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Treatment of advanced Metastatic Gastric Cancer: PowerPoint Presentation
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Treatment of advanced Metastatic Gastric Cancer:

Treatment of advanced Metastatic Gastric Cancer:

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Treatment of advanced Metastatic Gastric Cancer:

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  1. Treatment of advanced Metastatic Gastric Cancer: Ofer Purim Chief Gastrointestinal Malignancy Service Assuta Samson Hospital Ashdod, Israel PP-RB-IL-0019

  2. Gastric cancer: a global disease • 4th most common malignant disease ~ 930,000 • 2nd most common cause of cancer-related death worldwide ~700,000 • Falling incidence of distal gastric cancer • Increasing incidence of proximal gastric cancer • Wide geographical variation Incidence (males) 20/100000 10 - 20/100000 <10/100000 www.cancer.gov Kamangar F et al. J Clin Oncol 2006;24:2137–50

  3. Gastric cancer stage and survival rates 1

  4. Chemotherapy regimens used in gastric cancer treatment cisplatin-based oxaliplatin-based CF/FP XP ECF ECX FLP EOX EOF CAPOX/XELOX FLO FOLFOX taxane-based DCF mDCF FLOT paclitaxel docetaxel TPC FOLFIRI irinotecan + cisplatin 5-FU/LV Xeloda S-1 irinotecan monotherapy irinotecan-based

  5. Initial improvements but no major recent advances with chemotherapy in median OS BSC1 FAMTX2 C+S13 CF4 IF5 EOF6 DCF4 ECF6 ECX6 XP7 EOX6 0 5 10 15 11 Months BSC = best supportive care; F = 5-FU A = doxorubicin; MTX = methotrexate; S = S-1; C = cisplatin I = irinotecan; E = epirubicin; O = oxaliplatin;D = docetaxel X =Xeloda; FC = fluoropyrimidine + cisplatin; ECX = epirubicin/cisplatin/Xeloda, XP = Xeloda + cisplatin 1. Murad, et al. Cancer 1993; 2. Vanhoefer, et al. JCO 2000 3. Ajani, et al. ASCO GI 2009; 4. Van Cutsem, et al. JCO 2006 5. Dank, et al. Ann Oncol 2008; 6. Cunningham, et al. NEJM 2008 7. Kang, et al. Ann Oncol 2009

  6. Role of Docetaxel: V 325 Phase III R A N D O M I Z E Stratification Factors: Docetaxel 75 mg/m2 IV over 1 hr Cisplatin 75 mg/m2 IV over 1-3 hrsboth on Day 1 only Liver Involvement 5-FU 750 mg/m2/day by CIV over5 days Days 1-5 Prior Gastrectomy Cycles repeated every 3 weeks Measurable vsEvaluable Disease Cisplatin 100 mg/m2/IV over 1-3 hrs Weight Loss (>5%) inPrior 3 Months 5-FU 1000 mg/m2/day by CIV over5 days Days 1-5 Cycles repeated every 4 weeks Centers Adequate hydration and anti-emetics required, No Prophylactic Growth FactorsResponse assessment every 8 weeks independent of treatment schedule

  7. Results: TAX 325

  8. Untreated advanced oesophageal, GEJ or gastric cancer (n=1,002) R REAL-2: Phase III study in advanced oesophageal and gastric cancer ECF (n=263) epirubicin 50 mg/m2, cisplatin 60 mg/m2 d1, 5-FU 200 mg/m2 d1-21, q3w ECX (n=250) epirubicin 50 mg/m2, cisplatin 60 mg/m2 d1, Xeloda 625 mg/m2 bid d1-21, q3w EOF (n=245) epirubicin 50 mg/m2, oxaliplatin 130 mg/m2 d1, 5-FU 200 mg/m2 d1-21, q3w EOX (n=244) epirubicin 50 mg/m2, oxaliplatin 130 mg/m2 d1, Xeloda 625 mg/m2 bidd1-21, q3w • Primary endpoint: Non-inferiority in OS • of Xeloda (ECX or EOX vs. ECFor EOF) • of oxaliplatin (EOF or EOX vs. ECF or ECX) • Secondary endpoints: PFS, RR and safety Cunningham , et al. NEJM 2008

  9. REAL-2: OS* – EOX versus ECF 1.0 0.8 0.6 Survival estimate HR=0.80 (95% CI: 0.66–0.97)Log-rank p=0.02 0.4 0.2 9.9 11.2 0 0 12 24 36 Months *ITT population Cunningham, et al. NEJM 2008

  10. 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

  11. 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-positiveadvanced 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 aChosen at investigator’s discretion GEJ, gastroesophageal junction 1Bang et al; Abstract 4556, ASCO 2009

  12. OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) MedianOS 16.011.8 1.0 Event Events 120136 HR 0.65 95% CI 0.51, 0.83 0.9 FC + T 0.8 0.7 FC 0.6 0.5 0.4 0.3 0.2 11.8 16.0 0.1 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 12296 100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5 3 4 0 1 0 0 0

  13. Secondary end point: PFS MedianPFS 6.75.5 Event 1.0 Events 226235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 0.9 FC + T 0.8 FC 0.7 0.6 0.5 0.4 0.3 0.2 5.5 6.7 0.1 0.0 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 0 2 0 0 0

  14. Secondary end point: tumor response rate Intent to treat p=0.0017 Patients (%) 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 + PRCR, complete response; PR, partial response

  15. 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

  16. Second-Line Therapy in Gastric Cancer • 1,080 patients in three 1st-line phase III trials • 20% received 2nd line therapy • RR for 2nd-line therapy = 13% • Median OS = 5.6 months • Independent poor prognostic factors: • ECOG PS ≥ 2 • Liver mets • Peritoneal mets • Serum alkaline phosphatase ≥ 100 U/L Chau et al J Clin Oncol 2004

  17. Phase II Studies of microtubuli inhibitor as Second-Line Therapy for Gastric Cancer

  18. Irinotecan vs. Best Supportive Care in Second-line Gastric Cancer Thuss-Patience et al. ASCO 2009 Median Survival N Irinotecan 250 mg/m2 q 3weeks 21 4.1 mos P = 0.02 Best Supportive Care 19 2.4 mos HR = 0.48 (95% CI, 0.25-0.92)

  19. Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma 168 patients : R A N D O M I Z E Docetaxel 75 mg/m2 q 3 weeks Primary Endpoint: Overall Survival Best supportive care

  20. Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma Cook et al. ASCO 2013

  21. Role of VEGF Pathway in Tumor Growth • Ramucirumab (IMC-1121B; RAM) is a recombinant human IgG1 monoclonal antibody receptor antagonist designed to bind the extracellular domain of VEGF Receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation. VEGF-A VEGF-A VEGF-CVEGF-D Ramucirumab VEGF-CVEGF-D VEGF binds toVEGFR2 receptor;VEGF-C, -D competefor binding toVEGFR2 Ramucirumabbinds to VEGFR2, blocks VEGFligand binding VEGFR2 VEGFR2 Endothelial cell membrane Ligand binding activates VEGFR2 andp44/p42 MAP kinases No signaling Angiogenesis Tumor growth Inhibit new blood vesselformation and tumor growth

  22. REGARD Study Design Ramucirumab 8 mg/kg q2wk + BSC (n = 238) R A N D O M I Z E Treatment until disease progression or intolerable toxicity Tumor assessment, survival, and safety follow-up 2:1 S C R E EN Placebo q2wk + BSC (n = 117) N = 355 • Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial • Gastric or GEJ adenocarcinoma • Stratification factors: region, weight loss (≥10% vs. <10% over 3 months), location of primary tumor (gastric vs. GEJ) • Global: 6 continents, 30 countries, 120 study centers Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction Fuchs et al. Lancet 2013

  23. REGARD: Overall Survival No. at Risk Fuchs et al. Lancet 2013

  24. REGARD: Progression-free Survival No. at Risk Fuchs et al. Lancet 2013

  25. REGARD: CYRAMZA monotherapy significantly improved DCR1,2 DCR=disease control rate. References: 1. Fuchs CS et al. Lancet. 2014;383(9911):31-39. 2. Data on file. Eli Lilly and Company. 2014. I4T-IE-JVBD (CP12-0715).

  26. Median OS in randomized 2nd-line gastric cancer studies presented/published in 2009-2013 Ramucirumab vs PBO (BSC) 1 (n=355) 5.2 3.8 Docetaxel vs ASC2 (n=131) 5.2 3.6 CTX [Docetaxel or Irinotecan] vs BSC3 (n=202) 5.3 Irinotecan vs BSC4 (n=40) 1. Fuchs et al. Lancet 2013 2. Ford et al. Proc Gastrointestinal Cancer Symp 2013. LBA4. 3. Kang et al. J Clin Oncol 30:1513-1518, 2012 4. Thuss-Patience et al. EUR J CANCER 47: (2011) 2306-2314.

  27. RAINBOW: Study Design 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m2day 1,8 &15 of a 28-day cycle N = 330 R A N D O M I Z E Treat until disease progression or intolerable toxicity Survival and safety follow-up S C R E EN Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 N = 335 • Important inclusion criteria: • - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma • - Progression after 1st line platinum/fluoropyrimidine based chemotherapy • Stratification factors: • - Geographic region, • - Measurable vs non-measurable disease, • - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos) * GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

  28. RAINBOW: Ramucirumab in combination with paclitaxel significantly extended OS . Reference: 1. Wilke H et al. Lancet Oncol. 2014;15(11):1224–1235

  29. RAINBOW: ramucirumab in combination with paclitaxel significantly delayed disease progression Reference: 1. Wilke H et al. Lancet Oncol. 2014;15(11):1224–1235

  30. RAINBOW: ramucirumab in combination with paclitaxel significantly improved ORR Reference: 1. Wilke H et al. Lancet Oncol. 2014;15(11):1224–1235

  31. RAINBOW: Ramucirumab in combination with paclitaxel achieved a generally well-tolerated toxicity profile1 Adverse drug reactıons occurrıng at ıncıdence rate ≥5% ın patıents receıvıng ramucırumab ın combınatıon wıth paclıtaxel The discontinuation rate due to AEs was similar across both treatment arms—12% of patients treated with ramurcirumab + paclitaxel vs 11% of patients treated with placebo + paclitaxel.3 Reference: 1. Wilke H et al. Lancet Oncol. 2014;15(11):1224–1235

  32. RAINBOW: adverse events of special interest Clınıcally relevant adverse events assocıated wıth antıangıogenıc therapy No Grade 4 hypertension, proteinuria, infusion-related reactions or congestive heart failure was observed in the CYRAMZA + paclitaxel arm.2 Reference: 1. Wilke H et al. Lancet Oncol. 2014;15(11):1224–1235

  33. RAINBOW: The incidence of febrile neutropenia was low and similar in both treatment arms Reference: 1. Wilke H et al. Lancet Oncol. 2014;15(11):1224–1235

  34. Nivolumab (ONO-4538/BMS-936558) as Salvage Treatment After Second- or Later-Line Chemotherapy for Advanced Gastric or Gastroesophageal Junction Cancer (AGC): A Double-Blinded, Randomized, Phase 3 Trial Yoon-Koo Kang,1 Taroh Satoh,2 Min-Hee Ryu,1 Yee Chao,3 Ken Kato,4 Hyun Cheol Chung,5Jen-Shi Chen,6 Kei Muro,7 Won Ki Kang,8 Takaki Yoshikawa,9 Sang Cheul Oh,10 Takao Tamura,11Keun-Wook Lee,12 Narikazu Boku,4 Li-Tzong Chen13 1Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; 2Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan; 3Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; 4Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; 5Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Song Dang Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea; 6Division of Hematology/Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; 7Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 8Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 9Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan; 10Division of Hematology/Oncology, Internal Medicine Department, College of Medicine, Korea University, Seoul, Korea; 11Medical Oncology, Kindai University, Faculty of Medicine, Osakasayama, Japan; 12Division of Hematology/Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea; 13National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

  35. Study Design and Endpoints • Key eligibility criteria: • Age ≥ 20 years • Unresectable advanced or recurrent gastric or gastroesophageal junction cancer • Histologically confirmed adenocarcinoma • Prior treatment with ≥ 2 regimens and refractory to/intolerant of standard therapy • ECOG PS of 0 or 1 Nivolumab3 mg/kg IV Q2W • Patients were permitted to continue treatment beyond initial RECIST v1.1–defined disease progression, as assessed by the investigator, if receiving clinical benefit and tolerating study drug • Primary endpoint: • OS • Secondary endpoints: • Efficacy (PFS, BOR, ORR, TTR, DOR, DCR) • Safety • Exploratory endpoint: • Biomarkers • Stratification based on: • Country (Japan vs Korea vs Taiwan) • ECOG PS (0 vs 1) • Number of organs with metastases (< 2 vs ≥ 2) R 2:1 Placebo BOR, best overall response; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; IV; intravenous; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumors; TTR, time to tumor response.