hilarcholangiocarcinoma.NCCN Guidelines 13. Surgical resection results in 20-30% long term survival> 5 yearsKlatskin tumors-junction of the hepatic ducts arecomplicated by extensive perineural and lymphaticinvasion, bilateral liver involvement, and vascularencasementIntrahepatic cholangiocarcinoma is a contraindicationfor liver transplant at most centers. 14. Unresectable CCA or resectable Cholangio with PSCTumor size < 3 cmTumor above cystic ductNo intra- or extrahepatic metastasesNo intrahepatic CCA or GB involvementVascular encasement of the hilar vessels is not acontraindicationCA 19-9 > 100 with mass; Biliary ploidy by FISH with bileduct stricture 15. Neoadjuvant EBRT: 4000 to 4500 cGy + 5-FU2000 to 3000 cGy transcatheter iridiumCapecitabine until transplantation5-year survival with neoadjuvant therapy = 55%5-year survival after transplantation = 71%.Rosen HPB (Oxford). 2008 16. American Association for the Study of Liver DiseasesHeimbach J, et al: Liver Transplantation 10; 65-68, 2004 17. Disease-related factors Uncommon malignancies Unwell, elderly population, infection/obstruction Histological / cytological confirmation difficultLack of evidence Disease often not measurable Primarily small phase II and one phase III study ofgemcitabine-based combinations 18. Eligible patients (n=400*)Arm AGem 1000 mg/m2 D1,8,15 q 28d24 weeks (6 cycles)Arm BCisplatin 25 mg/m2+ Gem 1000 mg/m224 weeks (8 cycles)Randomized 1:1(stratified by centre, primary site, PS, priortherapy and locally advanced vs. metastatic)Upon disease progression, management will be on cliniciansdiscretion (mostly best supportive care)D1,8 q 21d* Including 86 patients in ABC-01+ QoL 19. Main inclusion criteria: Histologically / cytologically verified disease Adequate biliary drainage, no uncontrolled infection ECOG PS 0-2 LFTs: bilirubin 1.5 x ULN, ALT/ AST/ alk phos 3 x ULN( 5 if liver metastases) Measureable disease was not mandated 20. Primaryendpoint:OVERALL SURVIVALSecondaryendpoints: Progression-free survival Toxicity Quality of life (EORTC QLQ C-30)Samplesize: Powered to detect increase inMS from 8 to 11 monthsLog-rank test with 80% powerand two-sided a 5% level 21. Toxicity by patient Gem Cis/Gemn % n %White blood cells 18 11.0% 24 15.1%Platelets 13 8.0% 13 8.2%Hemoglobin 6 3.7% 10 6.3%Neutrophils 29 17.9% 36 22.6%Infection + neutropenia 12 7.5% 16 10.2%Infection - neutropenia 14 8.6% 10 6.4% 22. Toxicity by patient Gem (n, %) Cis/Gem (n, %)Anorexia 4 2.5% 3 1.9%Lethargy 27 16.6% 29 18.6%Nausea 5 3.1% 5 3.2%Renal function 2 1.2% 3 1.9%Vomiting 8 3.0% 8 5.1%Constipation 3 1.8% 2 1.3%Diarrhea 4 2.5% 7 4.5%Dyspnea 2 1.2% 5 3.2%Pedal oedema 5 3.1% 4 2.6%Pain 12 7.5% 14 9.0%Any grade 3 events 108 65.5% 102 64.2% 23. ResultGemn (%)Gem + Cisn (%)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 24. Treatment arm Gem Gem + CisNumber of patients n=206 n=204PFS events n(%) 155 (75.2) 135 (66.2)Median PFS (mo) 6.5 8.4Log rank p value 0.003Hazard ratio (95% CI) 0.72 (0.57, 0.90) 25. ABC-02 - Results:Overall Survival (ITT)Treatment arm Gem Gem + CisNumber of patients n=206 n=204Deaths n(%) 141 (68.5) 122 (59.8)Median survival (mo) 8.3 11.7Log rank p value 0.002Hazard ratio (95% CI) 0.70 (0.54, 0.89) 26. Cisplatin and gemcitabine significantly improves overallsurvival compared with gemcitabine monotherapy (11.7vs. 8.3 months)Benefit gained with no clinically significant added toxicityCisGem is recommended as a worldwide standard ofcare and the backbone for further studiesCaution required in patients with PS > 2 27. Gastrointest Cancer Res. 2011;4(5-6):155-60. 28. Rogers JE, et al. J Gastrointest Oncol 2014 29. Agents Target Patients RR PFS AuthorCombination Regimens First line therapyGEMOX-cetuximabEGFR 51 - 61% (4 mths) MalkaGEMOX-bevacizumabVEGF 35 407 months(median)ZhuSingle Agent Regimens First or Second lineAZD6244MEK1/2 22 145.4 months(median)Bekaii-SaabErlotinibEGFR 43 72.6 months(median)Philip et alLapatinibEGFR/HER2 17 01.8 months(median)RamanathanSorafenibBRAF/VEGFR 36 62 months(median)El-KhoueirySorafenibBRAF/VEGFR 46 22.3 months(median)BengalaZhu et al, JCO, 2009 30. Bile Acids Induce EGFR in CCA cells via TGF- and COX-2Hepatol. 2004;41(5):808-14 31. Wide range reported k-ras mutation in biliarycancer (10-45%)More likely in anomalous pancreato-biliary ductsLess likely in the setting of pre-existing adenomaIn Wt k-ras, EGFR-directed TKIs or Monoclonalantibodies are a consideration 32. Endpoint EstimatePartial response 8%Stable disease 43%24- week progression-free 17%Overall survival 7.5 mosJ Clin Oncol. 2006 (19):3069-3074 33. GEMOX + Cetuximab 500 mg/m2 bi-weeklyPri-endpoint: 4 month PFS (60% study arm)101 pts enrolledInterim analysis: manageable toxicity4 mth PFS 44% vs 61% (Interim Analysis)J Clin Oncl 27:15s, 2009 34. 268 pts randomized: GEMOX +ErlotinibPR higher in erlotinib group (40 vs.21, p=0.005)Higher PFS with erlotinib (59months vs 30 months) (p=0049)Median overall survival was thesame in both groupsLancet Oncol. 2012;13(2):181-8. 35. Phase 2: GEMOX+ Bevacizumab (10 mg/kg bi-weekly)35 pts enrolledMedian PFS 7 months (6 months was 63%)Toxicities: neutropenia, hypertension, ASTelevation, neuropathyPartial responses or SD associated withsignificant improvement in SUVLancet Oncol Nov 2009 (Epub) 36. Sorafenib: 400 mg twice a day46 patients were treated; 26 (56%) had receivedchemotherapy earlierProgression-free survival (PFS) was 2.3 months (range:0-12 months)Median overall survival was 4.4 months (range: 0-22months).El Khoureiy, ASCO 2007 37. TherapeuticTargetChemotherapy Agent PhaseMEK Nil ARRY-438162;AZD6244IIRaf kinase GemOx Sorafenib IIVEGF+EGFRGemcitabine Vandetanib Randomized IIVEGFR Gemcitabine/CisplatinCediranib(AZD2171)RandomizedII/IIIEGFR Gemcitabine + Erlotinib,Cetuximab,PanitumamabII/Randomized 38. MRN Mutations1 PTEN TP53 ARID1A IDH12 MCL13 FBXW7 KRAS TP53 SMAD4 MLL2CREBB4 STK11KRAS MCL15 6 CDKN2A KRAS SMAD4 TP537 KRAS SMAD4 GRIN2A TP538 BAP1 CDKN2A/B PBRM19 PIK3CA KRAS MCL1 MYC10 ARID1A TSC211 BRAF PIK3R112 ARID1IDH113 KRAS ARID1A IDH214 15 16 KRAS FBXW7 ARID1A MSH2 TP5317 BAP118 KRAS19 KRAS FBXW7 TP5320 PTEN KRAS MDM221 KRAS TP5322 CDK4 MYC23 24 ERBB2 FBXW7 CDKN2A SMAD4TP5325 ERBB2 ATM SMAD426 KRAS TP5327 EGFR PIK3CA CCND1 TP5328 IDH129 MCL1 MYST330 IDH131 NRAS ARID1A IDH132 MDM2KRAS ARID233 PIK3CA MCL1 ARID1A CDH1 EPHA7EPHB1 MSH634 BAP134 BRCA1 PTCH FBXW735 FGFR3-TACC 39. 1.000.750.500.250.00Proportion Survivingp = 0.0280 6 12 18 24 30 36 42 48 54 60MonthsKRAS-NegativeKRAS-Positive 40. 33 patients with intrahepatic cholangiocaMedian tumor size - 8.8 cm88% previously chemotherapyDose: 50.4 Gy (range, 3570 Gy), most with xeloda1-year PFS: 47%, and 1-year OS: 62%1-year OS rate was 100% with RT dose 60 GyGastrointest Cancer Res. 2010 Nov-Dec; (Suppl 1): S34 41. Intrahepatic Cholangio: 67.5 Gy in15 fractions. No concurrentchemotherapyN=571 and 2-year OS is 69% and 58%PFS is 41% and 28%respectively. 42. Locoregional Therapy: Y9048 90Y treatments wereadministered to hepaticsegments or lobes.Fatigue, abdominal pain commonRare: grade 3 bilirubin toxicity,gastroduodenal ulcer.PR 6 pts (27%), SD 15 patients(68%), and PD in 1 patient (5%).Median OS was 14.9 months.OS for pts without and with priorchemo was 31.8 months and 4.4months, respectively (P = .02).Cancer. 2008;113(8):2119-28. 43. Vascularity is lower than HCC, thus limitingthe value of TACERetrospective Study 60 casesDEB-TACE: PFS of 3.9 mos, OS 11.7 mos,cTACE: PFS of 1.8 mos OS of 5.7 mosChemo (GEMOX): PFS of 6.2 mos and OSof 11.0 mosEur J Gastroenterol Hepatol. 2012 (4):437-43. 44. Ann Surg Oncol. 2013 Jul 12 45. Approach to management of intrahepatic cholangiocarcinomaPatel, T. (2011) Cholangiocarcinomacontroversies and challengesNat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2011.20 46. LocalizedInduction Chemofollowed byChemoRTDisseminatedSystemicChemotherapyNGSAdd targetedagents based onmolecularphenotypeClinical trials:MEK + PazopanibFGFR InhibitorProton TherapySelect caseswith SD/PR> 6mos on chemo,consider OLT(investigational)