Management of advanced Gastric Cancer in the era of targeted therapy

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1 Management of advanced Gastric Cancer in the era of targeted therapy Osman M.Mansour Prof. Medical Oncology, NCI, Cairo University BGO: 28-3 October 215

2 Gastric Cancer: A Significant Problem in Some Countries Incidence of gastric cancer a <3.1 <7. <13.8 <22.2 <118.6 a Crude rate in males (all ages) per 1, population GLOBOCAN 22.

3 Management of Advanced Gastric Cancer: OS Effect of Chemotherapy vs Best Supportive Care on OS Patients, n Study Chemotherapy BSC HR (Fixed) HR (95% CI) Murad 1993 Pyrhonen 1995 Scheithauer ( ).25 ( ).49 ( ) Total HR (95% CI) ( ) Test for heterogeneity: x 2 = 3.32 (P =.19) Test for overall effect: Z = 6.15 (P <.1) Favors Chemotherapy Favors BSC Survival with BSC alone: 3 mos Chemotherapy improves OS compared with BSC: ~ 6-mo benefit Wagner AD, et al. J Clin Oncol. 26;24:

4 Activity of Single Agents in Advanced Gastric Cancer Agent Response Rate, % Mitomycin C 3 Doxorubicin 17 Epirubicin 19 Cisplatin 19 BCNU 18 5-fluorouracil 21 Etoposide (oral) 21 Hydroxurea 19 UFT 27 Capecitabine 19 S-1 45 Paclitaxel Docetaxel Irinotecan 18 ORR: ~ 2% Response duration: short Shah MA, et al. J Natl Compr Canc Netw. 21;8:

5 Monotherapy vs Combination Chemotherapy in Gastric Cancer: Meta-analysis Cullinan 1985 De Lisi 1986 Levi 1986 Cullinan 1994 Loehrer 1994 Colucci 1995 Barone 1998 Yamamura 1998 Popov 22 Ohtsu 23 Bouche Patients, n Study Combination Single-Agent HR (Fixed) HR (95% CI) Chemotherapy Chemotherapy ( ) 1.16 ( ).58 ( ).9 ( ).85 ( ).7 ( ).89 ( ).88 ( ).86 ( ) 1.4 ( ).65 ( ) Total HR (95% CI) ( ) Test for heterogeneity: x 2 = 12.3 (P =.27) Test for overall effect: Z = 3.28 (P =.1) Combination chemotherapy is superior to monotherapy for OS. Wagner AD, et al. J Clin Oncol. 26;24: Favors Combination Favors Single Agent

6 Advanced Gastric Cancer Chemotherapy: What regimen to use? BSC (1) FAMTX (2) C+S1 (3) CF (4) IF (5) EOF (6) DCF (4) ECF (6) ECX (6) XP (7) EOX (6) Median OS in patients with advanced GC (months) 1. Murad, et al. Cancer 1993; 2. Vanhoefer, et al. J Clin Oncol 2 3. Ajani, et al. J Clin Oncol 29; 4. Van Cutsem, et al. J Clin Oncol Dank, et al. Ann Oncol 28; 6. Cunningham, et al. N Engl J Med Kang, et al. Ann Oncol 29; 8. Bang and van Cutsem, et al. Lancet 21

7 Second Line Chemotherapy post Platinum + 5-FU Cougar Trial-2 (U.K.) (GI Symposium 213) pts with gastric and GEJ cancer BSC vs docetaxel 75 mg/m 2 every 3 weeks Responses in 7% of patients Kang (JCO): 22 pts with gastric cancer 2 Docetaxel 6 mg/m 2 or irinotecan 15 mg/m 2 every 3 weeks vs BSC RR 1% irinotecan, 17% for docetaxel 1-Ford et al GI Symposium Kang JCO 3: / 212

8 Phase III COUGAR-2 Trial: Docetaxel vs ASC in Esophagogastric Cancer Stratified by disease status (LA vs advanced), site (esophagus vs GEJ vs stomach), TTP ( vs -3 vs 3-6 mos, ECOG PS (-1 vs 2) Patients with locally advanced or metastatic OGC, PS -2, progression within 6 mos of chemotherapy (N = 168) Docetaxel 75 mg/m 2 IV q3w + Active Symptom Control (n = 84) Active Symptom Control (n = 84) Assess q3w for 18 wks, then q6w Primary objective: OS Secondary endpoints: response to docetaxel, TTP, QoL, toxicity Ford H, et al. ASCO GI 213. Abstract LBA4.

9 Patients Remaining Alive (%) COUGAR-2 Trial : OS 1 75 Docetaxel ASC HR:.67 (95% CI: ) ; P =.1 5 Median Survival, Mos (95% CI) Docetaxel: 5.2 ( ) ASC: 3.6 ( ) Mos From Randomization Pts at Risk, n Docetaxel ASC Ford H, et al. ASCO GI 213. Abstract LBA4.

10 Phase III Korean Study: BSC + Salvage Chemo + vs BSC Alone in Gastric Cancer Patients with metastatic gastric cancer, 1-2 previous chemo* regimens, ECOG PS -1 (N = 22) Docetaxel 6 mg/m 2 on Day 1 q3w or Irinotecan 15 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. 212;3:

11 Survival Probability Phase III Study of BSC + Salvage Chemo + vs BSC Alone in Gastric Cancer: OS Median OS CT + BSC (n = 133): 5.3 mos BSC alone (n = 69): 3.8 mos HR:.66 (95% CI: ; P =.7) No significant difference between docetaxel and irinotecan (p=.116) Pts at Risk, n CT + BSC 133 BSC Mos Kang JH, et al. J Clin Oncol. 212;3:

12 Second Line Chemo: Gastric Cancer AGC refractory to prior FP confirmed by imaging Age 2-75, PS -2, No history of CPT-11 or Taxane RANDOMIZATION Stratified by Institution, PS -1/2, target lesion -/+ weekly Paclitaxel 8 mg/m 2 d1, 8, 15 q4w IRI 15 mg/m 2 d1, 15 q4w Ueda et al Proc ASCO 212

13 Response Rate n CR PR SD PD NE CR+PR P wptx % IRI %.24 RECIST 1. Fisher s exact test

14 Probability (%) Progression Free Survival 1 n Median HR (95% CI) P wptx M IRI M 1.14 ( ).33 Log-rank test wptx IRI Number at risk (Months)

15 Probability (%) Overall Survival 1 n Median HR (95% CI) P wptx M IRI M 1.13 ( ) Log-rank test wptx IRI Number at risk (Months)

16 Molecular Targets: Gastric Cancer HER2 over expression: 1-25% - Proximal: 25-3% - Distal: 2-25% - Diffuse :<5% KRAS mutation: < 5-1% BRAF mutation: < 5% EGFR over expression: 5-8%, mutation: < 5% C-MET: Gene amplification 1-15%, IHC + 5 % Galizia W J Surg 31: 1458; 27 Mammano Anticancer Res 26: 3547; 26 Lee Oncogene 22: 6942; 23 Yano Oncol Rep 15: 65; 26 Gold GI CA Symp 28 Abs 96

the structure of low-grade gastric adenocarcinoma cells This is in contrast to breast cancer, where only complete membrane

17 GC has a different HER2 IHC staining pattern from breast cancer HER2 staining of gastric and GE junction tumour cell membranes may be: complete, basolateral, or lateral in nature HER2-positive gastric tumour 1 Basolateral/lateral staining occurs due to the structure of low-grade gastric adenocarcinoma cells This is in contrast to breast cancer, where only complete membrane staining is classified as HER2-positive HER2-positive breast tumour 2 1. Hofmann, et al. Histopathology 28; 2. Image courtesy of Dako

required for FISH (6-8 endoscopic biopsies) Hofmann M, et al.

18 Hetrogenous Expression of HER2 in Gastric cancer In gastric cancer, tumor Heterogeneity occurs in 5 3% of cases Screening of the entire specimen is required for FISH (6-8 endoscopic biopsies) Hofmann M, et al. Histopathology 28; 52:797 üschoff J, et al. Pathologie 21; 31:28-17 Van Cutsem E, Bang Y et al Gastric cancer 214

19 Immunohistochemistry (IHC) Subjective scoring of HER2 surface protein expression IHC + HER2 Negative IHC 1+ HER2 Negative IHC 2+ Equivocal IHC 3+ Positive In-Situ Hybridization (-ISH) Quantitative ratio of HER2 to normal genes (CEP17) Anti-HER2 therapy HER2/ CEP17 2. FISH neg = HER2- No HER2 gene amplification HER2/ CEP17 > 2. FISH positive = HER2+ HER2 gene amplification Paik, et al (22). Anti-HER2 therapy

20 HER-2 Positivity IHC Bang YJ, Van Cutsem E et al., The Lancet, 376(9742), 21

Anti-HER 2 Agents Trastuzumab HER1/ EGFR HER 2 HER 3 TDM-1 Pertuzumab Neratinib

Agents *TDM-1 *Pertuzumab *Neratinib *Everolimus Anti-HER2 MoAb HER2/EGFR inhibitor HER1

21 Anti-HER 2 Agents Trastuzumab HER1/ EGFR HER 2 HER 3 TDM-1 Pertuzumab Neratinib Lapatinib Lapatinib Everolimus Agent Trastuzumab Lapatinib Mechanism *Investigational Agents *TDM-1 *Pertuzumab *Neratinib *Everolimus Anti-HER2 MoAb HER2/EGFR inhibitor HER1 MoAb-chemo conjugate Prevents HER2/HER3 binding EGFR/HER2 inhibitor P13K/PTEN/mTOR pathway Gunby et al. Oncogenic Fusion Tyrosine Kinases As Molecular Targets for Anti-Cancer Therapy. Anti-Cancer Agents in Medicinal Chemistry, 27; 7: Images created by Kristine Abueg.

22 ToGA trial design Phase III, randomized, open-label, international, multicenter study 387 patients screened 1 81 HER2-positive (22.1%) Stratification factors - advanced vs metastatic - GC vs GEJ - measurable vs non-measurable - ECOG PS -1 vs 2 - capecitabine vs 5-FU a Chosen at investigator s discretion 1 Bang et al; Abstract 4556, ASCO 29 HER2-positive advanced GC (n=584) R 5-FU or capecitabine a + cisplatin (n=29) 5-FU or capecitabine a + cisplatin + trastuzumab (n=294)

23 Primary end point: OS Event FC + T FC Events Median OS HR.74 95% CI.6,.91 p value.46 Time (months) No. at risk T, trastuzumab

24 Secondary end point: Response Rate Patients (%) Intent to treat p=.145 p=.17 F+C + trastuzumab F+C 47.3% 41.8% p= % 34.5% 2.4% 5.4% CR PR ORR ORR= CR + PR CR, complete response; PR, partial response

25 Secondary end point: PFS Event FC + T FC Events Median PFS HR.71 95% CI.59,.85 p value.2 Time (months) No. at risk

26 Trastuzumab does not impact on the overall safety profile (1) Herceptin + XP/FP n=294 XP/FP n=29 Adverse event, % All grades* Grade 3/4 All grades* Grade 3/4 Renal impairment Pyrexia Mucosal inflammation Nasopharyngitis 13 6 Haematological AEs Neutropenia Anaemia Thrombocytopenia *Occurring in >1% of patients; occurring in >5% of patients; AEs, adverse events Bang & Van Cutsem et al 21

27 Trastuzumab does not impact on the overall safety profile (2) Herceptin + XP/FP n=294 XP/FP n=29 Adverse event, % All grades* Grade 3/4 All grades* Grade 3/4 Nausea Anorexia Vomiting Constipation Fatigue Diarrhoea Hand foot syndrome Abdominal pain Asthenia Stomatitis Weight decrease *Occurring in >5% of patients; occurring in >1% of patients Bang & Van Cutsem et al 21

28 Trastuzumab does not impact on the cardiac Safety profile 1,2 Cardiac adverse event, n (%) Herceptin + XP/FP n=294 XP/FP n=29 All grades Grade 3/4 All grades Grade 3/4 Cardiac AEs, total 17 (6) 4 (1) 18 (6) 9 (3) Cardiac failure 1 (<1) 1 (<1) 2 (<1) 2 (<1) LVEF drops* <5% 14 (5.9) 2 (1.1) <5% and by 1% 11 (4.6) 2 (1.1) Cardiac AEs leading to death 2 (<1) Acute MI; cardiac failure 2 (<1) Cardiac arrest; cardio-respiratory arrest *Measured at baseline and every 12 weeks; MI, myocardial infarction 1. Van Cutsem et al Bang & Van Cutsem et al 21

29 Trastuzumab-Based Therapy: Median OS > 1 Yr BSC [27] FAMTX [28] C + S-1 [29] CF [3] IF [31] EOF [32] DCF [3] ECF [32] ECX [32] XP [33] EOX [32] Trastuzumab + XP/FP [34] HER2 IHC 2+/FISH+ or IHC mos Median OS in Patients With Advanced Gastric Cancer (Mos) 27. Murad AM, et al. Cancer. 1993;72: Vanhoefer U, et al. J Clin Oncol. 2;18: Ajani JA, et al. J Clin Oncol. 21;28: Van Cutsem E, et al. J Clin Oncol. 26;24: Dank M, et al. Ann Oncol. 28;19: Cunningham D, et al. N Engl J Med. 28;358: Kang YK, et al. Ann Oncol. 29;2: Bang YJ, et al. Lancet. 21;376:

30 LOGIC Phase III Study: Lapatinib With CapeOx in HER2+ Gastric Cancer 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 125 mg QD Days Oxaliplatin 13 mg/m 2 Day 1 + Capecitabine 85 mg/m 2 BID (n = 272) Placebo QD Oxaliplatin 13 mg/m 2 Day 1 Capecitabine 85 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 213. Abstract LBA41.

31 Probability of Survival Lapatinib With CapeOx in HER2+ Gastric Cancer (TRIO-13): OS (PEP*) Primary Efficacy Population* Median OS, mos (95% CI) CapeOx + L (n = 249) CapeOx + P (n = 238) 12.2 ( ) 1.5 ( ) HR (95% CI; P value).91 ( ;.3492) Pts at Risk, n CapeOx + L.4.2 CapeOx + L CapeOx + P Mos Since Randomization ITT Analysis HR:.91 *Centrally confirmed HER2+ by FISH. CapeOx + P Hecht JR, et al. ASCO 213. Abstract LBA41.

32 Phase III TYTAN: Second-line Paclitaxel ± Lapatinib in HER2+ Gastric Cancer 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 15 mg/day + Paclitaxel 8 mg/m 2 Days 1, 8, 15 q4w (n = 13) Paclitaxel 8 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 213. Abstract 11.

33 Estimated Survival Function Second-line Paclitaxel ± Lapatinib in Gastric Cancer (TyTAN): OS, PFS OS L + P (n = 132) P (n = 129) Death, n (%) 98 (74) Mos Since Randomization OS, Mos (95% CI) 11. ( ) 15 (31) 8.9 ( ) HR:.84 (95% CI: ; P =.288) PFS L + P (n = 132) P (n = 129) Death, n (%) 11 (77) OS, Mos (95% CI) 5.4 ( ) 87 (67) 4.4 ( ) Mos Since Randomization Bang YJ, et al. ASCO GI 213. Abstract 11. ORR, % (95% CI) 27 ( ) 9 ( ) HR:.85 (95% CI: ; P =.2441)

34 Phase III JACOB: Trastuzumab + Chemo ± Pertuzumab in HER2+ Gastric Cancer 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 = 78) Primary endpoint: OS Pertuzumab 84 mg Trastuzumab 8 mg/kg x 1 then 6 mg/kg Cisplatin 8 mg/m 2 5-fluorouracil Capecitabine 8 mg/m 2 /24 h or 1 mg/m 2 BID x 14 d continuously for 12 h Placebo Trastuzumab 8 mg/kg x 1 then 6 mg/kg Cisplatin 8 mg/m 2 5-fluorouracil 8 mg/m 2 /24 h continuously for 12 h or Capecitabine 1 mg/m 2 BID x 14 d PD or toxicity Tabernero J, et al. ASCO 213. Abstract TPS415.

Antibody Drug Conjugate: TDM-1 (trastuzumab

Trastuzumab bound to cytotoxic chemotherapy

release of mertansine Juntilla, 21, Lewis,

35 Antibody Drug Conjugate: TDM-1 (trastuzumab emtansine) Immune CellsDM1 Immune Cells Trastuzumab bound to cytotoxic chemotherapy Trastuzumab Retains trastuzumab ADCC action Intracellular Chemo Delivery Apoptosis Mediate internalization & intracellular release of mertansine Juntilla, 21, Lewis, 211,Scaltriti, et al 27; Mukohara 211 Images created by Kristine Abueg

36 Phase II/III Study: Second-line T-DM1 vs Taxane for Advanced HER2+ Gastric Cancer 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 8 mg/m 2 /wk or Docetaxel 75 mg/m 2 q3w Phase II endpoints: safety, PK, PFS, ORR (N = 1) Phase III endpoints: OS, ORR, PFS, DoR, safety, TTP, Tx-related systems, PK ClinicalTrials.gov. NCT

37 OS (%) Phase III GRANITE-1 Study: Second-line Everolimus vs BSC in Adv Gastric Cancer Everolimus + BSC (n/n = 352/439) Placebo + BSC (n/n = 18/217) Censoring times Median OS Everolimus + BSC: 5.39 mos Placebo + BSC: 4.34 mos HR:.9 (95% CI: ; log-rank P =.1244) Mos Van Cutsem E, et al. ASCO GI 212. Abstract LBA3.

38 EGFR Directed Therapy: Phase III Trials COG: BSC vs Gefitinib (U.K.): Negative trial for OS EXPAND: Cape-Cis + / - Cetuximab (E.U.) REAL 3: EOC + / - Panitumumab (U.K.)

39 Phase III EXPAND: Cape/Cis ± Cetuximab in Untreated Advanced Gastric Cancer Stratified by disease stage (M 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 = 94) Cetuximab 4 mg/m 2 on Day 1, then 25 mg/m 2 qw + Capecitabine 1 mg/m 2 BID on Days Cisplatin 8 mg/m 2 on Day 1 (n = 455) Capecitabine 1 mg/m 2 BID on Days Cisplatin 8 mg/m 2 on Day 1 (n = 449) Primary endpoint: PFS Secondary endpoints: OS, ORR Lordick F, et al. Lancet Oncol. 213;14:

40 OS (%) Cape/Cis ± Cetuximab in Untreated Advanced Gastric Cancer (EXPAND): OS Median OS, Mos Cape/cis/cetux: 9.4 Cape/cis: 1.7 HR: 1. (95% CI: ; P =.95) Mos From Randomization Lordick F, et al. Lancet Oncol. 213;14:

41 Phase III REAL3: EOC ± Panitumumab in Advanced Gastroesophageal Cancer Patients with untreated advanced gastroesophageal adenocarcinoma (N = 553) Epirubicin 5 mg/m 2 on Day 1 + Oxaliplatin 13 mg/m 2 on Day 1 + Capecitabine 125 mg/m 2 /day on Days 1-21 (n = 275) Epirubicin 5 mg/m 2 on Day 1 + Oxaliplatin 1 mg/m 2 on Day 1 + Capecitabine 1 mg/m 2 /day on Days 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. 213;14:

42 REAL3 RR (Secondary end point) Best Response EOC (n=238) meoc-p (n=254) CR 5 (2%) 8 (3%) PR 95 (4%) 18 (43%) SD 51 (21%) 46 (18%) PD 19 (8%) 3 (12%) Not evaluable 68 (29%) 62 (24%) ORR 42% 46% Odds Ratio for Response 1.16 (95% CI: ) p-value.467 Waddell T, et al. Lancet Oncol. 213;14:

43 Probability of Survival (%) REAL3 PFS (Secondary end point) Median PFS (95% CI) % alive and progressionfree at 1 year (95% CI) 7.4m ( ) 21% (14% - 27%) 6.m ( ) 2% (14% - 26%) HR 1.22, p =.68 2 EOC EOC-P HR 1.22 (95% CI: ) Number at risk Months from Randomisation EOC EOC-P Waddell T, et al. Lancet Oncol. 213;14: Based on 331 events

44 Probability of Survival (%) REAL3 OS (Primary end point) 1 8 Median OS (95% CI) % alive at 1 year (95% CI) 11.3m ( ) 46% (38% - 54%) 6 8.8m ( ) 33% (26% - 41%) HR 1.37, p = EOC EOC-P HR 1.37 (95% CI: ) Number at risk Months from Randomisation EOC EOC-P Waddell T, et al. Lancet Oncol. 213;14: Based on 251 OS events

45 Survival Rate (%) Survival Following Gastric Cancer Resection by Circulating Plasma VEGF VEGF < 1 pg/ml P =.44 VEGF 1 pg/ml Survival Days Yoshikawa T, et al. Cancer Lett. 2;153:7-12.

46 AVAGAST: Bevacizumab in advanced gastric cancer 6 Cycles Locally advanced or metastatic gastric cancer (n=774) R Bevacizumab 7.5 mg/kg + XP Placebo + XP Bevacizumab 7.5 mg/kg + capecitabine/ 5-FU Placebo + capecitabine/ 5-FU Treat to PD Primary endpoint: OS Secondary endpoints: PFS, TTP, ORR, DOR, Safety, QoL and Biomarkers XP=capecitabine/5-FU + cisplatin. Ohtsu et al. J Clin Oncol 211;29:

47 AVAGAST: Results Both arms well tolerated without major toxicity differences +Bev +Placebo P value HR (95% CI) Median PFS, mos ( ) Response rate 46% 37%.3 Median OS, mos ( ) Ohtsu et al. J Clin Oncol 211;29:

48 *Cox regression for OS identified five significant prognostic factors: ECOG PS >1, prior gastrectomy, bone metastases, intestinal type histology and peritoneal metastases. All patients (n=774) were pooled into three risk groups: low ( risk factors), moderate (1 risk factor), high (>1 risk factor) AVAGAST: Results Risk group Region HR P value Low All (N=58) Asia Europe America Moderate All (N=27) Asia Europe America High All.8.37 N=(57) Asia Europe America.6.246

49 Ramucirumab: IgG1 Antibody to 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. 213;9:

50 REGARD: Phase III Study of Ramucirumab in Second-Line Gastric Cancer 346 patients who failed FU or CDDP-based therapy R A N D O M I Z E Ramucirumab + Best supportive care Placebo + Best supportive care Primary Endpoint: Overall Survival Fuchs CS et al. Lancet. 214;383:31-39

51 Overall Survival REGARD: Overall Survival HR (95% CI) =.776 (.63,.998) Log rank p-value (stratified) =.473 Ramucirumab Placebo Patients/Events 238/ /99 Median (mos) (95% CI) 5.2 ( ) 3.8 ( ) 6-month OS 42% 32% 12-month OS 18% 11% Ramucirumab Placebo Censored Fuchs CS et al. Lancet. 214;383:31-39 Months

52 Progression-Free Survival REGARD: Progression-Free Survival HR (95% CI) =.483 (.376,.62) Log rank p-value (stratified) <.1 Ramucirumab Placebo Patients/Events 238/ /18 Median (mos) (95% CI) 2.1 ( ) 1.3 ( ) 12-week PFS 4% 16% Ramucirumab Placebo Censored Fuchs CS et al. Lancet. 214;383:31-39 Months

53 REGARD: Adverse Events of Special Interest Grade 3 AEs Ramucirumab (n = 236) Placebo (n = 115) Hypertension 7.6% 2.6% Bleeding/hemorrhage 3.4% 2.6% Arteriothromboembolic 1.3% % Venous thromboembolic 1.3% 4.3% Proteinuria.4% % GI perforation.8%.9% Fistula (GI and non-gi).4%.9% Fuchs CS et al. Lancet. 214;383:31-39

54 Phase III RAINBOW Study: Paclitaxel ± Ramucirumab in second line Gastric Cancer 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 8 mg/m 2 on D 1, 8, 15 (n = 33) Placebo on D 1, 15 Paclitaxel 8 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 214. Abstract LBA7.

55 Probability of OS Paclitaxel ± Ramucirumab in Advanced Gastric Cancer (RAINBOW): OS Ram/Ptx Placebo/Ptx Patients/events, n 33/ /26 Median, mos 9.63 ( ) 7.38 ( ) (95% CI) 6-mo OS, % mo OS, % 4 3 HR:.87 (95% CI: ; P =.169).4.2 Δ mos = 2.3 mos Ram + Ptx Placebo + Ptx Censored Mos Wilke H, et al. ASCO GI 214. Abstract LBA7.

56 OS (%) OS (%) Paclitaxel ± Ramucirumab in Adv Gastric or GEJ Cancer (RAINBOW): OS by Age Younger Than 65 Yrs of Age Ramucirumab + Paclitaxel Placebo + Paclitaxel Median, Mos Ramucirumab + paclitaxel Placebo + paclitaxel Yrs of Age or Older Ramucirumab + Paclitaxel Placebo + Paclitaxel Median, Mos Ramucirumab + paclitaxel Placebo + paclitaxel Mos Muro K, et al. ASCO GI 215. Abstract Mos ITT population

57 Probability of PFS Paclitaxel ± Ramucirumab in Adv. Gastric Cancer (RAINBOW): PFS, Responses Ram/Ptx Placebo/Ptx Patients/events, n 33/ /296 Median, mos 4.4 ( ) 2.86 ( ) (95% CI) 6-mo PFS, % mo PFS, % 22 1 ORR, % P =.1 DCR 8 64 P <.1 HR:.635 (95% CI: ; P <.1).2.1 Ram + Ptx Placebo + Ptx Censored Mos Wilke H, et al. ASCO GI 214. Abstract LBA7.

58 PFS (%) PFS (%) Paclitaxel ± Ramucirumab in Adv Gastric or GEJ Cancer (RAINBOW): PFS by Age Younger Than 65 Yrs of Age Ramucirumab + Paclitaxel Median, Mos 4.3 Placebo + Paclitaxel 2.8 Ramucirumab + paclitaxel Placebo + paclitaxel Yrs of Age or Older Ramucirumab + Paclitaxel Median, Mos 4.6 Placebo + Paclitaxel 2.9 Ramucirumab + paclitaxel Placebo + paclitaxel Mos Muro K, et al. ASCO GI 215. Abstract Mos ITT population

59 Paclitaxel ± Ramucirumab in Adv Gastric or GEJ Cancer (RAINBOW): AEs by Age For both age groups, more pts on the ramucirumab arm discontinued treatment due to AEs and had dose modifications (delays, omissions, reductions) and grade 3/4 events Number of pts discontinuing treatment because of AEs (any grade and grade 3/4) similar in both age groups, regardless of treatment AE Leading to Discontinuation, n (%) Ram/Pac (n = 24) < 65 Yrs 65 Yrs Placebo/Pac (n = 26) Ram/Pac (n = 123) More frequent dose modifications for paclitaxel in pts 65 yrs Placebo/Pac (n = 123) Any grade 6 (29.4) 5 (24.3) 42 (34.1) 3 (24.4) Grade 3 45 (22.1) 35 (17.) 28 (22.8) 2 (16.3) Muro K, et al. ASCO GI 215. Abstract 11.

60 Met Pathway and Targeted Agents 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 Epithelial/cancer cell MEK Akt RAS/RAF/MEK/ERK ERK Invasion/metastasis Appleman LJ. J Clin Oncol. 211;29: Survival Proliferation

61 Phase II Study: FOLFOX ± Onartuzumab in Metastatic Gastroesophageal Cancer Stratified by histology and prior gastrectomy Pts with metastatic gastroesophageal cancer; no prior treatment for metastatic disease; HER2 neg; ECOG PS /1 (N = 123) mfolfox6* + Onartuzumab 1 mg/kg q2w 12 cycles (n = 62) mfolfox6* + Placebo q2w 12 cycles (n = 61) Onartuzumab 1 mg/kg Placebo Disease progression *Oxaliplatin 85 mg/m 2, leucovorin 2 mg/m 2, 5-fluorouracil 4 mg/m 2 bolus and 24 mg/m 2 IV. Primary endpoints: PFS in ITT population and MET-positive subgroup ( 5% high IHC staining) Secondary endpoints: OS, ORR, safety Target HRs:.7 in ITT population and.6 in MET-positive subgroup Shah MA, et al. ASCO GI 215. Abstract 2.

62 PFS Probability (%) FOLFOX ± Onartuzumab in Metastatic Gastroesophageal Cancer: Survival PFS in MET Positive Median PFS 5.95 vs 6.8 Stratified HR: 1.38 (95% CI:.6-3.2; P =.4514) Mos No significant PFS improvement with onartuzumab (in both ITT and MET positive) No difference in median OS with onartuzumab in ITT (1.61 vs mos) or MET-positive (8.51 vs 8.48 mos) populations Asian pts had longer PFS and OS regardless of treatment arm, consistent with previously described trends in gastric cancer [16] Placebo + mfolfox6 (n = 19) Onartuzumab + mfolfox6 (n = 16) Shah MA, et al. ASCO GI 215. Abstract Wang J, et al. Ann Surg Oncol. 215;[Epub ahead of print].

63 FOLFOX ± Onartuzumab in Metastatic Gastroesophageal Cancer: Safety Most common AEs ( 25% of pts): nausea, vomiting, diarrhea, constipation, abdominal pain, peripheral neuropathy, neutropenia, fatigue, peripheral edema AEs leading to withdrawal: 53% with onartuzumab vs 33% with placebo Any Grade Grade 3 AEs of Special Interest, n (%) Onartuzumab + mfolfox6 (n = 6) Placebo + mfolfox6 (n = 6) Onartuzumab + mfolfox6 (n = 6) Placebo + mfolfox6 (n = 6) Embolic/thromboembolic events (arterial) Embolic/thromboembolic events (venous) 2 (3.3) 1 (1.7) 14 (23.3) 5 (8.3) 7 (11.7) 3 (5.) Gastrointestinal perforation 3 (5.) 2 (3.3) 2 (3.3) 1 (1.7) Edema 37 (61.7) 1 (16.7) 6 (1.) 2 (3.3) Shah MA, et al. ASCO GI 215. Abstract 2.

64 Phase II Study: ECX ± Rilotumumab in Gastric or GEJ Cancer Stratified by ECOG PS ( 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 Oliner KS, et al. ASCO 212. Abstract 45. Rilotumumab 15 mg/kg + Epirubicin 5 mg/m 2 on Day 1 + Cisplatin 6 mg/m 2 on Day 1 + Capecitabine 625 mg/m 2 BID on Days 1-21 (n = 4) Rilotumumab 7.5 mg/kg + Epirubicin 5 mg/m 2 on Day 1 + Cisplatin 6 mg/m 2 on Day 1 + Capecitabine 625 mg/m 2 BID on Days 1-21 (n = 42) Placebo Epirubicin 5 mg/m 2 on Day 1 Cisplatin 6 mg/m 2 on Day 1 Capecitabine 625 mg/m 2 BID on Days 1-21 (n = 39)

65 Oliner KS, et al. ASCO 212. Abstract 45.

66 OS (%) PFS (%) ECX ± Rilotumumab in Gastric or GEJ Cancer (Phase II): PFS, OS in MET High Pts Mos Mos *HR adjusted for baseline disease extent and ECOG PS. Oliner KS, et al. ASCO 212. Abstract 45. Rilotumumab + ECX (n = 27) Placebo + ECX (n = 11) OS Rilotumumab + ECX (n = 27) Placebo + ECX (n = 11) Median Mos (8% Cl) 6.9 ( ).51 ( ) 4.6 ( ) Median Mos (8% Cl) 11.1 ( ).29 ( ) 5.7 ( ) HR+ (95% Cl) P Value MET-evaluable OS HR:.95 ITT OS HR: HR+ (95% Cl) P Value.12

67 Phase III RILOMET-1 Study: First-line ECX ± Rilotumumab in MET+ Gastric Cancer Patients with MET+, unresectable metastatic or locally advanced gastric canceror GEJ cancer (Planned N = 45) 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. NCT

68 Comprehensive Molecular Characterization of Gastric Adenocarcinoma: Molecular platforms 5% 9% 2% 22% The Cancer Genome Atlas Research Network. Nature 214; 513:22-29

69 Phase Ib KEYNOTE-12: Pembrolizumab in PD-L1+ Advanced Gastric Cancer Pts with recurrent or metastatic gastric or GEJ cancer; PD-L1 positive*; ECOG PS -1 (N = 39) Pembrolizumab 1 mg/kg q2w CR PR or SD PD Discontinuation permitted Treat for 24 mos or until PD or intolerable toxicity Discontinue *Assessed in archival tissue by IHC; stromal staining or 1% of tumor cells positive required. Clinically stable pts remain on treatment until disease progression confirmed by second scan 4 wks later. Primary efficacy endpoint: response by RECIST v1.1 Secondary endpoints: duration of response, PFS, OS Muro K, et al. ASCO GI 215. Abstract 3.

70 Pembrolizumab in PD-L1+ Advanced Gastric Cancer (KEYNOTE-12): ORR Response, % Central Review (n = 36)* Investigator Review (n = 39) ORR (95% CI) 22.2 ( ) 33.3 ( ) Best Overall response CR PR SD PD No assessment 2.8 Not determined 8.3 *Pts with measurable disease by RECIST v1.1 at baseline. All responses confirmed. Pts with evaluable disease at baseline who discontinued due to clinical progression prior to first scan. Pts with evaluable disease at baseline for whom best response could not be determined. Muro K, et al. ASCO GI 215. Abstract 3.

71 Change From Baseline (%) Pembrolizumab in PD-L1+ Adv Gastric Cancer (KEYNOTE-12): Tumor Shrinkage Change in Tumor Size From Baseline (RECIST v1.1; Central Review) Muro K, et al. ASCO GI 215. Abstract 3. Discontinued On treatment Wks

72 PFS (%) OS (%) Pembrolizumab in PD-L1+ Advanced Gastric Cancer (KEYNOTE-12): PFS, OS 1 PFS 1 OS Mos Pts at Risk, n mo PFS rate: 24% Median PFS: 1.9 mos (95% CI: ) Median time to response: 8 wks (range: 7-16) Median duration of response: 24 weeks (range: 8-33+) Muro K, et al. ASCO GI 215. Abstract Mos Pts at Risk, n mo OS rate: 69% Median OS: not reached

73 Pembrolizumab in PD-L1+ Advanced Gastric Cancer (KEYNOTE-12): Safety Most common treatment-related AEs: fatigue, decreased appetite, hypothyroidism, arthralgia 1 death due to grade 5 hypoxia Grade 3-5 AEs, n (%) *Considered treatment related. Pts (N = 39) Pts with an event 4 (1.3) Events Decreased appetite 1 (2.6) Fatigue (grade 3) 1 (2.6) Hypoxia (grade 5)* 1 (2.6) Peripheral sensory neuropathy (grade 3) 1 (2.6) Pneumonitis (grade 4 1 (2.6) Muro K, et al. ASCO GI 215. Abstract 3.

74 Pembrolizumab in PD-L1+ Adv Gastric Cancer (KEYNOTE-12): Conclusions Single-agent pembrolizumab led to durable responses in 22% of pts by central review (33% per investigator) * Median time to response: 8 wks (range: 7-16) Median duration of response: 24 wks (range: 8-33) Trend toward association of higher PD-L1 expression with improved ORR, PFS, and OS Acceptable safety and tolerability profile Phase II KEYNOTE-59 study under way: pembrolizumab ± cisplatin/5-fluorouracil in pts with advanced gastric or GEJ cancer ** * Muro K, et al. ASCO GI 215. Abstract 3. ** ClinicalTrials.gov. NCT

75 Thank you

Chemotherapy for Advanced Gastric Cancer

Chemotherapy for Advanced Gastric Cancer Andrés Cervantes Professor of Medicine DISCLOSURE OF INTEREST Employment: None Consultant or Advisory Role: Merck Serono, Roche, Beigene, Bayer, Servier, Lilly,