1. Gemcitabine With or Without Cisplatin in Patients with Advanced or Metastatic Biliary Tract Cancer (ABC): Results of a Multicentre, Randomized Phase III Trial (The UK ABC-02 Trial) Valle JW et al. ASCO 2009; Abstract 4503. (Oral Presentation)

2. Source: Valle JW et al. ASCO 2009; Abstract 4503. Introduction Biliary tract cancers (BTC: cholangiocarcinoma, gall bladder cancer, ampullary cancer) are rare, lethal cancers with rising incidence –Cholangiocarcinoma, the most common BTC, accounts for 3% of all GI cancers globally (Vauthey Sem Liver Dis 1994) –5-year survival: 5-10% No standard of care exists for BTC –Few underpowered phase III chemotherapy studies –Small phase II studies, mostly 5-FU or gemcitabine-based ABC-01: Randomized Phase II study (N = 86) - Cisplatin (Cis)/Gemcitabine (Gem) appeared superior to Gem (GI Cancers Symposium 2006;Abstract 98) –6-mos PFS: 57.1% vs 47.7% –Median TTP: 8.0 mos vs 4.0 mos –ORR: 24% vs 15% –Tumor control rate: 76% vs 58% Current study objectives: –Prospectively evaluate the activity and safety of Cis/Gem vs Gem in patients with advanced or metastatic BTC in a large, multicenter phase III study

3. ABC-02: Phase III Multicenter Study (N = 410*) Eligibility Histologically/cytologically verified disease Adequate biliary drainage No uncontrolled infection LFTs: bilirubin < 1.5 x ULN, ALT/AST/alk phos < 3 x ULN (< 5 if liver metastases) No prior systemic treatment R Gemcitabine 1,000 mg/m 2 Cisplatin 25 mg/m 2 D1, 8 q21 days 24 weeks (8 cycles) Primary site: Gallbladder/bile duct/ampulla 36%/60%/4% Gemcitabine 1,000 mg/m 2 D1, 8, 15 q28 days 24 weeks (6 cycles) Primary site: Gallbladder/bile duct/ampulla 37%/58%/5% Source: Valle JW et al. ASCO 2009; Abstract 4503. Upon disease progression, management will be at clinician’s discretion (mostly best supportive care) *Includes 86 patients from ABC-01

4. Grade 3/4 Adverse Events Adverse event Gem (n = 165) Cis/Gem (n = 159) Any Grade 3/4 event65.5%64.2% Anorexia2.5%1.9% Lethargy16.6%18.6% Nausea3.1%3.2% Renal function1.2%1.9% Vomiting3.0%5.1% Constipation1.8%1.3% Diarrhea2.5%4.5% Dyspnea1.2%3.2% Pedal edema3.1%2.6% Pain7.5%9.0% Source: Valle JW et al. ASCO 2009; Abstract 4503.

5. Additional Grade 3/4 Adverse Events Adverse event Gem (n = 165) Cis/Gem (n = 159) Bilirubin13.1%10.7% ALT18.1%9.6% AST11.4%8.2% Infection (with neutropenia)7.5%10.2% Infection (without neutropenia)8.6%6.4% Hematologic Gr 3/4 event WBC11.0%15.1% Platelets8.0%8.2% Hemoglobin3.7%6.3% Neutrophils17.9%22.6% Source: Valle JW et al. ASCO 2009; Abstract 4503.

6. Radiologic Response: Investigator-Assessed Gem N (%) Cis/Gem N (%) Not assessed*74 (36%)56 (27%) Assessed*132 (64%)148 (73%) GemCis/Gem Complete response (CR)0.8%0.7% Partial response (PR)15.2%25.0% Stable disease (SD)55.3%53.4% Progressive disease25.0%18.9% Clinical benefit (CR + PR + SD)94 (71.2%)117 (79.1%) p-value = 0.256 Source: Valle JW et al. ASCO 2009; Abstract 4503. *Patients not required to have measurable disease at study entry and some patients still in follow-up

7. Progression-Free Survival: Intention-to-Treat Source: With permission from Valle JW. ASCO 2009; Abstract 4503. Treatment armGemGem + Cis Number of patientsn = 206n = 204 PFS events n (%)155 (75.2)135 (66.2) Median PFS (mo)6.58.4 Log rank p value0.003 Hazard ratio (95% CI)0.72 (0.57, 0.90) Progression- free survival 1.00 0.75 0.50 0.25 0.00 Gemcitabine Gemcitabine + Cisplatin 0100200300400500600700800900 1000 Follow up time (days)

8. Overall Survival: Intention-to-Treat Source: With permission from Valle JW. ASCO 2009; Abstract 4503. 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) Survival 1.00 0.75 0.50 0.25 0.00 0100200300400500600700800900 1000 Follow up time (days) Gemcitabine Gemcitabine + Cisplatin

9. Summary and Conclusions Cis/Gem significantly improves OS and PFS compared to Gem –Median OS: 11.7 mos vs 8.3 mos –Reduced risk of death by 30% (HR = 0.70, p = 0.002) –Median PFS: 8.4 mos vs 6.5 mos –Reduced risk of disease progression by 28% (HR = 0.72, p = 0.003) First demonstration of a survival benefit in advanced BTC Benefit gained without additional clinically significant toxicity –Lethargy is the most common Grade 3/4 AE in both arms: Cis/Gem (18.6%) and Gem (16.6%) –Slight excess of Grade 3/4 neutropenia with Cis/Gem vs Cis: 22.6% vs 17.9%, respectively –Therapy withdrawal due to toxicity: Cis/Gem n=8, Gem n=11 Cis/Gem is recommended as a worldwide standard of care and should serve as the backbone of future studies Source: Valle JW et al. ASCO 2009; Abstract 4503.