Metastatik Mide Kanserinde Sistemik Tedavi. Dr Özlem Er

Metastatik Mide Kanserinde Sistemik Tedavi Dr Özlem Er

Metastatik Mide Kanserinde Sistemik Tedavi 1. Basamak Sistemik Tedavi / HER2 (+) MMK Tedavisi EGFR VEGF MET 2. Basamak Sistemik Tedavi / HER2 (+) MMK Tedavisi Dosetaxel / İrinotekan Ramucirumab ± Paklitaxel

Mide Kanseri: Global Hastalık 4. sıklıkta: ~ 930,000 olgu/yıl Kansere bağlı ölümlerde dünyada 2. sırada: ~ 700,000 ölüm/yıl Distal mide kanseri sıklığı azalıyor Proksimal mide kanseri insidansı artıyor Coğrafik dağılım değişken Insidans (Erkekler) 20/100,000 10 to 20/100,000 < 10/100,000 Kamangar F, et al. J Clin Oncol. 2006;24:2137-2150. National Cancer Institute. 2010.

Türkiye Kanser Verileri

Winer E, et al. JCO 2008

Metastatik Mide Kanserinde Sistemik Tedavi Hastaların yaklaşık 2/3ü ileri evrede başvurmaktadır Kore ve Japonya da tarama programları olması nedeniyle istisnai durum söz konusu İleri evre hastalık: Palyatif kemoterapi standart Coğrafi bölgelere göre tedavi kombinasyonları farklılık göstermektedir Konvansiyonel KT etkinliği sınırlıdır, ortanca sağkalım ~ 10 ay Prediktif biobelirleyiciler tedavi stratejilerini belirlemede yardımcı olur HER2: Trastuzumab tedavisi için prediktif biobelirleyici Kim R, et al. Crit Rev Oncol Hematol. 2013;88:416-426. Lim SM, et al. World J Gastroenterol. 2014;20:2042-2050. Bang YJ, et al. Lancet. 2010;376:687-697.

Metastatik Mide Kanseri: GS Effect of Chemotherapy vs Best Supportive Care on OS Patients, n Study Chemotherapy BSC HR (Fixed) HR (95% CI) Murad 1993 Pyrhonen 1995 Scheithauer 1996 30 21 52 10 20 51 0.33 (0.17-0.64) 0.25 (0.13-0.47) 0.49 (0.33-0.74) Total HR (95% CI) 103 81 0.39 (0.28-0.52) Test for heterogeneity: x 2 = 3.32 (P =.19) Test for overall effect: Z = 6.15 (P <.00001) 0.1 0.2 0.5 1.0 2.0 5.0 BSC : 3 ay Kemoterapi vs BSC: ~ 6-ay fark Favors Chemotherapy Favors BSC Wagner AD, et al. J Clin Oncol. 2006.

MMK de Tek Ajan Etkinliği Agent Response Rate, % Mitomycin C 30 Doxorubicin 17 Epirubicin 19 Cisplatin 19 BCNU 18 5-fluorouracil 21 Etoposide (oral) 21 Hydroxurea 19 UFT 27 Capecitabine 19 S-1 45 Paclitaxel 17-23 Docetaxel 17-29 Irinotecan 18 ORR: ~ 20% Yanıt süresi: Kısa Shah MA, et al. J Natl Compr Canc Netw. 2010

Monoterapi vs Kombinasyon KT Cullinan 1985 De Lisi 1986 Levi 1986 Cullinan 1994 Loehrer 1994 Colucci 1995 Barone 1998 Yamamura 1998 Popov 2002 Ohtsu 2003 Bouche 2004 51 42 94 183 64 35 36 37 30 175 89 Patients, n Study Combination Single-Agent HR (Fixed) HR (95% CI) Chemotherapy Chemotherapy 51 43 93 69 94 36 36 34 30 105 45 0.90 (0.61-1.33) 1.16 (0.26-5.15) 0.58 (0.43-0.77) 0.90 (0.69-1.16) 0.85 (0.61-1.19) 0.70 (0.42-1.16) 0.89 (0.55-1.42) 0.88 (0.55-1.41) 0.86 (0.32-2.29) 1.04 (0.82-1.32) 0.65 (0.45-0.95) Total HR (95% CI) 836 636 0.83 (0.74-0.93) Test for heterogeneity: x 2 = 12.30 (P =.27) Test for overall effect: Z = 3.28 (P =.001) Kombinasyon KT ile GS daha iyi. 0.1 0.2 0.5 1.0 2.0 5.0 Favors Combination Favors Single Agent Wagner AD, et al. J Clin Oncol. 2006.

Kombinasyon Kemoterapi Study Treatment n ORR, % Median TTP, Mos Median OS, Mos V325 [18] V306 [19] REAL-2 [20] Kang [21] JCOG 9912 [22] SPIRITS [23] FLAGS [24] Cisplatin/5-FU 224 25 3.7 8.6 Docetaxel/cisplatin/5-FU 221 37 5.6 9.2 Cisplatin/5-FU 163 26 4.2 8.7 Irinotecan/5-FU/LV 170 32 5.0 9.0 ECF 263 41 6.2 9.9 EOF 245 42 6.5 9.3 ECX 250 46 6.7 9.9 EOX 244 48 7.0 11.2 Cisplatin/5-FU 137 32 5.0 9.3 Cisplatin/capecitabine 139 46 5.6 10.5 5-FU 234 9 2.9 10.8 Cisplatin/irinotecan 236 38 4.8 12.3 S-1 234 28 4.2 11.4 S-1 150 27 4.0 11.0 Cisplatin/S-1 148 42 6.0 13.0 Cisplatin/5-FU 508 32 5.5 7.9 Cisplatin/S-1 521 29 4.8 8.6 P Value.02 NS.02 NS NS.036.198 Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997. Dank M, et al. Ann Oncol. 2008;19:1450-1457. Cunningham D, et al. N Engl J Med. 2008;358:36-46. Kang YK, et al. Ann Oncol. 2009;20:666-673. Boku N, et al. Lancet Oncol. 2009;10:1063-1069. Narahara H, et al. Gastric Cancer. 2011;14:72-80. Ajani JA, et al. J Clin Oncol. 2010;28:1547-1553.

Probability of Survival (%) MMK de Uzun Dönem Sağkalım: REAL 2 Çalışması 100 80 60 Good risk 0 RF Moderate risk 1-2 RF Poor risk 3-4 RF n Median Survival, Mos 1-Yr Survival, % (95% CI) 261 583 61 13.6 9.5 5.1 54.6 (48.4-60.4) 39.2 (35.2-43.1) 16.4 (8.4-26.7) Risk Factor HR (95% CI) P Value PS 0-1 1 40 20 2 2.044 (1.53-2.73) <.0001 Liver metastasis 1.473 (1.22-1.78) <.0001 Peritoneal metastasis 1.546 (1.21-1.97) <.0001 Alkaline phosphatase 100 U/L 1.114 (0.923-1.345).14 0 0 1 2 3 4 5 6 7 Yrs Since Random Allocation Chau I, et al. J Clin Oncol. 2009;27:e3-e4.

Mide Kanserinde HER2 Mide ve özefagogastrik karsinomlar Lokal ileri inoperabl/rekürren/metastatik Trastuzumab tedavisi düşünülüyorsa IHC ve FISH, veya diğer in situ hibridizasyon yöntemleri NCCN ToGA çalışmasındaki IHC kriterlerini öneriyor. IHC 3+ veya IHC 2+/FISH pozitif veya IHC 2+/SISH pozitif 1. NCCN. Clinical practice guidelines in oncology: gastric cancer. 2. 2. Ruschoff J, et al. Mod Pathol, 2012;25:637-650. 3. 3. Bang Y, et al. Lancet. 2010;376:687-689.

Mide Kanserinde HER2 Pozitivitesi: IHC Score Surgical Specimen Staining Pattern Biopsy Specimen Staining Pattern HER2 Overexpr. Assessment 0 No reactivity or membranous reactivity in < 10% of tumor cells No reactivity or no membranous reactivity in any tumor cell Negative 1+ Faint or barely perceptible membranous reactivity in 10% of tumor cells; cells are reactive only in part of their membrane Tumor cell cluster with faint or barely perceptible membranous reactivity irrespective of % of tumor cells stained Negative 2+ Weak to moderate complete, basolateral or lateral membranous reactivity in 10% of tumor cells Tumor cell cluster with weak to moderate complete, basolateral or lateral membranous reactivity irrespective of % of tumor cells stained Equivocal 3+ Strong complete, basolateral or lateral membranous reactivity in 10% of tumor cells Tumor cell cluster with strong complete, basolateral or lateral membranous reactivity irrespective of % of tumor cells stained Positive Bang Y, et al. Lancet. 2010;376:687-689.

İleri Evre HER2+ Mide Kanserinde Trastuzumab + KT: ToGA Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU Patients with advanced gastric cancer screened for HER2 status (N = 3803) Patients with HER2+ advanced gastric cancer (n = 810; 22% of successful screenings) Primary endpoint: OS R (n = 584) 5-FU or Capecitabine* + Cisplatin 80 mg/m 2 q3w x 6 + Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose) (n = 294) 5-FU or Capecitabine* + Cisplatin 80 mg/m 2 q3w x 6 (n = 290) *Selected at investigator s discretion: 5-FU 800 mg/m 2 /day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m 2 BID on Days 1-14 q3w x 6. Bang YJ, et al. Lancet. 2010;376:687-697.

Survival Probability Trastuzumab + KT (ToGA): GS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Pts at Risk, n 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 FC + T FC 11.1 13.8 71 47 Mos 56 32 Events 167 182 43 24 30 16 Median OS 21 14 13.8 11.1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 13 7 12 6 HR 0.74 6 5 95% CI 0.60-0.91 4 0 1 0 0 0 P Value.0046 Bang YJ, et al. Lancet. 2010;376:687-697.

Trastuzumab + KT (ToGA): OS Alt gruplar Bang YJ, et al. Lancet. 2010;376:687-697.

M.-H. Ryu et al. / European Journal of Cancer xxx (2015)

M.-H. Ryu et al. / European Journal of Cancer xxx (2015)

Trastuzumab-Bazlı Tedavi: Ortanca GS > 1 Yıl BSC [27] FAMTX [28] C + S-1 [29] CF [30] IF [31] EOF [32] DCF [30] ECF [32] ECX [32] XP [33] EOX [32] Trastuzumab + XP/FP [34] HER2 IHC 2+/FISH+ or IHC 3+ 12 mos 0 5 10 15 Median OS in Patients With Advanced Gastric Cancer (Mos) 27. Murad AM, et al. Cancer. 1993;72:37-41. 28. Vanhoefer U, et al. J Clin Oncol. 2000;18:2648-2657. 29. Ajani JA, et al. J Clin Oncol. 2010;28:1547-1553. 30. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997. 31. Dank M, et al. Ann Oncol. 2008;19:1450-1457. 32. Cunningham D, et al. N Engl J Med. 2008;358:36-46. 33. Kang YK, et al. Ann Oncol. 2009;20:666-673. 34. Bang YJ, et al. Lancet. 2010;376:687-697.

TRIO-013/LOGIC Faz III : Lapatinib + CapeOx (HER2+) Stratified by prior (neo)adjuvant therapy (yes vs no), region (Asia vs North America vs rest of world) Patients with confirmed HER2+ advanced, unresectable, or metastatic gastric, esophageal, or gastroesophageal cancer (N = 545) Lapatinib 1250 mg QD Days 1-21 + Oxaliplatin 130 mg/m 2 Day 1 + Capecitabine 850 mg/m 2 BID (n = 272) Placebo QD Oxaliplatin 130 mg/m 2 Day 1 Capecitabine 850 mg/m 2 BID (n = 273) Primary endpoint: OS Secondary endpoints: PFS, ORR, DoR, clinical benefit, safety/toxicity, QoL, molecular/pharmacogenetic analyses Hecht JR, et al. ASCO 2013. Abstract LBA4001.

Probability of Survival Lapatinib + CapeOx (TRIO-013): GS (PEP*) 1.0 0.8 0.6 Primary Efficacy Population* Median OS, mos (95% CI) CapeOx + L (n = 249) CapeOx + P (n = 238) 12.2 (10.6-14.2) 10.5 (9.0-11.3) HR (95% CI; P value) 0.91 (0.73-1.12;.3492) Pts at Risk, n CapeOx + L 0.4 0.2 0 CapeOx + L CapeOx + P 0 5 10 15 20 25 30 35 40 45 Mos Since Randomization 249 199 133 83 47 24 9 3 3 238 189 106 53 34 17 11 7 2 2 ITT Analysis HR: 0.91 *Centrally confirmed HER2+ by FISH. CapeOx + P Hecht JR, et al. ASCO 2013. Abstract LBA4001.

Faz III JACOB: Trastuzumab + KT ± Pertuzumab (HER2+) Stratified by region (Japan vs North America/Western Europe/Australia vs Asia [excluding Japan] vs South America/Eastern Europe), previous gastrectomy, HER2 (IHC 3+ vs IHC 2+ and ISH+) 21-day cycle Patients with HER2+ metastatic gastric/gej cancer (planned N = 780) Primary endpoint: OS Pertuzumab 840 mg Trastuzumab 8 mg/kg x 1 then 6 mg/kg Cisplatin 80 mg/m 2 5-fluorouracil 800 mg/m 2 /24 h continuously for 120 h or Capecitabine 1000 mg/m 2 BID x 14 d Placebo Trastuzumab 8 mg/kg x 1 then 6 mg/kg Cisplatin 80 mg/m 2 5-fluorouracil 800 mg/m 2 /24 h continuously for 120 h or Capecitabine 1000 mg/m 2 BID x 14 d PD or toxicity Tabernero J, et al. ASCO 2013. Abstract TPS4150.

EGFR Sinyal İletimi PTEN PI3-K AKT RAS RAF SOS py K K py GRB2 py MEK STAT MAPK Gene transcription Cell-cycle progression G2 M S G1 Proliferation/Maturation Survival/Apoptosis Angiogenesis Metastasis

CALGB 80403/ECOG 1206: Cetuximab + KT Stratified according to ECOG PS (0-1 vs 2) and adenocarcinoma vs squamous cell carcinoma Patients with metastatic esophageal cancer or GE junction cancer (N = 245) ECF + Cetuximab* 21-day cycle Epirubicin 50 mg/m 2 IV on Day 1 + Cisplatin 60 mg/m 2 IV on Day 1 + Fluorouracil 200 mg/m 2 /day on Days 1-21 (n = 82) IC + Cetuximab* 21-day cycle Irinotecan 65 mg/m 2 IV on Days 1 and 8 + Cisplatin 30 mg/m 2 IV on Days 1 and 8 (n = 83) FOLFOX + Cetuximab* 14-day cycle Leucovorin 400 mg/m 2 IV on Day 1 + Oxaliplatin 85 mg/m 2 IV on Day 1 + Fluorouracil 400 mg/m 2 IV bolus on Day 1 + 2400 mg/m 2 IV given over 48 hrs on Days 1-2 (n = 80) *Cetuximab given weekly with 400 mg/m 2 IV loading dose followed by 250 mg/m 2 IV. Enzinger PC, et al. ASCO 2010. Abstract 4006.

Cetuximab + KT(ECOG 1206): Sonuçlar EFC-C (n = 67) IC-C (n = 71) FOLFOX-C (n = 72) Response rate, % 58 46 54 Median OS, mos 11.5 8.9 12.4 Median PFS, mos 5.9 5.0 6.7 Median TTF, mos 5.5 4.5 6.7 Enzinger PC, et al. ASCO 2010. Abstract 4006.

Cetuximab + KT (ECOG 1206): Advers Olaylar AE, % *P =.03 P =.01 EFC-C (n = 67) IC-C (n = 71) FOLFOX-C (n = 72) Any grade 3/4 75 86 79 Grade 3/4 GI AE 28 42* 22 Death 6 0 0 Enzinger PC, et al. ASCO 2010. Abstract 4006.

Faz III EXPAND: Cape/Cis ± Cetuximab Stratified by disease stage (M0 vs M1), previous esophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio), chemotherapy (yes vs no) 21-day cycle Patients with locally advanced unresectable or metastatic stomach cancer or GEJ cancer (N = 904) Cetuximab 400 mg/m 2 on Day 1, then 250 mg/m 2 qw + Capecitabine 1000 mg/m 2 BID on Days 1-14 + Cisplatin 800 mg/m 2 on Day 1 (n = 455) Capecitabine 1000 mg/m 2 BID on Days 1-14 + Cisplatin 800 mg/m 2 on Day 1 (n = 449) Primary endpoint: PFS Secondary endpoints: OS, ORR Lordick F, et al. Lancet Oncol. 2013;14:490-499.

OS (%) Cape/Cis ± Cetuximab (EXPAND): GS 100 80 60 Median OS, Mos Cape/cis/cetux: 9.4 Cape/cis: 10.7 HR: 1.00 (95% CI: 0.87-1.17; P =.95) 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Mos From Randomization Lordick F, et al. Lancet Oncol. 2013;14:490-499.

Faz III REAL3: EOC ± Panitumumab Patients with untreated advanced gastroesophageal adenocarcinoma (N = 553) Epirubicin 50 mg/m 2 on Day 1 + Oxaliplatin 130 mg/m 2 on Day 1 + Capecitabine 1250 mg/m 2 /day on Days 1-21 (n = 275) Epirubicin 50 mg/m 2 on Day 1 + Oxaliplatin 100 mg/m 2 on Day 1 + Capecitabine 1000 mg/m 2 /day on Days 1-21 + Panitumumab 9 mg/kg on Day 1 (n = 278) Primary endpoint: OS Secondary endpoints: PFS, ORR, toxicity, patient-reported outcomes, KRAS mutation status Waddell T, et al. Lancet Oncol. 2013;14:481-489.

OS (%) EOC ± Panitumumab (REAL3): GS 100 80 Median OS, Mos (95% CI) EOC: 11.3 (9.6-13.0) meoc + P: 8.8 (7.7-9.8) HR: 1.37 (95% CI: 1.07-1.76; P =.013) 60 40 20 0 0 6 12 18 24 30 36 Pts at Risk, n Mos From Randomization EOC 275 135 49 12 3 meoc + P 278 130 38 10 2 Waddell T, et al. Lancet Oncol. 2013;14:481-489.

Survival Rate (%) Plazma VEGF & Sağkalım 100 80 VEGF < 100 pg/ml P =.044 60 VEGF 100 pg/ml 40 20 0 0 100 200 300 400 500 600 700 Survival Days Yoshikawa T, et al. Cancer Lett. 2000;153:7-12.

Survival Rate (%) Tumor Endotelyal Expresyonu & Sağkalım 100 80 VEGF negative (n = 61) 60 VEGF positive (n = 34) 40 20 P <.05 0 0 10 20 30 40 50 60 Mos After Surgery Maeda K, et al. Cancer. 1996;77:858-863.

Faz III AVAGAST : Cape/Cis ± Bevacizumab 21-day cycle Patients with untreated unresectable locally advanced or metastatic stomach cancer or GEJ cancer (N = 774) Bevacizumab 7.5 mg/kg on Day 1 + Cisplatin 80 mg/m 2 on Days 1 x 6 cycles + Capecitabine* 1000 mg/m 2 BID on Days 1-14 (n = 387) Placebo on Day 1 + Cisplatin 80 mg/m 2 on Day 1 x 6 cycles + Capecitabine* 1000 mg/m 2 BID on Days 1-14 (n = 387) PD or toxicity *Patients unable to take oral medication received 5-FU 800 mg/m 2 /day on Days 1-5 instead of capecitabine. Primary endpoint: OS Ohtsu A, et al. J Clin Oncol. 2011;29;3968-3976.

Cape/Cis ± Bevacizumab (AVAGAST): Sonuçlar Result Bevacizumab Placebo P Value HR (95% CI) Median PFS, mos 6.7 5.3.004 0.80 (0.68-0.93) ORR, % 46 37.03 -- Median OS, mos 12.1 10.1.10 0.87 (0.73-1.03) İyi tolere edilmiş, major toksisite oranları her iki kolda düşük. Ohtsu A, et al. J Clin Oncol. 2011;29;3968-3976.

Cape/Cis ± Bevacizumab (AVAGAST): GS Region Placebo + Chemo (n = 387) Bev + Chemo (n = 387) Median OS, Mos Delta HR 95% CI Asia 12.1 13.9 1.8 0.97 0.75-1.25 Europe 8.6 11.1 2.5 0.85 0.63-1.14 Pan-America 6.8 11.5 4.7 0.63 0.43-0.94 Ohtsu A, et al. J Clin Oncol. 2011;29;3968-3976.

Met Yolağı ve Hedefe Yönelik İlaçlar Heparin Proteoglycans Pro-HGF Stromal/mesenchymal cell β α α β α Rilotumumab Ficlatuzumab HGF (activated) β Onartuzumab MET Cabozantinib Crizotinib Foretinib MGCD265 FAK GRB2 PI3K GAB1 Ras Raf MEK Epithelial/cancer cell Akt RAS/RAF/MEK/ERK ERK Invasion/metastasis Survival Proliferation Appleman LJ. J Clin Oncol. 2011;29:4837-4838.

Faz II: ECX ± Rilotumumab Stratified by ECOG PS (0 vs 1), locally advanced vs metastatic Patients with unresectable, locally advanced or metastatic gastric cancer or GEJ cancer, no prior systemic therapy for advanced disease (N = 121) Primary endpoint: PFS Secondary endpoints: OS, ORR, PK, biomarkers Rilotumumab 15 mg/kg + Epirubicin 50 mg/m 2 on Day 1 + Cisplatin 60 mg/m 2 on Day 1 + Capecitabine 625 mg/m 2 BID on Days 1-21 (n = 40) Rilotumumab 7.5 mg/kg + Epirubicin 50 mg/m 2 on Day 1 + Cisplatin 60 mg/m 2 on Day 1 + Capecitabine 625 mg/m 2 BID on Days 1-21 (n = 42) Placebo Epirubicin 50 mg/m 2 on Day 1 Cisplatin 60 mg/m 2 on Day 1 Capecitabine 625 mg/m 2 BID on Days 1-21 (n = 39) Oliner KS, et al. ASCO 2012. Abstract 4005.

OS (%) PFS (%) ECX ± Rilotumumab (Faz II): PFS, GS (MET High ) 100 80 60 40 20 100 0 0 2 4 6 8 10 12 14 16 80 60 40 20 Mos 0 0 2 4 6 8 10 12 14 16 Mos *HR adjusted for baseline disease extent and ECOG PS. PFS Rilotumumab + ECX (n = 27) Placebo + ECX (n = 11) OS Rilotumumab + ECX (n = 27) Placebo + ECX (n = 11) Median Mos (80% Cl) Median Mos (80% Cl) HR+ (95% Cl) P Value 11.1 (9.2-13.3) 0.29 (0.11-0.76).012 5.7 (4.5-10.4) HR+ (95% Cl) P Value 6.9 (5.1-7.5) 0.51 (0.24-1.10).085 4.6 (3.7-5.2) MET-evaluable OS HR: 0.95 ITT OS HR: 0.73 Oliner KS, et al. ASCO 2012. Abstract 4005.

RILOMET-2 A phase 3, multicenter, randomized, double-blind, placebocontrolled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma T Doi, et al J Clin Oncol 33, 2015

Faz III RILOMET-1 : ECX ± Rilotumumab (MET+ hastalar) Patients with MET+, unresectable metastatic or locally advanced gastric cancer or GEJ cancer (Planned N = 450) Rilotumumab 15 mg/kg q21d + Epirubicin, Cisplatin, Capecitabine (ECX) Placebo q21d + Epirubicin, Cisplatin, Capecitabine (ECX) Primary endpoint: OS Secondary endpoints: PFS, ORR, TTP, DCR, TTR, safety ClinicalTrials.gov. NCT01697072.

Faz III MetGastric : FOLFOX ± Onartuzumab Patients with MET+, HER2-negative, metastatic gastric cancer or GEJ cancer (planned N = 800) Onartuzumab mfolfox6* Placebo mfolfox6* Progression or unacceptable toxicity *mfolfox6: oxaliplatin 85 mg/m 2, folinic acid 400 mg/m 2 (or as deemed appropriate), or levofolinic acid 200 mg/m 2 (or as deemed appropriate), 5-FU 400 mg/m 2 followed by 2400 mg/m 2 q2w. Primary endpoint: OS in MET 2+/3+ and ITT populations Secondary endpoints: PFS, ORR, QoL, safety ClinicalTrials.gov. NCT01697072.

Metastatik Mide Kanserinde 1. Basamak Sistemik Tedavi Global sorun Kemoterapi temel tedavi biçimi HER2 pozitif: İlk sıra kemoterapiye Trastuzumab eklenmesi GS artırıyor Pertuzumab TDM-1

Metastatik Mide Kanserinde 2. Basamak Sistemik Tedavi

Irinotekan vs BSC Irinotecan 250 mg/m 2 every 3 wks N 21 Median Survival 4.1 mos P =.02 Best Supportive Care 19 2.4 mos HR: 0.48 (95% CI: 0.25-0.92) Thuss-Patience PC, et al. ASCO 2009. Abstract 4540.

Cougar-02: Dosetaxel vs BSC 168 patients R A N D O M I Z E Docetaxel 75 mg/m 2 every 3 wks Best Supportive Care Primary endpoint: OS Cook N, et al. ASCO 2013. Abstract 4023.

Cougar-02: RR ve GS Docetaxel, Mos BSC, Mos P Value Response rate 7% NR OS 5.2 3.6.01 Cook N, et al. ASCO 2013. Abstract 4023.

Faz III Kore Çalışması: BSC + KT vs BSC Patients with metastatic gastric cancer, 1-2 previous chemo* regimens, ECOG PS 0-1 (N = 202) Docetaxel 60 mg/m 2 on Day 1 q3w or Irinotecan 150 mg/m 2 q2w (n = 133) Best Supportive Care (n = 69) Treatment continued until progression, toxicity, or withdrawal Primary endpoint: OS *Fluoropyrimidines and/or platinum agents. Including analgesics, paracentesis, psychosocial care, nutritional support, blood transfusion, palliative radiotherapy, or nonprotocol BSC measures. Kang JH, et al. J Clin Oncol. 2012.

2. Sıra KT: Faz III Çalışma Ortanca yaş: 56 yıl 1 sıra: 73%; 2 sıra: 27% PS 0: 54% >1 M+ bölgesi: 65% <3 ay tedavisiz süre: 74% KT 3 sıra: 40% vs 22%; P =.011 Yaşam kalitesi verisi yok CT + BSC (n = 133) BSC (n = 69) OS, mos 5.3 3.8 HR: 0.66 (95% CI: 0.48-0.89; P =.007) Kang JH, et al. J Clin Oncol. 2012.

Survival Probability Faz III Çalışma BSC + KT vs BSC: GS 1.0 0.8 0.6 Median OS CT + BSC (n = 133): 5.3 mos BSC alone (n = 69): 3.8 mos HR: 0.66 (95% CI: 0.48-0.89; P =.007) 0.4 0.2 0 Pts at Risk, n CT + BSC 133 BSC 69 0 3 101 45 6 9 12 15 18 21 Mos 64 15 36 11 26 7 18 5 Kang JH, et al. J Clin Oncol. 2012.

Tumor Weight (g) VEGFR2 Xenograft Model (TMK-1) 0.75 0.50 0.25 0 Control DC101 Jung YD, et al. Eur J Cancer. 2002;38:1133-1140.

Ramucirumab: IgG1 Ab VEGFR-2 Ramucirumab: a IgG1 monoclonal antibody that binds the extracellular domain of VEGF receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation VEGF-C VEGF-D VEGF-A Ramucirumab VEGF-A VEGF-C VEGF-D VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2 VEGFR2 Endothelial cell membrane VEGFR2 Ramucirumab binds to VEGFR2, blocks VEGF ligand binding Ligand binding activates VEGFR2 and p44/p42 MAP kinases Angiogenesis Tumor growth No signaling Inhibit new blood vessel formation and tumor growth Wadha R, et al. Future Oncol. 2013;9:789-795.

Faz III REGARD : BSC ± Ramucirumab Stratified by geographic region, weight loss (> vs < 10% over 3 mos), location of primary tumor (gastric vs GEJ) Patients with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidinecontaining combination therapy, ECOG PS 0-1 (N = 355) Ramucirumab 8 mg/kg IV q2w + BSC (n = 238) BSC + Placebo (n = 117) Treatment until PD, unacceptable toxicity, or death Primary objective: OS Secondary endpoints: PFS, 12-wk PFS, ORR, DOR, QoL, safety Fuchs CS, et al. Lancet. 2014;383:31-39.

Proportion Remaining Alive BSC ± Ramucirumab (REGARD): GS 1.0 0.8 Ramucirumab Placebo Censored Ramucirumab Placebo Patients/events, n 238/179 117/99 Median, mos 5.2 (4.4-5.7) 3.8 (2.8-4.7) (95% CI) 0.6 6-mo OS, % 42 32 12-mo OS, % 18 11 0.4 HR: 0.776 (95% CI: 0.603-0.998; P =.0473) 0.2 0 Pts at Risk, n Ramucirumab Placebo 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28 Mos 238 117 154 66 92 34 49 20 17 7 7 4 3 2 0 1 0 0 Fuchs CS, et al. ASCO GI 2013. Abstract LBA5.

BSC ± Ramucirumab (REGARD): Yanıt Oranı Response Best overall response Ramucirumab (n = 238) Placebo (n = 117) n % n % CR 1 0.4 0 0 -- PR 7 2.9 3 2.6 -- SD 108 45.4 24 20.5 -- PD 78 32.8 63 53.8 -- Not evaluable/not assessed 44 18.5 27 23.1 -- P Value Response rate: CR + PR 8 3.4 3 2.6.756 Disease control rate: CR + PR + SD 116 48.7 27 23.1 <.0001 Fuchs CS, et al. ASCO GI 2013. Abstract LBA5. Fuchs CS, et al. Lancet. 2014;383:31-39.

Proportion Without Progression BSC ± Ramucirumab (REGARD): PFS 1.0 0.8 0.6 Ramucirumab Placebo Censored Ramucirumab Placebo Patients/events, n 238/199 117/108 Median, mos 2.1 (1.5-2.7) 1.3 (1.3-1.4) (95% CI) 12-wk PFS, % 40 16 0.4 HR: 0.483 (95% CI: 0.376-0.620; P <.0001) 0.2 0 Pts at Risk, n Ramucirumab Placebo 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mos 238 117 213 92 113 27 65 11 61 7 45 4 30 2 18 2 18 2 11 2 5 2 4 1 2 1 1 0 1 0 1 0 1 0 0 0 Fuchs CS, et al. Lancet. 2014;383:31-39.

BSC ± Ramucirumab (REGARD): Yan Etkiler Adverse Event, % Ramucirumab (n = 236) Placebo (n = 115) Any Grade Grade 3 Any Grade Grade 3 Fatigue 36 6 40 10 Abdominal pain 29 6 28 3 Decreased appetite 24 3 23 3 Vomiting 20 3 25 4 Constipation 15 < 1 23 3 Anemia 15 6 15 8 Dysphagia 11 2 10 4 Dyspnea 9 2 13 6 Fuchs CS, et al. Lancet. 2014;383:31-39.

BSC ± Ramucirumab (REGARD): *Yan Etkiler Adverse Event, % Ramucirumab (n = 236) Placebo (n = 115) Any Grade Grade 3 Any Grade Grade 3 Hypertension* 16 8 8 3 Bleeding/Hemorrhage 13 3 11 3 Arteriothromboembolic 2 1 0 0 Venous thromboembolic 4 1 7 4 Proteinuria 3 < 1 < 3 < 0 GI perforation < 1 < 1 < 1 < 1 Fistula (GI and non-gi) < 1 < 1 < 1 < 1 Infusion-related reaction < 1 0 2 0 Cardiac failure < 1 0 0 0 *Includes increased blood pressure. No grade 4 hypertension observed among ramucirumab-treated patients. Fuchs CS, et al. Lancet. 2014;383:31-39.

No Deterioration in ECOG PS (%) BSC ± Ramucirumab (REGARD): Time to PS 2 100 80 60 Median Time to ECOG PS 2, Mos Ramucirumab: 5.1 Placebo: 2.4 HR: 0.586 (95% CI: 0.414-0.829; P =.002) 40 20 Pts at Risk, n Ramucirumab Placebo 0 0 3 6 9 12 15 18 Mos to ECOG PS 2 238 117 Ramucirumab (n = 238) Placebo (n = 117) Censored 85 13 32 4 13 2 2 1 Fuchs CS, et al. Lancet. 2014;383:31-39. 1 0 0 0

Randomize 2. Basamak Mide Kanseri Çalışmaları (2009-2013): Ortanca GS Ramucirumab vs BSC [1] (n = 355) Median OS by Study Arm, Mos 3.8 5.2 Docetaxel vs ASC [2] (n = 131) 3.6 5.2 Chemo (docetaxel or irinotecan) vs BSC [3] (n = 202) 3.8 5.3 Irinotecan vs BSC [4] (n = 40) 2.4 4.0 1. Fuchs CS, et al. Lancet. 2014;383:31-39. 2. Ford H, et al. ASCO GI 2013. Abstract LBA4. 3. Kang JH, et al. J Clin Oncol. 2012;30:1513-1518. 4. Thuss-Patience PC, et al. Eur J Cancer. 2011;47:2306-2314. 0 1 2 3 4 5 6 Active treatment BSC/ASC

Faz III RAINBOW : Paclitaxel ± Ramucirumab Stratified by geographic region, measurable vs nonmeasurable disease; TTP on first-line treatment (< 6 mos vs 6 mos) 4-wk cycle Patients with metastatic or locally advanced gastric cancer or GEJ cancer and progression on first-line chemotherapy (N = 665) Ramucirumab 8 mg/kg on D1, 15 Paclitaxel 80 mg/m 2 on D 1, 8, 15 (n = 330) Placebo on D 1, 15 Paclitaxel 80 mg/m 2 on D 1, 8, 15 (n = 335) Progression or intolerable toxicity Primary endpoint: OS Secondary endpoints: PFS, ORR, TTP Wilke H, et al. ASCO GI 2014. Abstract LBA7.

Probability of OS Paclitaxel ± Ramucirumab (RAINBOW): GS 1.0 0.8 Ram/Ptx Placebo/Ptx Patients/events, n 330/256 335/260 Median, mos 9.63 (8.48-10.81) 7.38 (6.31-8.38) (95% CI) 6-mo OS, % 72 57 12-mo OS, % 40 30 0.6 HR: 0.807 (95% CI: 0.678-0.962; P =.0169) 0.4 0.2 0 Δ mos = 2.3 mos Ram + Ptx Placebo + Ptx Censored 0 4 8 12 16 20 24 28 Mos Wilke H, et al. ASCO GI 2014. Abstract LBA7. Lancet Oncol. 2014 Oct;15(11):1224-35

Probability of PFS Paclitaxel ± Ramucirumab (RAINBOW): PFS, Yanıt Oranı 1.0 0.9 0.8 0.7 0.6 0.5 Ram/Ptx Placebo/Ptx Patients/events, n 330/279 335/296 Median, mos 4.40 (4.24-5.32) 2.86 (2.79-3.02) (95% CI) 6-mo PFS, % 36 17 12-mo PFS, % 22 10 ORR, % 28 16 P =.0001 DCR, % 80 64 P <.0001 HR: 0.635 (95% CI: 0.536-0.752; P <.0001) 0.4 0.3 0.2 0.1 0 Ram + Ptx Placebo + Ptx Censored 0 2 6 10 Wilke 14 H, et al. ASCO 18 GI 2014. Abstract 22 LBA7 Mos Lancet Oncol. 2014 Oct;15(11):1224-35

Paclitaxel ± Ramucirumab (RAINBOW): Etkinlik Outcome Region* Ram + Ptx Median OS, mos Median PFS, mos Placebo + Ptx Delta HR/Odds Ratio 95% CI Asia 12.1 10.5 1.6 0.99 0.73-1.43 EU/NA/AUS + Central/South America 8.5 5.9 2.6 0.73 0.59-0.91 Asia 5.5 2.8 2.7 0.63 0.47-0.83 EU/NA/AUS + Central/South America 4.2 2.9 1.3 0.64 0.52-0.79 ORR, % Asia 33.9 20.2 13.7 2.24 1.18-4.24 EU/NA/AUS + Central/South America 24.9 14.0 10.9 2.09 1.28-3.41 *Accrual: Asia, n = 223; EU/NA/AUS, n = 398; Central/South America, n = 44. Wilke H, et al. ASCO GI 2014. Abstract LBA7. Lancet Oncol. 2014 Oct;15(11):1224-35

Ramucirumab

Ramucirumab Çalışmaları

Faz III TYTAN: İkinci Basamak Paclitaxel ± Lapatinib (HER2+) Stratified by gastrectomy status, previous trastuzumab Patients with HER2+ gastric cancer and progression on 1 previous regimen (5-FU and/or cisplatin) (N = 261) Lapatinib 1500 mg/day + Paclitaxel 80 mg/m 2 Days 1, 8, 15 q4w (n = 130) Paclitaxel 80 mg/m 2 Days 1, 8, 15 q4w (n = 131) Patients from China, Japan, Korea, Taiwan Primary endpoint: OS Secondary endpoints: PFS, ORR, safety, QoL Bang YJ, et al. ASCO GI 2013. Abstract 11.

Estimated Survival Function Faz III TyTAN: Paclitaxel ± Lapatinib GS, PFS OS PFS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 L + P (n = 132) P (n = 129) Death, n (%) 98 (74) 0 5 10 15 20 25 30 35 40 45 Mos Since Randomization L + P (n = 132) P (n = 129) Death, n (%) 101 (77) OS, Mos (95% CI) 11.0 (9.5-14.5) 105 (31) 8.9 (7.4-11.1) PFS, Mos (95% CI) 5.4 (3.9-5.7) 87 (67) 4.4 (3.7-5.6) 0 5 10 15 20 25 30 35 40 45 Mos Since Randomization HR: 0.84 (95% CI: 0.54-1.11; P =.2088) ORR, % (95% CI) 27 (19.2-34.9) 9 (4.3-14.7) HR: 0.85 (95% CI: 0.53-1.13; P =.2441) Bang YJ, et al. ASCO GI 2013. Abstract 11.

Trastuzumab-DM1 Target expression: HER2 Monoclonal antibody: Trastuzumab Trastuzumab Cytotoxic agent: DM1 Highly potent cytotoxic agent DM1 MCC Linker: SMCC Systemically stable T-DM1 Average drug:antibody ratio 3.5:1

Faz II/III:İkinci Basamak T-DM1 vs Taxan (HER2+) Stratified by region, ECOG PS, prior gastrectomy, previous HER2-targeted therapy Patients with previously treated locally advanced or metastatic HER2+ gastric cancer or GEJ cancer (Planned N = 412) T-DM1 3.6 mg/kg q3w T-DM1 2.4 mg/kg qw Investigator s Choice Paclitaxel 80 mg/m 2 /wk or Docetaxel 75 mg/m 2 q3w Phase II endpoints: safety, PK, PFS, ORR (N = 100) Phase III endpoints: OS, ORR, PFS, DoR, safety, TTP, Tx-related systems, PK ClinicalTrials.gov. NCT01641939.

OS (%) Faz III GRANITE-1: 2. sıra Everolimus vs PBO 100 80 60 40 20 Everolimus + BSC (n/n = 352/439) Placebo + BSC (n/n = 180/217) Censoring times Median OS Everolimus + BSC: 5.39 mos Placebo + BSC: 4.34 mos HR: 0.90 (95% CI: 0.75-1.08; log-rank P =.1244) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Mos Van Cutsem E, et al. ASCO GI 2012. Abstract LBA3.

PD-1 Expression (%) PD-1 Expression (%) PD-1: Mide Kanseri CD4+ ve CD8+ T Hücrelerinde Expresyon Yüksek P =.0001 P =.0002 90 P =.0035 90 P =.029 70 70 50 50 30 30 10 0 0 PBMC Normal Cancer PBMC Normal Cancer 10 Saito H, et al. J Surg Oncol. 2013;107:517-522.

Pembrolizumab

Relationship between PD-L1 expression and clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-pd-1 monoclonal antibody pembrolizumab (Pembro; MK- 3475) in KEYNOTE-012. Pembrolizumab: Anti-PD-1 monoklonal ab PD-L1 expresyonu (+) *Pembrolizumab 10 mg/kg/2 hf - 1^ ORR - 2^ Yanıt süresi, PFS ve GS. - Sonuçlar: -Ortanca izlem süresi 8.8 ay(6.2-12.6) -5 hastada grade 3-5 advers olay -ORR : 22% (95% CI 10-39) (merkezi değ) ve 33% (95% CI 19-50) (araştırmacı değ) -Ortanca yanıta kadar geçen süre 8 hf (7-16) -Ortanca yanıt süresi 24 hf (8+ to 33+). -PD-L1 expressyon düzeyi ORR ile ilişkili (1-sided P = 0.10). -6-ay PFS oranı 24% -6-ay OS oranı 69% Clinical trial information: NCT01848834

KEYNOTE-012 ASCO GI 2015, Abstract 3 Clinical trial information: NCT01848834

Metastatik Mide Kanserinde 2. Basamak Sistemik Tedavi Terapötik yaklaşımlarda moleküler hedefler önemli yer tutuyor Hedefe yönelik tedavi ile ilk başarı elde edildi İkinci basamak Ramucirumab GS anlamlı uzatıyor Ramucirumab ile sağkalım yararı Dosetaxel veya İrinotekan ile benzer Ramucirumab Paklitaxel ile kombinasyonu GS belirgin uzatıyor İkinci basamak tedavi yeni standart

Mide Kanserinde Güncel Tedavi Global sorun Yaklaşımı: 2015 Hastaların önemli bir kısmının sağkalımı <1y 1. basamak tedavide kemoterapi temel tedavi biçimi HER2 pozitif hastalarda ilk sıra kemoterapiye Trastuzumab eklenmesi GS artırıyor 2. basamak tedavi yeni standart Gelecekte yeni ajanlar ve yeni fırsatlar tanımlanacak c-met yolağı önemli bir hedef oluşturuyor PD-1 monoklonal Ab umut vaad ediyor Genomik veriler yeni hedeflerin tanımlanmasını sağlayabilir

Genomik İnstabilite ve Onkogenez

Number of Multilevel Events per Sample Fokal Amplifikasyonlar: Ust/Alt GI Adenokarsinomlar 3 2 P <.0005 P <.0005 P <.05 Colorectal Gastric Esophageal 1 0 Multicopy Amplifications Dulak AM, et al. Cancer Res. 2012;72:4283-4393.

Amplifiye Fokal SCNA Cytoband Residual q-value Peak Boundaries (Mb) Number of Genes in Peak Candidate Target(s)* Gut Adenocarcinoma Types Represented Gut Adenocarcinomas 12p12.1 8.04E-51 25.23-25.34 3 KRAS E, G 18q11.2 5.05E-37 17.95-18.05 1 GATA6 E, G, C 17q12 4.34E-35 34.97-35.27 10 ERBB2 E, G, C 19q12 5.97E-34 34.95-35.10 1 CCNE1 E, G 8q24.21 8.23E-34 128.50-128.83 2 MYC E, G, C 8p23.1 2.10E-32 11.41-11.71 4 GATA4 E, G 11q13.2 5.26E-22 68.97-69.49 5 CCND1, FGF3, FGF4, E, G FGF19 7q21.2 3.36E-17 92.32-92.50 1 CDK6* E 6p21.1 2.12E-16 43.79-43.99 2 VEGFA E, G 7p11.2 6.71E-16 54.92-55.28 1 EGFR E, G 17q21.2 2.23E-11 37.02-37.21 7 E 9p13.3 7.03E-09 35.52-35.93 24 E 12q15 6.23E-08 67-09-68.25 10 MDM2, FRS2 E, G 7q22.1 1.41E-07 98.41-99.02 16 E 13q13.1 2.04E-06 32.18-33.33 4 E 10q22.2 1.10E-05 75.00-75.80 16 E 7q31.2 1.32E-05 115.98-116.42 6 MET E 1q21.3 1.69E-05 146.23-150.89 106 MCL1 E 1q42.3 1.71E-04 233.02-233.42 4 G 10q26.12 3.17E-04 122.75-123.37 1 FGFR2 E 13q14.11 3.67E-04 40.27-40.83 10 E *BOLD = potential target Dulak AM, et al. Cancer Res. 2012;72:4283-4393.

TEŞEKKÜRLER Dr Özlem ER