1. Treatment of Biliary Cancers Abby B. Siegel, MD, MS Columbia University Co-Chair, SWOG Hepatobiliary Committee NCI Task Force, Hepatobiliary Cancers

2. Biliary Anatomy Adapted from De Groen et al, NEJM 1999 Oct 28;341(18):1368-78

3. Treatment armGemGem + Cis Number of patientsn=206n=204 Deaths n(%) 141 (68.5)122 (59.8) Median survival (mo)8.311.7 Log rank p value0.002 Hazard ratio (95% CI)0.70 (0.54, 0.89) Gemcitabine With or Without Cisplatin in Advanced or Metastatic Biliary Cancer (UK ABC-02 trial)

4. Gemcitabine/Cisplatin in Perspective A standard for advanced disease Study results influenced by: GB vs IHCC vs EHCC Included ampullary cancers Patient selection: –AST/ALT/Alk phos<3XULN –T Bili < 1.5 ULN –Accrual in select centers with experience –27% locally advanced disease Caution about using Gem/cis as the only backbone in first line therapy What about other effective therapies: Gem/cape?

5. Single Agent Targeted Therapy TargetAgents in testingStudy type# of patientsResults VEGF/Ras-Raf- MAPK Sorafenib (SWOG 0514) Phase II single agent NCT01093222 N=31Median PFS 3 mo Median OS 9 mo SorafenibPhase II single agent NCT00238212 N=46Median PFS 2.3 mo Median OS 4.4 mo EGFR/Her-2 neuTrastuzumabPhase II single agentClosed d/t slow accrual 1CR ErlotinibPhase II single agent NCT00033462 N=42Median TTP 2.6 mo Median OS 7.5 mo LapatinibPhase II single agentN=17Median PFS 1.8 mo Median OS 5.2 mo mTORSirolimusPhase II single arms for HCC and ICC N=93/9 SD Median survival 7 mo MEKMEK-162Phase IN=261CR AZD6244Phase II single agentN=281 CR Median TTP 5.4 mo AKTMK-2206Phase II single agent (Second line) On-going Bengala C et al, British Journal of Cancer 2010,102: 68 – 72; Rizell et al, Int J Clin Oncol 2007 13:66-70 Philip, P. A. et al. J Clin Oncol 2006, 24:3069-3074, Ramantaan et al, Cancer Chemother Pharmacol 2009 64:777–783

6. Combination Targeted Agents TargetsAgentsStudy typeNumber of patients Results VEGF/EGFRBevacizumab and Erlotinib Phase II (Ph II consortium) 34 pts (interim report) RR 17% Median TTP 8 months Bevacizumab and Erlotinib Phase II (Wisconsin) NCT00356889 53RR 12% Median TTP 4.4 OS 9.9 months Bevacizumab and Erlotinib Phase II (Denmark) NCT00350753 On-going VEGF/EGFR Ras/Raf Sorafenib and Erlotinib Phase II (SWOG0941) NCT01093222 32RR 6% (unconf) PFS 2 months OS 6 months

7. Cytotoxic Chemotherapy with Targeted Agents CombinationTargeted agent(s) Study typeNumberResults Gemcitabine, oxaliplatin CetuximabRand Phase II150RR 29% Median PFS 6 mo Median OS 12.4 mo Gemcitabine, oxaliplatin ErlotinibPhase III268RR 30% Median PFS 5.8 mo Median OS 9.5 mo Gemcitabine, oxaliplatin BevacizumabPhase II35RR 40% PFS 8.8 mo OS 11.6 mo Gemcitabine, oxaliplatin, capecitabine PanitumumabPhase II NCT00779454 On-going Gemcitabine, oxaliplatin SorafenibPhase II NCT00955721 On-going Gemcitabine, cisplatin SorafenibPhase II (MSK) NCT00919061 On-going Gemcitabine, capecitabine BevacizumabPhase II NCT01007552 On-going GemcitabineVandetanib (VEGFR/EGFR) Randomized Phase II NCT00753675 On-going

8. Adjuvant Therapy for Biliary Cancers No clear prospective randomized data Best evidence so far is a meta-analysis 6712 patients, non significant improvement in OS for any adjuvant therapy (HR 0.74, p=0.06)

9. Adjuvant Therapy for Biliary Cancer: Horgan A M et al. JCO 2012;30:1934-1940

10. Adjuvant Therapy for Biliary Cancers No large randomized trials yet, and no clear guidelines Metaanalysis suggests possible benefit of chemotherapy for all, particularly for node (+) and margin positive disease Radiation is often added in margin (+) disease I usually give 6 months gem or gem/cis for margin (-), consider XRT + chemo for margin (+) disease; consider re-resection also Horgan et al. JCO 2012;30:1934-1940

11. Adjuvant Therapy: SWOG 0809 Eligibility –Gallbladder cancer or EHCC –At least one of the following: T2-T4 N1 Positive margins Gemcitabine 1000 mg/m2 IV over 30 min D1 and D8 + Capecitabine 750 mg/m2 PO BID x 14 days X 4 cycles Gemcitabine 1000 mg/m2 IV over 30 min D1 and D8 + Capecitabine 750 mg/m2 PO BID x 14 days X 4 cycles Concurrent EBRT with Capecitabine 665 mg/m2 BID x 7 days For 6 weeks 4500 cGy (5 days a week, 180 cGy daily) with 900 cGy boost Concurrent EBRT with Capecitabine 665 mg/m2 BID x 7 days For 6 weeks 4500 cGy (5 days a week, 180 cGy daily) with 900 cGy boost

12. Adjuvant Therapy in Biliary Cancers: Current Landscape BILCAP (UK): Phase 3: capecitabine versus observation in GB, IHCC, EHCC (n=360) French phase 3 study: gemcitabine and oxaliplatin versus observation in GB, IHCC, EHCC (n=190) ACTICCA-01: Phase 3: adjuvant gemcitabine and cisplatin versus BSC or capecitabine (depends on BILCAP)

13. Potential New Targets in Cholangiocarcinoma MEK IDH1/2 FGFR

14. MEK Inhibition in Cancer Therapy RAS-RAF-MEK pathway implicated in many tumors B-Raf mutations: 0-22% Bile duct tumors K-Ras mutations 3-54% Bile duct tumors H-Ras K-Ras N-Ras A-RafB-RafC-Raf MEK1&2 ERK1&2 Receptor Tyrosine Kinase Mutated and activated in multiple cancers Activation of Transcription/Proliferation

15. MEK Inhibitors in Biliary Cancer TreatmentTargetNo. of Patients RR (%)PFS (months) OS (months) Toxicity Profile ( grade 3 and 4) AZD6244 (first and second line) MEK 1/2 2812 1 CR 5.49.8Fatigue (8%), diarrhea ( 16%), rash, cellulitis No ocular toxicities reported MEK162 (ARRY- 438162) (first and second line) MEK 1/2 26 eval8 1 CR 2.6N/AAnasarca, hypokalemia, hyponatremia, upper/lower gastrointestinal hemorrhage and mucositis (1 pt each) Retinopathy was the most frequently reported event (6 pts) Bekaii-Saab et al. JCO 2011 29:2357-63, Finn et al, GI ASCO 2012

16. Mek Inhibition Second Line: Trametinib (SWOG 1310) Patients with refractory advanced biliary cancer who have failed one prior line of treatment Randomize 5-FU or capecitabine a (N = 40) Single Agent Trametinib (2mg QD) (N=40)

17. IDH Pathway Yen et al, Oncologist 2012 17:5-8 Yen et al, Oncologist 2012 17:5-8

18. IDH Mutations Seen in Cholangiocarcinomas Borger et al, Oncologist, 2010 17:72-79 Borger et al, Oncologist, 2010 17:72-79

19. IDH Inhibitors Isocitrate dehydrogenase mutations lead to production of 2-hydroxyglutamate 2HG as potential non-invasive biomarker of response –Plasma –MRS Inhibitors being actively developed

20. FGFR2 Fusions Define a Unique Molecular Subtype of Cholangiocarcinoma Wu Y et al. Cancer Discovery 2013;3:636-647, Arai et al, Hepatology 2013, EPUB ahead of print

21. Optimizing the Evaluation of Targeted Agents in Cholangiocarcinoma Choosing the “relevant” target(s) or combination of targets Having appropriate preclinical models Stratifying by site if target differs based on location Enriching clinical trial population for target