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Esophagogastric Cancer

Esophagogastric Cancer. Barbara Burtness, MD Fox Chase Cancer Center June 3, 2013. Lapatinib in combination with capecitabine plus oxaliplatin in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: The TRIO-013/LOGiC Trial.

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Esophagogastric Cancer

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  1. Esophagogastric Cancer Barbara Burtness, MDFox Chase Cancer Center June 3, 2013

  2. Lapatinib in combination with capecitabine plus oxaliplatin in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: The TRIO-013/LOGiC Trial JR Hecht, Y Bang, S Qin, H Chung, J Xu, J Park, K Jeziorski, Y Shparyk, PM Hoff, AF Sobrero, P Salman, J Li, S Protsenko, ME Buyse, K Afenjar, T Kaneko, A Kemner, S Santillana, MF Press, DJ Slamon Translational Research In Oncology

  3. HER2 in Gastric Cancer Amplified in 7-34%1 Amplification may predict resistance to conventional modalities2 OS INT0116 According to Treatment Arm 1. 1. Gravalos and Jimeno. Ann Oncol 2008; 19:1583 2. Gordon M A et al. Ann Oncol 2013;annonc.mdt106

  4. HER2 Directed Therapy in Gastric Cancer • ToGA Trial demonstrated survival advantage for addition of trastuzumab in HER2 + gastric cancer1 1. Bang et al. Lancet 2010; 376:687

  5. Comparing Lapatinib and Trastuzumab Antibody may also exert anticancer activity via recruitment of immune effectors Interpatient variation in lapatinib drug metabolism and bioavailability is significant Pharmacogenomic predictors, role of smoking undefined Markers of resistance MET associated with lapatinib resistance in HER2 activated gastric cancer cell lines1 Secondary HER2 mutations described in acquired lapatinib resistance in BrCa2 Downstream signaling intermediaries Kras mutation 6%, PTEN loss 15%3 • Chen CT et al. Mol Cancer Ther. 2012 Mar;11(3):660-9. • Kancha RK, et al. PLoS One. 2011;6(10):e26760. • Okines et al. Eur J Can 2013; S0959:115

  6. Lapatinib in Gastric Cancer Lapatinib administered to 47 chemonaive metastatic gastric cancer patients at 1500 mg orally daily1 PR =9% Median TTF 1.9 months OS 4.8 months Gene expression of HER2, IL-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS 1. Iqbal S, et al. Ann Oncol. 2011;22:2610.

  7. OS by gene expression Iqbal S, et al. Ann Oncol. 2011;22:2610-5

  8. TRIO-013/LOGiC Study Design Day 1: Oxaliplatin 130 mg/m2 Day 1−14: Capecitabine 850 mg/m2, bid Day 1−21: Lapatinib 1250 mg, qd (one cycle = 21 days) • Confirmed histology • Local/central HER-2+ • Confirmed eligibility R Day 1: Oxaliplatin 130 mg/m2 Day 1−14: Capecitabine 850 mg/m2, bid Day 1−21: Placebo, qd (one cycle = 21 days) • Stratification factors • Prior (neo)Adjuvant therapy • Region (Asia, North America, Rest of the World) Primary Efficacy Population (PEP) (HER-2 status confirmed by FISH) Tumor tissue sent to central lab

  9. Primary Endpoint: Overall Survival (PEP) 1.0 CapeOx+L CapeOx+P 0.8 0.6 Cumulative survival probability 0.4 0.2 0.0 Subjects at risk CapeOx+L 249 199 133 83 47 24 9 3 3 CapeOx+P 238 189 106 53 34 17 11 7 2 2 0 5 10 15 20 25 30 35 40 45 Time since randomization (months) ITT analysis HR 0.91

  10. Overall Survival: Subgroup Analysis Hazard ratio (95% CI) Primary efficacy population (N=487) Region Asia (n=193) North America (n=17) Rest of World (n=277) Prior adjuvant use Yes (n=38) No (n=449) Age (years) <60 (n=236) ≥60 (n=251) Baseline ECOG status 0−1 (n=444) 2 (n=43) Primary site Esophagus (n=20) GE Junction (n=43) Gastric (n=424) Histological type Diffuse (n=19) Intestinal (n=436) Other (n=32) Pylorus intact Yes (n=373) No (n=114) HER2 status (all FISH+) IHC 0 (n=27) IHC 1+ (n=54) IHC 2+ (n=108) IHC 3+ (n=297) IHC 0−1+ (n=81) IHC 2−3+ (n=405) 0.91 (0.73, 1.12) 0.68 (0.48, 0.96) 1.61 (0.53, 4.83) 1.04 (0.79, 1.37) 1.52 (0.68, 3.41) 0.83 (0.67, 1.04) 0.69 (0.51, 0.94) 1.08 (0.81, 1.45) 0.88 (0.70, 1.10) 0.76 (0.41, 1.44) 0.87 (0.32, 2.35) 0.90 (0.44, 1.85) 0.89 (0.71, 1.11) 0.64 (0.25, 1.65) 0.93 (0.75, 1.17) 0.58 (0.26, 1.29) 0.80 (0.63, 1.01) 1.06 (0.67, 1.68) 0.56 (0.24, 1.31) 1.16 (0.61, 2.20) 0.79 (0.50, 1.25) 0.90 (0.69, 1.18) 0.91 (0.55, 1.51) 0.86 (0.68, 1.09) 0 5 2 4 1 3 Hazard Ratio (CapeOx+L / CapeOx+P) Favors CapeOx+P Favors CapeOx+L

  11. TRIO/LOGIC Vs. ToGA

  12. Conclusions Lapatinib Trial Lapatinib and capecitabine/oxaliplatin did not lead to a significant survival advantage over capecitabine/oxaliplatin Impact on RR comparable to trastuzumab Source of regional differences not clear Role of markers of resistance c-MET, EGFR, IL-8 Can acquired HER2 mutations be identified? Studies ongoing to assess role of pertuzumab, TDM-1

  13. A phase III randomized clinical trial of adjuvant paclitaxel followed by oral fluorinated pyrimidines for locally advanced gastric cancer –SAMIT Study- K. Yoshida, A. Tsuburaya, M. Kobayashi, S. Yoshino, M. Takahashi, N. Takiguchi, K. Tanabe, N. Takahashi, H. Imamura, N. Tatsumoto, A. Hara, K. Nishikawa, R. Fukushima, A. Kurita, H. Kojima, Y. Miyashita, K. Oba, ME Buyse, S. Morita, J. Sakamoto, Stomach Cancer Adjuvant Multi-institutional Trial, SAMIT, Group

  14. Adjuvant Therapy in Gastric Cancer JAMA. 2010;303(17):1729-1737.

  15. Adjuvant Systemic Therapy CA80101 randomized 546 patients to Macdonald (bolus 5-FU/LV, infusional 5-FU RT, bolus 5-FU/LV) vs. ECF-> 5FU/RT -> ECF ECF did not improve OS [HR 1.03, P = .80] Toxicity profile favored ECF over bolus 5-FU/LV1 CLASSIC trial randomized 1035 patients with D2 lymph node dissection to observation or adjuvant capecitabine/oxaliplatin 3-year DFS 74% on cape/ox vs. 60% for observation [HR 0.56, P<.001] 1. Fuchs CS et al. Proc ASCO 2011 2. Bang et al. Proc ASCO 2011

  16. Study schemeRandomized phase III,two-by-two factorial design PTX 80 mg/m2 48wks 48wks X 3  36wks X 3  36wks S-1 80 mg/m2 UFT 267 mg/m2

  17. DFS: Sequential, CD vs Monotherapy, AB 3yr DFS AB, Mono: 54.0% (95%CI: 50.2-57.6) CD, Seq. : 57.2% (95%CI: 53.4-60.8) Superiority of Sequential HR: 0.92 (95%CI: 0.80-1.07; p=0.273)

  18. DFS: UFTbase vs S-1 base 3yr DFS AC, UFT base: 53.0% (95%CI: 49.2-56.6) BD, S-1 base : 58.2% (95%CI: 54.4-61.8) Non-inferiority of UFT HR:1.23 (95%CI:1.07-1.43), p = 0.151 Superiority of S-1 HR: 0.81, p = 0.0057

  19. DFS in Each Arms Months

  20. SAMIT Conclusions Sequential taxane -> fluoropyrimidine not superior to fluoropyrimidine monotherapy 2 x 2 factorial design not optimal for assessing the 2nd component of a sequential regimen May alter PK, toxicity profile, select for resistance pathways, early progressors are not evaluated Did not exclude HER2 amplified Biomarkers of taxane sensitivity should be explored

  21. 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 EudraCT Number: 2006-005046-37 ISRCTN 13366390

  22. Second Line Therapy of Advanced Gastric Cancer N=40 compared IRI to BSC1 PS 0-2 OS 4 vs. 2.4 m [HR 0.48, p=.012]1 Phase III of 2nd line chemo (N=133)vs. BSC (N=69)2 PS 0-1 OS 5.3 vs. 3.8 m [HR 0.67, p=.007] No difference between IRI and docetaxel GRANITE: 439 randomized to everolimus, 217 to placebo3 Median OS everolimus 5.4 m vs 4.3 m [NS] • Thuss-Patience et al. Eu J Cancer 2011; 47:2306 • Kang et al. J Clin Oncol 2012; 13:1513. • Van Cutsem et al. J Clin Oncol 30, 2012 (suppl 4; abstr LBA3)

  23. Overall Survival: WJOG n Median HR (95% CI) p wPTX 108 9.5M CPT-11 111 8.4M 1.13 (0.86-1.49) 0.38 Probability (%) (Months) Number at risk wPTX CPT-11 108 111 80 75 36 29 10 10 2 3 0 1 0 1

  24. Trial Design Arm A (n=84): Docetaxel 75mg/m2 IV every 3 weeks for up to 6 cycles + ASC Assess every 3 weeks for 18 weeks, then every 6 weeks Adenocarcinoma of esophagus, esophagus-gastric junction or stomach refractory to platinum and fluoropyrimide RANDOMISE 1:1 n=168 Arm B (n=84): Active symptom control May include: Radiotherapy, analgesia, anti-emetics, steroids Stratified by: 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)

  25. 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

  26. Conclusions Second line therapy extends survival in advanced gastric cancer and is an appropriate standard of care Docetaxel is an appropriate choice, although toxic in this population Patient selection based on performance status and peritoneal carcinomatosis may be useful in identifying group of patients in whom this strategy will also be clinically meaningful Future studies may identify biomarkers to aid selection between taxanes and irinotecan

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