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Charles S. Fuchs, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Will targeting the VEGF-receptor prove to be any more successful in gastroesophageal adenocarcinoma than did targeting its ligand VEGF?. Charles S. Fuchs, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA. VEGF-Mediated Signaling. PlGF. VEGF-A. VEGF-B. VEGF-C. VEGF-D.

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Charles S. Fuchs, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

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  1. Will targeting the VEGF-receptor prove to be any more successful in gastroesophageal adenocarcinoma than did targeting its ligand VEGF? Charles S. Fuchs, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

  2. VEGF-Mediated Signaling PlGF VEGF-A VEGF-B VEGF-C VEGF-D VEGFR1 VEGFR2 VEGFR3

  3. Survival Following Gastric Cancer Resection Circulating Plasma VEGF Yoshikawa. Cancer Letters 2000;153:7-12

  4. Survival Following Gastric Cancer Resection Tumor Endothelial Expression (IHC) Maeda. Cancer 1996;77:858-63

  5. Tumoral VEGF A Expression and Survival in Gastric Cancer: A Meta-Analysis Ji et al TumorBiol 2013

  6. AVAGAST: Bevacizumab in advanced gastric cancer 6 Cycles • Primary endpoint: OS • Secondary endpoints: PFS, TTP, ORR, DOR, Safety, QoL and Biomarkers Bevacizumab 7.5 mg/kg + capecitabine/5-FU Bevacizumab7.5 mg/kg + XP Locally advanced or metastatic gastric cancer (n=736) Treat to PD R Placebo + capecitabine/5-FU* Placebo + XP XP=capecitabine/5-FU + cisplatin. Ohtsu et al. J Clin Oncol 29;3968-3976-2011

  7. AVAGAST: Results • Both arms well tolerated without major toxicity differences Ohtsu et al. J Clin Oncol 29;3968-3976-2011

  8. AVAGAST: OS by Region Ohtsu et al. J ClinOncol 29;3968-3976-2011

  9. Human Xenografts in Nude Mice 4500 1500 A431 GBM-18 glioblastoma 4000 epidermoid 3500 breast 3000 1000 2500 3500 4T1 2000 500 3000 1500 Meantumor volume (mm3) 1000 vehicle 2500 0 500 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 50 55 60 65 2000 0 LLC 2500 2000 BxPC-3 1500 SK-RC-29 lung pancreatic vehicle 5000 renal 2000 1500 1000 800 ug 4000 1500 500 3000 1000 1000 400 ug 0 2000 0 5 10 15 20 25 30 35 40 500 800 ug 500 1000 1200 ug 0 0 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 0 5 10 15 20 25 30 35 40 45 50 55 60 0 5 10 15 20 25 30 35 40 Proof-of-ConceptDC101 Inhibits Tumor Growth Mouse Tumors Days post tumor implantation Days post tumor implantation Prewett. Cancer Res 1999; 59: 5209-18

  10. Anti-VEGFR2 in gastric cancer xenograft modelTMK-1 cell line Jung YD. Eur J Cancer 2002;38:1133

  11. TMK-1 xenograft (ctd.) Vascularity(CD31) Proliferation(PNCA) TumorApoptosis EndothelialApoptosis Jung YD. Eur J Cancer 2002;38:1133

  12. 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

  13. 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

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

  15. Median OS in randomized 2nd-line gastric cancer studies presented/published in 2009-2013 5.2 Ramucirumab vs PBO (BSC) (n=355) 3.8 5.2 Docetaxel vs ASC1 (n=131) 3.6 CTX [Docetaxel or Irinotecan] vs BSC2 (n=202) 5.3 Irinotecan vs BSC3 (n=40) 1. Ford et al. Proc Gastrointestinal Cancer Symp 2013. LBA4. 2. Kang et al. J Clin Oncol 30:1513-1518, 2012 3. Thuss-Patience et al. EUR J CANCER 47: (2011) 2306-2314.

  16. RAINBOW: Study Design 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel80 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

  17. RAINBOW: Overall Survival Δ mOS = 2.3 months Censored No. at risk

  18. RAINBOW: Progression-free Survival & Response Rates Censored No. at risk

  19. Forest Plot of Overall Survival by Subgroups -Stratified Analysis 0.2 0.5 1 2 a Region 1: Europe, United States, and Australia; Region 2: Brazil, Chile, Mexico, and Argentina; Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore. Favors RAM+PTX Favors PBO+PTX

  20. Forest Plot of Progression-Free Survival by Subgroups - Stratified Analysis 0.2 0.5 1 2 a Region 1: Europe, United States, and Australia; Region 2: Brazil, Chile, Mexico, and Argentina; Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore. Favors RAM+PTX Favors PBO+PTX

  21. RAINBOW: Efficacy by Geographic Region *Accrual: Asia n=223; EU/NA/AUS n=398; Central / South America n=44

  22. Treatment-Emergent Adverse Events Occurring in ≥ 20% of Patients and ≥ 5% Higher in the RAM + PTX Arm †Consolidated AE terms are comprised of synonymous MedDRA preferred terms: fatigue includes asthenia; neutropenia includes neutrophil count decreased; neuropathy includes peripheral sensory neuropathy; paraesthesia; neuropathy peripheral, polyneuropathy; hypoasethesia, neuralgia, dysaesthesia; abdominal pain includes abdominal pain upper and abdominal pain lower; leukopenia includes white blood cell decreased; hypertension includes blood pressure increased, hypertensive cardiomyopathy, procedural hypertension, systolic hypertension.

  23. Adverse Events of Special Interest †Each AESI category is comprised of consolidated synonymous MeDRA preferred terms.

  24. RAINBOW: Results and Conclusions • RAINBOW met the primary endpoint • RAM + PTX conferred a statistically significant and clinically meaningful OS benefit of > 2 months (median); risk reduction of death by 19% • Significant benefits in PFS and ORR were observed • RAINBOW and REGARD demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric and GEJ cancer after prior chemotherapy

  25. Apatinib, VEGFR TKI, in Refractory Gastric Cancer 144 patients who failed ≥ 2 lines of therapy R A N D O M I Z E Apatinib 850 QD Primary endpoint: PFS Apatinib 425 BID Placebo QD Li J et al. JCO 2013;31:3219-3225

  26. Apatinib in Refractory Gastric Cancer: PFS P < 0.001 Li J et al. JCO 2013;31:3219-3225

  27. Apatinib in Refractory Gastric Cancer: OS *P < 0.001 Li J et al. JCO 2013;31:3219-3225

  28. ToGA: A Randomized, Open Label Multicenter Phase III Study Capecitabine1 or iv 5-FU2†+ cisplatin3 (n=290) HER2-positive* advancedgastric or GEJ cancer (n=584) 3807 patients screened 810 HER2-positive (22.1%) R Capecitabine or iv 5-FU2†+ cisplatin3+Trastuzumab (n=294) • Stratification factors • Advanced vs. metastatic disease • GC vs. GEJ • Measurable vs. non-measureable • ECOG PS 0-1 vs. 2 • Capecitabine vs. 5-FU • †Chosen at investigator’s discretion • 1 1000 mg/m2 bid d1-14 q3w x 6 cycles • 2 800 mg/m2/day continuous iv infusion d1-5 q3w x 6 cycles • 3 80 mg/m2 q3w x 6 cycles • 4 8 mg/kg loading dose followed by 6 mg/kg q3w until disease progression *IHC 3+ or FISH+5-FU=5-fluorouracil; GEJ=gastroesophageal junction; R=randomization; ECOG PS =Eastern Cooperative Oncology Group performance score. Bang YJ, et al. Lancet. 2010;376:687-697. 28

  29. ToGA Primary Endpoint: Overall Survival 1.0 0.9 0.8 0.7 F+C+Trastuzumab 0.6 F+C 0.5 Probability 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 F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin. 29 Bang YJ, et al. Lancet. 2010;376:687-697.

  30. 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

  31. CAPOX + bevacizumab + trastuzumab

  32. MET Amplification as a Predictor of Drug Sensitivity in Gastric and Esophageal Adenocarcinoma Graziano et al J Clin Onc 2011: 230 pts: 10% MET amplifications Worse prognosis Yapp et al J Clin Onc 2011: Phase I trial of ARQ197 Minor regression in gastric cancer Smollen et al PNAS, 2006

  33. Presented at ASCO 2012

  34. Oliner et al ASCO 2012

  35. Oliner et al ASCO 2012

  36. RILOMET-1: ECX +/- Rilotumumab in MET-High Gastroesophageal Adenocarcinoma 450 pts with MET+ gastroesophageal adenoca R A N D O M I Z E ECX + Rilotumumab Primary Endpoint: Overall Survival ECX + Placebo

  37. Phase III Trial of FOLFOX+/- MetMAb in Gastric Adenocarcinoma 800 pts with previously untreated advanced disease: R A N D O M I Z E FOLFOX + MetMAb Primary Endpoint: Overall Survival FOLFOX + Placebo

  38. C-Met and Angiogenesis • Hypoxia promoted invasive growth by activation of met • In RIP-Tag2 mice, combined anti-VEGF and c-Met inhibition inhibited invasion and metastasis • KRC-408, c-Met inhibitor, inhibited both cell growth in angiogenesis in gastric cancer models Pennacchieti et al Cancer Cell 2003 Sennino et al Cancer Disc 2012 Hong et al Cancer Letters 2013

  39. Inter-relation between Angiogenesis and Immune Response in Cancer

  40. Increased PD-1 Expression on CD4 and CD8 T cells in Gastric Cancer Saito et al J Surg Oncol 2013; 107:517

  41. We are defining the genome of Esophageal and Gastric cancers….

  42. Distinct Pattern of Focal Amplifications Between Upper/Lower GI Adenocarcinomas High-Level Amplifications Dulak, Schumacher et al Cancer Research 2012

  43. Statistical analysis of focal amplifications across gut adenocarcinomas BOLD= potential target

  44. VEGF Inhibition in Gastric Cancer • VEGF inhibition offers a clear benefit in advanced gastric cancer • For all patients, 2nd-line ramucirumab significantly improves overall survival • Survival benefit for ramucirumab appears comparable to 2nd-line docetaxelor irinotecan • Addition of ramucirumabto 2nd-line paclitaxel significantly improves overall survival • Combining VEGF inhibition with other targeted approaches may offer greater benefit

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