Use Irinotecan or a Taxane for nd Line

Use Irinotecan or a Taxane for nd Line GE Cancer Therapy: 2 Don’t Use What Dr. Fuchs Tells You to Use Jordan D. Berlin, M. D. Ingram Professor of Cancer Research Co-director, GI Oncology Director, Phase I Research Vanderbilt-Ingram Cancer Center

Disclosures • Advisory Boards here and there in last year – – – – – Genentech/Roche Karyopharm Amgen Astra Zeneca BMS Lilly/Imclone Symphogen Celgene Vertex Ipsen • Current Research Support – Amgen, Lilly/Imclone, Pfizer, Novartis, Abbvie, Immunomedics, Otsuka, Merrimack, Oncomed, Genentech/Roche, Taiho

So what is the data for second-line chemotherapy?

AIO: Small trial of irinotecan vs BSC Fig. 2 Overall survival (intention to treat population) Median survival Irinotecan: 4. 0 months, BSC: 2. 4 months; one sided logrank test: p = 0. 012; HR: 0. 48 (95% CI: 0. 25– 0. 92). Peter C. Thuss-Patience , Albrecht Kretzschmar , Dmitry Bichev , Tillman Deist , Axel Hinke , Kirstin Breithaupt , . . . European Journal of Cancer, Volume 47, Issue 15, 2011, 2306 - 2314

Salvage Chemotherapy for Pretreated Gastric Cancer: A Randomized Phase III Trial Comparing Chemotherapy Plus Best Supportive Care With Best Supportive Care Alone Jung Hun Kang, Soon Il Lee, Do Hyoung Lim, Keon. Woo Park, Sung Yong Oh, Hyuk-Chan Kwon, In Gyu Hwang, Sang-Cheol Lee, Eunmi Nam, Dong Bok Shin, Jeeyun Lee, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang and Se Hoon Park⇑ JCO Aug 20, 2012: 3035

Next 2 nd line Chemotherapy (SLC) RCT Screening & consent for RCT Refused RCT, but prefer SLC Willing to participate RCT Refused RCT, but prefer BSC 2: 1 randomization SLC Docetaxel or irinotecan BSC SLC N = 202 RCT + PPT Clinical. Trials. gov, NCT 00821990 BSC RCT: randomized controlled trial PPT: patient-preference trial From Park ASCO 2011

Kaplan-Meier estimates for overall survival in randomly assigned patients. OS 5. 3 vs 3. 8 months, HR 0. 66, p = 0. 007 Kang J H et al. JCO 2012; 30: 1513 -1518 © 2012 by American Society of Clinical Oncology

COUGAR-02: Randomised phase III study of docetaxel versus active symptom control in patients with relapsed esophago-gastric adenocarcinoma N Cook, A Marshall, JM Blazeby, JA Bridgewater, J Wadsley, FY Coxon, W Mansoor, S Madhusudan, S Falk, GW Middleton, D Swinson, I Chau, J Thompson, D Cunningham, P Kareclas, JA Dunn, HER Ford On behalf of COUGAR 02 investigators and NCRI Upper GI Clinical Studies Group Trial funded by Cancer Research UK grant CRUK/07/013 Eudra. CT Number: 2006 -005046 -37 ISRCTN 13366390

Trial Design Arm A (n=84): Docetaxel 75 mg/m 2 IV every 3 weeks for up to 6 cycles + ASC Adenocarcinoma of esophagus, esophagus-gastric junction or stomach refractory to platinum and fluoropyrimide Stratified by: Assess every 3 weeks for 18 weeks, then every 6 weeks RANDOMISE 1: 1 n=168 Arm B (n=84): Active symptom control May include: Radiotherapy, analgesia, anti-emetics, steroids 1. Disease status (Locally advanced vs metastatic); 2. Site of disease (Esophagus vs GEJ vs Stomach); 3. Time to progression after previous chemotherapy ( 0 vs 0 -3 vs 3 -6 months); 4. ECOG PS ( 0/1 vs 2)

Overall survival Median survival: 5. 2 months (95% CI 4. 1 -5. 9) for Docetaxel 3. 6 months (95% CI 3. 3 -4. 4) for ASC Hazard ratio 0. 67 (95% CI 0. 49 -0. 92), p=0. 01

This is a difficult population to treat Docetaxel BSC 23% 36% Death 15% 38% PD 40% 2% Tox 31% N/A Treatment N/A 14% Completed 18 weeks Reason off • These patients are sick • Most do not complete treatment plan • We still need to learn how best to select patients who will benefit

Randomized phase III study of irinotecan (IRI) versus weekly paclitaxel (w. PTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG 4007 trial Ueda S, Hironaka S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I, Gastrointestinal Group of West Japan Oncology Group

WJOG 4007 Trial – Second line chemotherapy for metastatic gastric cancer AGC refractory to prior FP confirmed by imaging Age 20 -75, PS 0 -2, No history of CPT-11 or Taxane RANDOMIZATION Stratified by Institution, PS 0 -1/2, target lesion -/+ weekly Paclitaxel IRI 80 mg/m 2 d 1, 8, 15 q 4 w 150 mg/m 2 d 1, 15 q 4 w Ueda ASCO 2012

Progression Free Survival n Median HR (95% CI) Probability (%) w. PTX 2. 3 3. 6 M IRI 3. 6 108 111 2. 3 M 1. 14 (0. 88 -1. 49) 0. 33 Log-rank test (Months) Number at risk w. PTX IRI P 108 111 66 46 16 18 9 8 3 6 2 2 2 1 0 0 FAS

Overall Survival n Median HR (95% CI) P 108 9. 5 M IRI Probability (%) w. PTX 111 8. 4 M 1. 13 (0. 86 -1. 49) 0. 38 Log-rank test (Months) Number at risk w. PTX IRI 108 111 80 75 36 29 10 10 2 3 0 1 Udea ASCO 2012

Reasons for Treatment Discontinuation w. PTX Total (n=106) Disease Progression IRI (n=110) (n=216) 93 ( 88%) 96 ( 87%) 189 Adverse Event 6 ( 6%) 10 ( 9%) 16 Withdraw 5 ( 5%) 2 ( 2%) 7 Death 1 ( 1%) 2 Other 1 ( 1%) 2 PPS

Post-Study Chemotherapy (3 rd line) w. PTX IRI (n=108) (n=111) Received 3 rd line CT 97 (90%) 80 (72%) CPT-11 containing 81 (75%) 5 ( 5%) Taxane containing 8 ( 7%) 67 (60%) Others 8 ( 7%) P 0. 001 Fisher’s exact test FAS

FROM KANG STUDY SHOWN EARLIER Kaplan-Meier estimates for overall survival in patients treated with best supportive care (BSC), docetaxel, or irinotecan. Kang J H et al. JCO 2012; 30: 1513 -1518 © 2012 by American Society of Clinical Oncology

Chemotherapy Conclusions • Basically, it works – It is not super, but HR of 0. 67 or better fairly consistently – Either irinotecan or taxane—both are reasonable – Don’t give both at the same time. That’s just mean • Probably works best in highly selected patients as in the WJOG study – PS 0 -1 – Doubtful it benefits PS = 2 – But it would be nice to have more selection factors

Phase 3 Trial of Everolimus in Previously Treated Patients With Advanced Gastric Cancer: GRANITE -1 Eric Van Cutsem*, K. H. Yeh, Y. J. Bang, L. Shen, J. A. Ajani, Y. X. Bai, H. C. Chung, H. M. Pan, K. Chin, K. Muro, Y. H. Kim, H. Smith, C. Constantini, S. Rizvi, T. Sahmoud, A. Ohtsu On behalf of the GRANITE-1 Investigators * University Hospital Leuven/Belgium Presented at the 2012 Gastrointestinal Cancers Symposium. 20

Overall Survival (FAS) Probability of overall survival (%) 100 Censoring Times Everolimus + BSC (n/N = 352/439) Placebo + BSC (n/N = 180/217) 80 Everolimus + BSC: 5. 39 months Placebo + BSC: 4. 34 months 60 Hazard ratio: 0. 90 (95% CI, 0. 75 -1. 08) Log-rank P value = 0. 1244 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 16 13 12 18 6 8 20 3 4 22 1 1 24 0 0 Time (months) No. of patients still at risk Time (months) 0 Everolimus 439 217 Placebo 2 355 172 4 253 117 6 195 82 8 139 60 10 87 35 12 52 28 14 30 16 21

Figure 2 Kaplan-Meier estimates of overall survival (A) and progression-free survival (B) REGARD TRIAL OS HR = 0. 776 The Lancet, Volume 383, Issue 9911, 2014, 31 - 39 Charles S Fuchs , Jiri Tomasek , Cho Jae Yong , Filip Dumitru , Rodolfo Passalacqua , Chanchal Goswami , Howard S. . . http: //dx. doi. org/10. 1016/S 0140 -6736(13)61719 -5 Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial

Let’s Compare: Trials vs BSC Chemotherapy Targeted Therapy AIO (irinotecan) HR 0. 48 Granite-1 (everolimus) HR 0. 90 Kang (irinotecan or docetaxel) HR 0. 66 REGARD (ramucirumab) HR 0. 776 Cougar-02 (docetaxel) HR 0. 67 It all comes down to hazard ratio: For chemotherapy, it is very consistent, but for targeted agents, it is consistently not as good

So, if I were Dr. Fuchs, I would concede defeat and “If you can’t beat ‘em, join ‘em”

RAINBOW: A Global, Phase 3, Randomized, Double-Blind Trial of Ramucirumab and Paclitaxel (PTX) Versus Placebo and PTX in the Treatment of Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma Following Disease Progression on First-Line Platinum- and Fluoropyrimidine-Containing Combination Therapy H. Wilke* Eric Van Cutsem, Sang Cheul Oh, György Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg Lipatov, Tae You Kim, David Cunningham, Atsushi Ohtsu, Philippe Rougier, Michael Emig, Roberto Carlesi, Kumari Chandrawansa, Kei Muro *On behalf of the RAINBOW Investigators

26 RAINBOW: Randomized Phase III Trial 2 nd Line Paclitaxel +/- Ramucirumab Paclitaxel 80 mg/m 2 d 1, 8, 15 + Ramucirumab IV q 2 weeks Second line metastatic gastric and GEJ adenocarcinoma R 1: 1 Paclitaxel 80 mg/m 2 d 1, 8, 15 + Placebo q 2 weeks Primary EP: OS N = 665

RAINBOW: Overall Survival HR (95% CI) = 0. 807 (0. 678, 0. 962) Stratified log rank p-value = 0. 0169 Patients / Events Median(mos) (95% CI) 6 -month OS 12 -month OS RAM + PTX PBO + PTX 330 / 256 335 / 260 9. 63 (8. 48, 10. 81) 7. 36 (6. 31, 8. 38) 72% 57% 40% 30% Δ m. OS = 2. 3 months Censored No. at risk RAM + PTX PBO + PTX 330 335 308 294 267 241 228 180 185 143 148 109 116 81 78 64 60 47 41 30 24 22 13 13 6 5 1 2 0 0

Overall conclusion • Thanks to the organizers for giving me the obviously better choice – I can stick with hazard ratio and not even point out the price differentials • And also, thank the organizers for not giving Dr. Fuchs the option of combining targeted and chemo • And also, thank Drs. Van Cutsem, Bendell, Kang, and Cook for the slides of theirs I used.