Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer Eric Van Cutsem* Y-K Kang, HC Chung, L Shen, A Sawaki, F Lordick, J Hill, M Lehle, A Feyereislova, Y-J Bang *University Hospital Gasthuisberg, Leuven, Belgium

Disclosure slide Research funding/advisory board: Amgen Merck KGaA Novartis Pfizer Roche Sanofi-Aventis

Rationale for trastuzumab in HER2-positive GC There is no universal standard treatment, but fluoropyrimidine (capecitabine / 5-FU) / platinum (cisplatin / oxaliplatin)-based chemotherapy considered as reference regimen epirubicin or docetaxel sometimes added biologicals are under investigation Unmet need for new treatment options in advanced gastric cancer Some gastric adenocarcinomas are HER2 positive Trastuzumab is effective against HER2-overexpressing GC cell lines in vitro and in vivo References Ross JS, McKenna BJ. Cancer Invest 2001; 19: 554–568. Shinohara H et al. J Surg Res 2002; 102: 169–177. Allgayer H et al. J Clin Oncol 2000; 18: 2201–2209. Fujimoto-Ouchi K et al. Cancer Chemother Pharmacol 2007; 59: 795-805. Slamon DJ et al. N Engl J Med 2001; 344: 783-792. Marty M et al. J Clin Oncol 2005; 23: 4265-4274. Smith I et al. Lancet 2007; 369: 29-36. Gravalos C, Jimeno A. Ann Oncol 2008; 19: 1523-1529. Fujimoto-Ouchi et al 2007; Gravalos & Jimeno 2008

HER2 and trastuzumab mechanism of action HER2 receptor trastuzumab Trastuzumab Inhibits HER2-mediated signalling in HER2-positive tumors Prevents HER2 activation by blocking extracellular domain cleavage Activates antibody-dependent cellular cytotoxicity

ToGA trial design Phase III, randomized, open-label, international, multicenter study 5-FU or capecitabinea + cisplatin (n=290) 3807 patients screened1 810 HER2-positive (22.1%) HER2-positive advanced GC (n=584) R 5-FU or capecitabinea + cisplatin + trastuzumab (n=294) Stratification factors advanced vs metastatic GC vs GEJ measurable vs non-measurable ECOG PS 0-1 vs 2 capecitabine vs 5-FU Eligibility criteria for the ToGA trial include: >18 years of age, HER2-positive histologically confirmed gastric cancer or gastro-oesophageal adenocarcinoma, with inoperable, locally advanced or recurrent and/or metastatic disease. The ToGA trial planned to recruit 584 patients. An additional 10 patients, who had already signed the informed consent form when the screening cut-off was reached, were allowed to enter the trial, resulting in a total of 594 patients recruited. The primary end point is overall survival in the two treatment arms. Secondary end points include progression-free survival, overall response rate, clinical benefit rate, duration of response and safety profile. aChosen at investigator’s discretion GEJ, gastroesophageal junction 1Bang et al; Abstract 4556, ASCO 2009

Treatment regimens Capecitabine 1000 mg/m2 bid d1-14 q3w x 6 5-Fluorouracil 800 mg/m2/day continuous iv infusion d1-5 q3w x 6 Cisplatin 80 mg/m2 q3w x 6 Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg q3w until PD

ToGA trial end points Primary end point: Secondary end points overall survival Secondary end points PFS, TTP, ORR, Clinical Benefit Rate, Duration of Response, QoL, safety, pain intensity, analgesic consumption, weight change, pharmacokinetics Sample size assumptions median OS improvement from 10 to 13 months (HR 0.77) α-level = 0.05, 80% power required sample size: 584 patients randomized 1:1 Analyses 1st pre-planned interim analysis after 230 events (50%) 2nd interim analysis after 345 events (75%) considered final by Independent Data Monitoring Committee Eligibility criteria for the ToGA trial include: >18 years of age, HER2-positive histologically confirmed gastric cancer or gastro-oesophageal adenocarcinoma, with inoperable, locally advanced or recurrent and/or metastatic disease. The ToGA trial planned to recruit 584 patients. An additional 10 patients, who had already signed the informed consent form when the screening cut-off was reached, were allowed to enter the trial, resulting in a total of 594 patients recruited. The primary end point is overall survival in the two treatment arms. Secondary end points include progression-free survival, overall response rate, clinical benefit rate, duration of response and safety profile.

Main patient selection criteria Inclusion criteria Adenocarcinoma of stomach or GEJ Inoperable locally advanced and/or metastatic disease Measurable (RECIST), or non-measurable evaluable disease HER2-positive tumor (centrally assessed) IHC 3+ and/or FISH+ Adequate organ function and ECOG performance status ≤2 Written informed consent Exclusion criteria Previous adjuvant chemotherapy within 6 months Chemotherapy for advanced disease Congestive heart failure or baseline LVEF <50% Creatinine clearance <60 mL/min IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction

Patient demographics and baseline characteristics F+C n=290 F+C + trastuzumab n=294 Sex, % Male / Female 75 / 25 77 / 23 Age, median (range) years 59.0 (21-82) 61.0 (23-83) Weight, median (range) kg 60.3 (28-105) 61.5 (35-110) Region, n (%) Asia C/S America Europe Other 166 (56) 26 (9) 95 (32) 9 (3) 158 (53) 27 (9) 99 (33) 14 (5) Type of GC (central assessment) Intestinal Diffuse Mixed 74.2a 8.7a 17.1a 76.8b 8.9b 14.3b Prior gastrectomy 21.4 24.1 Highest recruitment was from Korea, Japan, China and Russia F, fluoropyrimidine; C, cisplatin an=287; bn=293

Stratification factors Characteristic, % F+C n=290 F+C + trastuzumab n=294 Metastatic disease 96.6 Measurable disease 88.6 91.5 Primary site Stomach GE junction 83.4 16.6 80.3 19.7 ECOG PS 0 1 2 36.2 54.5 9.3 34.4 55.4 10.2 Fluoropyrimidine Capecitabine 5-FU 87.9 12.1 87.1 12.9

Primary end point: OS Event 1.0 Median OS 13.8 11.1 0.9 Events 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 11.1 13.8 0.1 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 1 T, trastuzumab

Secondary end point: PFS Event 1.0 Median PFS 6.7 5.5 Events 226 235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 0.9 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 0.1 5.5 6.7 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (months) No. at risk 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 2

Secondary end point: tumor response rate Intent to treat Patients (%) p=0.0017 F+C + trastuzumab p=0.0145 F+C 47.3% 41.8% 34.5% 32.1% p=0.0599 5.4% 2.4% CR PR ORR ORR= CR + PR CR, complete response; PR, partial response

Efficacy: OS subgroup analysis Category Subgroup N 95% CI HR All 584 0.60, 0.91 0.74 GEJ Primary site 106 0.42, 1.08 0.67 Stomach 478 0.60, 0.96 0.76 0-1 ECOG PS 527 0.56, 0.89 0.71 2 57 0.51, 1.79 0.96 Fluoropyrimidine 5-FU 73 0.40, 1.23 0.70 Capecitabine 511 0.60, 0.95 0.75 279 0.84 <60 Age group 0.62, 1.14 >60 305 0.49, 0.88 0.66 Region Asia 319 0.61, 1.11 0.82 C/S America 52 0.21, 0.90 0.44 Europe 190 0.44, 0.89 0.63 Other 23 0.48, 3.08 1.22 Diffuse GC type 51 0.56, 2.05 1.07 Intestinal 438 0.54, 0.88 0.69 Mixed 91 0.51, 1.46 0.86 No Yes Prior gastrectomy 451 133 0.72 0.81 0.57, 0.91 0.49, 1.34 1-2 No. metastatic sites 298 0.68, 1.26 0.93 >2 285 0.43, 0.77 0.57 HER2 result IHC 0/FISH+ 61 0.48, 1.76 0.92 IHC 1+/FISH+ 70 0.70, 2.20 1.24 IHC 2+/FISH+ 159 0.51, 1.11 0.75 IHC 3+/FISH+ 256 0.41, 0.81 0.58 IHC 3+/FISH- 15 0.20, 3.38 0.83 0.2 0.4 0.6 1 2 3 4 5 Favors T Risk ratio Favors no T

Efficacy: OS by HER2 status Subgroup Median OS (months) Hazard ratio 95% CI 0.2 0.4 0.6 1 2 3 4 5 N All 584 11.1 vs 13.8 0.74 0.60, 0.91 Pre-planned analysis IHC0/FISH+ IHC1+/FISH+ IHC2+/FISH+ IHC3+/FISH+ IHC3+/FISH- 61 70 159 256 15 7.2 10.2 10.8 12.3 17.7 vs 10.6 8.7 12.3 17.9 17.5 0.92 1.24 0.75 0.58 0.83 0.48, 1.76 0.70, 2.20 0.51, 1.11 0.41, 0.81 0.20, 3.38 Exploratory analysis IHC0 or 1+/FISH+ IHC2+/FISH+ or IHC3+ 131 446 8.7 11.8 vs 10.0 16.0 1.07 0.65 0.70, 1.62 0.51, 0.83 Favors T Risk ratio Favors no T

OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) Event 1.0 Median OS 16.0 11.8 Events 120 136 HR 0.65 95% CI 0.51, 0.83 0.9 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 0.1 11.8 16.0 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 228 218 218 198 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5 3 4 1

Exposure to trial treatments F+C n=290 F+C + trastuzumab n=294 Median Range Trastuzumab Cycles Treatment duration, months Dose intensity, % 8 4.9 100.1 1-49 0.03-33.21 84.8-156.7 Cisplatin Cycles Treatment duration, months Dose intensity, % 5 3.4 91.1 1-16 0.03-15.19 23.5-103.7 6 3.5 89.4 1-14 0.03-12.89 52.0-108.6 Capecitabine Cycles Treatment duration, months Dose intensity, % 3.9 86.7 1-20 0.03-15.65 3.6-110.0 85.9 1-20 0.10-16.83 14.3-107.5 5-FU Cycles Treatment duration, months Dose intensity, % 4 2.9 95.7 1-11 0.13-7.56 33.4-102.0 3.6 98.3 1-6 0.16-5.10 61.1-101.5 Treatment duration converted from days to months by dividing by 365/12=30.416

2nd-line treatment received after progression Treatment, n (%) F+C n=290 F+C + trastuzumab n=294 Patients receiving any therapy 131 (45) 122 (42) Chemotherapy 124 (43) 113 (38) Cytotoxic therapy received by >5% of patients Docetaxel Paclitaxel 5-FU Irinotecan Cisplatin Oxaliplatin S-1 40 (14) 35 (12) 52 (18) 56 (19) 21 (7) 20 (7) 38 (13) 53 (18) 47 (16) 14 (5) 22 (7) HER2 targeting therapy Lapatinib Trastuzumab 3 (1) 2 (<1) 4 (1) 3 (1) Radiotherapy 17 (6) Surgery 13 (4) 8 (3)

Cause of death F+C n=290 F+C + trastuzumab n=294 Total deaths, n (%) 182 (63) 167 (57) Deaths due to progressive disease, n (%) 148 (50) 60-day mortality, n (%) 20 (7) 15 (5) Treatment-related mortality, n (%) 3a (1) 10b (3) Treatment related deaths 3 in chemotherapy arm: sepsis, death, pancytopenia. 10 in trastuzumab + chemotherapy arm: 2 pneumonia, 1 MI, 1 angina unstable and 1 cardiac failure in same patient,  1 gastric haemorrhage, 2x death, 1 depressed level of consciousness, 1 thrombocytopenia, 1 renal failure. Please note that 1 patient reported death due to angina unstable and cardiac failure, investigator could not identify which one lead to death. The events ´death´ are unknown cases although queried several times. aSepsis, pancytopenia, unknown bPneumonia (2), myocardial infarction, angina unstable and cardiac failure in same patient, gastric hemorrhage, depressed level of consciousness, thrombocytopenia, renal failure, unknown (2)

Safety: hematological AEs F+C n=290 F+C + trastuzumab n=294 All Grade 3/4 Neutropenia Febrile neutropenia Anemia Thrombocytopenia 57 3 21 11 30 10 53 5 28 16 27 12 AE, adverse event

Safety: non-hematological AEs F+C n=290 F+C + trastuzumab n=294 All Grade 3/4 Nausea Vomiting Fatigue Diarrhea Constipation Asthenia Stomatitis Weight decrease Abdominal pain 63 46 28 32 18 15 14 7 8 2 4 3 1 67 50 35 37 26 19 24 23 16 6 9 <1 AEs occurring in >10% of patients

Safety: cardiac AEs Cardiac event, n (%) F+C (n=290) F+C + trastuzumab (n=294) All Grade 3/4 Cardiac AEs, total 18 (6) 9 (3) 17 (6) 4 (1) Cardiac failure 2 (<1) 1 (<1) Asymptomatic LVEF dropsa <50% <50% and by 10% 2 (1.1) 2 (1.1) 14 (5.9) 11 (4.6) Cardiac AEs leading to death 2 (<1) Cardiac arrest; cardio-respiratory arrest 2 (<1) Acute MI; angina unstable and cardiac failure Cardiac AEs related to treatment aMeasured at baseline and every 12 weeks; MI, myocardial infarction

Summary ToGA met the primary end point trastuzumab reduces the risk of death by 26% when combined with a reference chemotherapy (HR 0.74) prolongs the median survival by nearly 3 months (11.1 to 13.8 months; p=0.0046) in patients with HER2-positive advanced GC All secondary efficacy parameters (PFS, TTP, ORR, CBR, DoR) were also significantly improved Addition of trastuzumab to chemotherapy was well tolerated: there was no difference in overall safety profile, including cardiac AEs, between treatment arms

Conclusions Trastuzumab is the first biological to show a survival benefit in advanced gastric cancer Trastuzumab in combination with chemotherapy is a new treatment option for patients with HER2-positive advanced gastric adenocarcinoma

ToGA trial: acknowledgements to the patients the investigators, co-investigators, and study teams at the 142 centers in 24 countries (Asia, Australia, Europe, Latin-America, South Africa) the study team at Roche my team in Leuven my wife and 3 daughters 25