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Overview of Targeted Therapies for Esophageal and Gastric Cancers

Overview of Targeted Therapies for Esophageal and Gastric Cancers. Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Unit Sarah Cannon Research Institute Nashville, TN. Basic Numbers. Esophageal cancer 17,460 new cases in the U. S. 2012 15,070 deaths

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Overview of Targeted Therapies for Esophageal and Gastric Cancers

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  1. Overview of Targeted Therapies for Esophageal and Gastric Cancers Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Unit Sarah Cannon Research Institute Nashville, TN

  2. Basic Numbers • Esophageal cancer • 17,460 new cases in the U. S. 2012 • 15,070 deaths • Gastric cancer • 21,320 new cases in the U. S. 2012 • 10,540 deaths • 5 year survival rate <5% for patients with metastatic disease

  3. Why targeted therapy? • Going after what makes the cancer a cancer • Our drug development is catching up with the lab • Identification of certain pathways that are key in cancer development and survival • We are still learning • One set of targets does not fit all • All of the pathways talk to each other • Side effect profiles are different, but can be just as toxic to the patient • Chronic cancer treatment?

  4. Can Targeted Therapies Improve Outcomes? • Pathways with targeted therapies where we have data or are currently under later stage study • HER2 • VEGF • EGF • mTOR • Met

  5. ToGA trial – HER2 + gastric cancer 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 Bang, Y., et al. Lancet, 2010

  6. Primary end point: OS MedianOS 13.811.1 1.0 Event Events 167182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 0.9 FC + T 0.8 FC 0.7 0.6 0.5 0.4 0.3 0.2 11.1 13.8 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 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 0 1 0 0 0 Van Cutsem ASCO 2009 T, trastuzumab

  7. 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 Van Cutsem ASCO 2009

  8. ToGA: Overall Survival (FISH+ or IHC3+) Bang, Y. Lancet, 2010

  9. ToGA Survival: IHC 2+/FISH+ or IHC 3+ (Post-hoc Exploratory Analysis) Bang, Y. Lancet, 2010

  10. 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 Van Cutsem ASCO 2009

  11. LOGiC Trial: Gastric Cancer Randomized Phase III Adenocarcinoma of the stomach, GEJ, or esophagus HER2 positive (FISH+, IHC 3+) No previous treatment for advanced disease N = 545 CapOx (Oxaliplatin 130 mg/m2 IV Day 1 for up to 8 cycles + Capecitabine 850 mg/m2 BID Days 1-14) + Lapatinib 1250 PO daily R A N D O M I Z E CapOx (as above) + Placebo daily • Stratification • Region of the world • Prior neoadjuvant and/or adjuvant chemotherapy

  12. TYTAN Trial: Second Line Gastric Cancer Randomized Phase III Adenocarcinoma of the stomach, GEJ, or esophagus HER2 positive Second Line China, Korea, Japan, Taiwan N = 261 Paclitaxel 80 mg/m2 IV D1, 8, 15 of 28 day cycle + Lapatinib 1500 PO daily N = 130 R A N D O M I Z E Paclitaxel 80 mg/m2 IV D1, 8, 15 of 28 day cycle N = 131 • Stratification • Prior gastrectomy • Prior anti HER2 therapy Bang GI ASCO 2013

  13. TYTAN ITT Population HER2 IHC 3+ Bang GI ASCO 2013

  14. T-DM1 structure Target expression: HER2 Monoclonal antibody: Trastuzumab Cytotoxic agent: DM1 Highly potent cytotoxic agent T-DM1 Linker: MCC Systemically stable T-DM1 is a novel ADC Trastuzumab Average drug:antibody ratio ≅3.5:1

  15. TrastuzumabEmtansine: Phase II Study of 2L treatment for HER2+ Metastatic Gastric Cancer Phase II n=100 2L Her2 positive mGC PS: 0 -1 IHC 3+ or IHC 2+/ISH+ Prior Ctx + prior HER2 N=412 T-DM1 3.6 mg/kg q3 wk 2 T-DM1 2.4 mg/kg/wk 2 Stratified by: region, PS, prior gastrectomy, prior HER2-targeted tx 1 Chemotherapy** • Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100 • * Dose selection based on PK/safety/efficacy • ** Investigator’s choice between paclitaxel 80 mg/m2/wk and docetaxel 75 mg/m2 q 3 wk

  16. HER2 blockade for gastric cancers TOGA trial shows survival benefit using trastuzumab for patients with advanced gastric cancer We should be testing patients early What is the definition of HER2 positivity? IHC 3+ and/or FISH + But do FISH+ with IHC 0/1+ benefit? What are the next steps (follow breast cancer)? Lapatinib TDM-1 Trastuzumab plus lapatinib? Pertuzumab combinations? Neoadjuvant use?

  17. AVAGAST: A Randomized Double-Blind Placebo- Controlled Phase III Study Capecitabine*/Cisplatin (XP) + Placebo q3w Locally advanced or metastatic gastric cancer R Capecitabine*/Cisplatin (XP) + Bevacizumab q3w Stratification factors: 1. Geographic region 2. Fluoropirimidine backbone 3. Disease status *5-FU also allowed if cape contraindicated Cape 1000mg/m2 oral bid, d1–14, 1-week rest Cisplatin 80mg/m2 d1 Bevacizumab 7.5 mg/kg d1 Maximum of 6 cycles of cisplatin Cape and bevacizumab/placebo until PD Starting dose of bev/placebo: 30 minutes, subsequent doses: 15 minutes Kang ASCO 2010

  18. Overall Survival Survival rate XP + Placebo XP + Bev 1.0 HR = 0.87 95% CI 0.73–1.03 p = 0.1002 0.9 0.8 0.7 12.1 0.6 0.5 10.1 0.4 0.3 0.2 0.1 0.0 12 0 15 18 21 24 3 9 6 Study month Number at risk 54 50 0 0 XP + Placebo XP + Bev 387 387 343 355 271 291 204 232 146 178 98 104 15 19 Kang ASCO 2010

  19. Progression-Free Survival Progression-free survival rate XP + Placebo XP + Bev 1.0 HR = 0.80 95% CI 0.68–0.93 p = 0.0037 0.9 0.8 0.7 6.7 0.6 0.5 5.3 0.4 0.3 0.2 0.1 0.0 12 0 15 18 21 24 3 9 6 Study month Number at risk 15 11 0 0 XP + Placebo XP + Bev 387 387 279 306 145 201 86 123 55 71 32 38 3 3 Kang ASCO 2010

  20. Best Overall Response: Measurable Disease Population Kang ASCO 2010

  21. Regional Differences in Efficacy Kang ASCO 2010

  22. Patient Characteristics by Region *1 additional patient had an ECOG PS of 4 Kang ASCO 2010

  23. Gastric cancer types • Intestinal type • Well-differentiated • Related to gastritis, gastric atrophy, intestinal metaplasia • More common in in older men, East Asia, Eastern Europe, Central and South America • Decreasing incidence • Diffuse type • Undifferentiated • Related to pangastritis • More common in younger patients, M = F • Increasing incidence • Worse prognosis

  24. Gastric cancer by location • Gastric cardia tumors • Rapidly increasing incidence in the West • Correlates with the increasing incidence of esophageal and GE junction adenocarcinoma • Poorer prognosis than distal stomach • Shares demographic and pathologic features of Barrett’s-associated esophageal cancer • Not associated with atrophic gastritis and intestinal metaplasia • Different genetic polymorphisms seen between cardia and non-cardia tumors, suggesting they have different biology El-Serag 2002, Powell 1992

  25. AVAGAST Conclusions Overall the study was negative for survival benefit However, looking at the Americas patients there appears to be a benefit to using bevacizumab Highlights the difference in gastric cancers in different parts of the world – different epidemiology, different survivals, different responses to treatment

  26. REGARD: Randomized Phase III Trial 2nd Line Ramicirumab vs. Placebo 26 Ramucirumab IVq 2 weeks Second line metastatic gastric and GEJ adenocarcinoma R 1:1 Placeboq 2 weeks Press release 10/12: met primary endpoint of OS and secondary endpoint of PFS Press release 1/23/13: OS 5.2 vs. 2.6 mo PFS 2.1 vs. 1.3 mo Primary EP: OS N = 355

  27. RAINBOW: Randomized Phase III Trial 2nd Line Paclitaxel +/- Ramicirumab 27 Paclitaxel 80 mg/m2 d1, 8, 15 + Ramucirumab IVq 2 weeks Second line metastatic gastric and GEJ adenocarcinoma R 1:1 Paclitaxel 80 mg/m2 d1, 8, 15 + Placeboq 2 weeks Primary EP: OS N = 665

  28. Randomized Phase II Trial 1st Line FOLFOX +/- Ramucirumab 28 Ramucirumab IV+ FOLFOX q 2 weeks First line metastatic esophagogastric adenocarcinoma R 1:1 Placebo + FOLFOXq 2 weeks Primary EP: PFS

  29. REAL-3 Waddell ASCO 2012

  30. Waddell ASCO 2012

  31. Waddell ASCO 2012

  32. Waddell ASCO 2012

  33. Waddell ASCO 2012

  34. Waddell ASCO 2012

  35. EXPAND: Randomized Phase III Trial 1st Line Capecitabine/Cisplatin +/- Cetuximab 35 Cetuximab IV+ Capecitabine/Cisplatin q 3 weeks N = 455 First line metastatic gastric and GEJ adenocarcinoma N = 904 R 1:1 Capecitabine/Cisplatinq 3 weeks N = 449 Primary EP: PFS Lordick ESMO 2012

  36. EXPAND

  37. Gefitinib in advanced esophageal cancer progressing after chemotherapy Gefitinib 500mg od (n=225) Patients progressing following chemotherapy Simple randomisation Planned: 18 months to recruit 450 patients Primary endpoint: Overall survival - powered to detect an increase in 1 year survival from 10 to 18%, 82.5% power, 5% significance level. Secondary endpoints: PFS, toxicity & PROs Placebo (n=225) • Multi-centre • Double-blind – patients, clinicians and trial office staff blinded to trial treatment • Treated until progression • Regular CT scans

  38. Overall Survival ESMO 29th Sept 2012

  39. Progression free survival Days on protocol therapy Placebo: median 35; IQR 27 to 62; range 0 to 372 Gefitinib: median 42; IQR 27 to 91; range 0 to 680 ESMO 29th Sept 2012

  40. EGFR Inhibition for Gastric Cancers • Three negative randomized trials • Anything to biomarkers? • REAL-3 does not show anything predictive, only prognostic, but numbers are low • EXPAND – 97% tumor sample acquisition – will this help us learn anything? • Gefitinib – biomarker studies also pending – are TKI’s different than antibodies? • Squamous vs. adenocarcinomas? • Small randomized phase II of cetuximab for SCC showed potential benefit – like head and neck? • Lordick, et al, ASCO 2008, n = 66, RR 19 vs. 13%, PFS 5.7 vs. 3.6 mo, OS 9.5 vs. 5.5 mo

  41. PI3K/Akt/mTOR Pathway in Gastric Cancer • The PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, is dysregulated in 50%-60% of gastric cancers1-3 • Everolimus, an oral mTOR inhibitor, showed efficacy in preclinical models of gastric cancer1,4-6 • In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability7 mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase. 1Xu DZ et al. BMC Cancer. 2010;10:536; 2Lang SA et al. Cancer. 2007;120:1803-10; 3Yu G et al. Clin Cancer Res. 2009;15:1821-29; 4Taguchi F et al. Invest New Drugs. 2011;29:1198-205; 5Cejka D et al. Anticancer Res. 2008;28:3901-08; 6Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7Doi T et al. J Clin Oncol. 2010;28:1904-1910.

  42. Phase 3 GRANITE-1 Study Design Everolimus 10 mg PO daily+ BSC* (n = 439) RANDOMIZE (N = 656) SCREEN Safety follow-up: EOT + 28 d Treatment until disease progression or intolerable toxicity Survival follow-up: every 3 mo 2 1 Placebo PO daily + BSC (n = 217) • Stratification by region: Asia vs rest of world • Stratification by number of lines of previous systemic chemotherapy (1 vs 2) BSC, best supportive care; EOT, end of treatment; PO, orally. ClinicalTrials.gov identifier: NCT00879333. Van Cutsem GI ASCO 2012

  43. Overall Survival (FAS) 100 Censoring Times Everolimus + BSC (n/N = 352/439) Placebo + BSC (n/N = 180/217) 80 Kaplan-Meier medians Everolimus + BSC: 5.39 months Placebo + BSC: 4.34 months 60 Hazard ratio: 0.90 (95% CI, 0.75-1.08) Probability of overall survival (%) Log-rank Pvalue = 0.1244 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months) No. of patients still at risk Time (months) 0 2 4 6 8 10 12 14 16 18 20 22 24 Everolimus 439 355 253 195 139 87 52 30 13 6 3 1 0 217 172 1 17 82 60 35 28 16 12 8 4 1 0 Placebo

  44. Overall Survival by Stratification Factors (FAS) Hazard Ratio (95% CI) All (N = 656) 0.90 (0.75-1.08) Prior chemotherapy 1 (n = 313) 0.94 (0.73-1.23) 2 (n = 343) 0.90 (0.70-1.15) Region Asia (n = 363) 0.96 (0.75-1.23) ROW (n = 293) 0.85 (0.65-1.10) 1 prior chemo & Asia (n = 146) 0.94 (0.63-1.39) Cross-class. of strata 2 prior chemo & Asia (n = 217) 0.98 (0.71-1.35) 1 prior chemo & ROW (n = 167) 0.91 (0.64-1.31) 2 prior chemo & ROW (n = 126) 0.74 (0.50-1.09) 0.6 0.8 1.0 1.2 1.4 Everolimus 10 mg/d Placebo In favor of ROW, rest of world.

  45. Progression-Free Survival (FAS) 100 Censoring Times Everolimus + BSC (n/N = 386/439) Placebo + BSC (n/N = 206/217) 80 Kaplan-Meier medians Everolimus + BSC: 1.68 months Placebo + BSC: 1.41 months 60 Hazard ratio: 0.66 (95% CI, 0.56-0.78) Probability of progression-free survival (%) Log-rank P value < 0.0001 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Time (months) No. of patients still at risk Time (months) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Everolimus 439 367 179 117 92 60 44 37 27 20 13 10 6 5 3 3 2 1 1 0 0 0 217 168 55 28 23 17 8 7 6 3 2 2 2 2 2 2 2 2 2 2 1 0 Placebo

  46. Rationale for Targeting MET • Met is a receptor tyrosine kinase. • Following binding to its only known ligand, hepatic growth factor (HGF), Met receptors dimerize, leading to growth, migration and survival signals • Met is amplified, mutated, overexpressed in many tumors • Met expression is associated with a worse prognosis in many cancers including NSCLC, colorectal, gastric, and breast cancers • Met pathway also implicated in resistance to bevacizumab in colorectal cancer patients and resistance to EGFR inhibitors

  47. Activation of Met in Cancer MUTANT MET INCREASED MET AUTOCRINE HGF Paracrine HGF Paracrine HGF Other Focal Amp LUNG HCC (Childhood) PAPIL. RENAL (Hereditary & Sporadic) BREAST COLORECTAL ESOPHAGEAL GASTRIC GLIOMA HNSCC LUNG MELANOMA MESOTHELIOMA OVARIAN PANCREATIC RENAL GASTRIC LUNG Met CRC GLIOMA OSTEOSARCOMA PANCREATIC GASTRIC

  48. Met Pathway and Targeted Agents Appleman (2011) JCO ePub

  49. Development of Met IHC as a Diagnostic • Intensity of Met staining on tumor cells scored on 0–3+ scale 1+ 2+ 3+ 1+ 3+ 2+ ‘Met High’ is defined as: ≥50% tumor cells with a staining intensity of 2+ or 3+

  50. AMG-102 for gastric cancer • Met receptor overexpression is associated with poor prognosis for gastric cancer patients • Update on randomized phase II trial • ECX plus AMG-102 (rilotumumab) at 7.5 or 15 mg/kg (n = 82) vs. ECX plus placebo (n = 39) • Met high defined as > 50% tumor cells positive for Met expression (n = 27 vs. 11) Oliner ASCO 2012

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