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Metastatic Gastric Cancer John L. Marshall, MD Lombardi Cancer Center Georgetown University Washington DC.

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Presentation on theme: "Metastatic Gastric Cancer John L. Marshall, MD Lombardi Cancer Center Georgetown University Washington DC."— Presentation transcript:

1 Metastatic Gastric Cancer John L. Marshall, MD Lombardi Cancer Center Georgetown University Washington DC

2 4th most common malignant disease ~ 930,000 2nd most common cause of cancer-related death worldwide ~700,000 Falling incidence of distal gastric cancer Increasing incidence of proximal gastric cancer Wide geographical variation Gastric cancer: a global disease Kamangar F et al. J Clin Oncol 2006;24:2137–50  20 / <10 /  10 -  20 / Incidence (males)

3 Neo-adjuvant and adjuvant therapy for gastric cancer: different strategies Post-operativeChemoradiotherapy (trend to perioperative CT in academic centers) in academic centers) Peri-operativeChemotherapy (ECF- 5FU/cisplatin) Post-operativeChemotherapy (5FU/Xeloda or combination) Postoperative CT

4 North American Perspective We see more proximal tumors Surgery first dominates in community hospitals Chemotherapy first dominates in academic centers We are unsure what to do with radiation Our patients are typically quite ill from the beginning

5 State of the Art More than one disease –Gastric- low acid –Esophageal – tobacco, alcohol –GE Junction- high acid Different cancers in different parts of the world –Asia ≠ Western No regional or global standards –Surgical differences –Chemotherapy differences –Sequence of therapy differences  (Chemo, Surgery, Radiation)

6 Esophagogastric Cancer: Siewart Classification From Siewart, J Surg Onc 2005, v. 90: 139

7 Role of Docetaxel: V 325 Phase III R A N D O M I Z E Stratification Factors: Liver Involvement Prior Gastrectomy Measurable vs Evaluable Disease Weight Loss (>5%) in Prior 3 Months Centers Adequate hydration and anti-emetics required, No Prophylactic Growth Factors Response assessment every 8 weeks independent of treatment schedule Cisplatin 100 mg/m 2 /IV over 1-3 hrs Cycles repeated every 4 weeks Docetaxel 75 mg/m 2 IV over 1 hr Cisplatin 75 mg/m 2 IV over 1-3 hrs both on Day 1 only 5-FU 750 mg/m 2 /day by CIV over 5 days Days 1-5 Cycles repeated every 3 weeks 5-FU 1000 mg/m 2 /day by CIV over 5 days Days 1-5

8 Results: TAX 325 DCF (227)CF (230) 36.7%ORR (P=0.02) 25.4% 5.6 monthsMed. TTP (p=0.0004) 3.7 months 9.2 monthsMed. Survival (HR=1.29, p=0.02) 8.6 months 40.2%1-yr. Survival31.6% 18.4%2-yr. Survival8.8%

9 Toxicity: TAX 325 DCF (221) Gr. 3-4 Toxicity (% of Pts) CF (224) 82% Neutropenia 57% 66% Received GCSF 20% 30% Neutro. Fever/Infect. 13% 20% Diarrhea 8% 21% Stomatitis 27% 15% Vomiting 19% 8% Neurologic 3% 3.6 % Death from Toxicity 5.4 %

10 DCF is too toxic- and not worth it mDCF vs DCF Shah et al: ASCO 4014, 2010 DCF is “spicy”- requires G-CSF mDCF less so –72 patients randomized –mDCF had a better survival Does dose intensity matter in GI cancers?

11 Advanced Gastric Cancer: REAL-2 Cunningham, NEJM 2008, v 358, p pts with unresectable esophageal/ gastric cancer enrolled 6/00-5/05 –63 yo (22-83) –81% male –78% metastatic –40% gastric, 35% esophageal, 25% GEJ –90% adenoCA –11% PS2 Primary endpoint: –Survival –non-inferiority design (23% boundary)

12 REAL-2 2x2 design (ECF, EOF, ECX, EOX) Cycles repeated every 21 days –Epirubicin 50 mg/m2 IV D#1 –Cisplatin 60 mg/m2 IV D#1 or Oxaliplatin 130 mg/m2 IV D#1 –5-Fluorouracil 200 mg/m2/d IVCI or Capecitabine 625 mg/m2 PO BID

13 Cunningham, NEJM 2008, v358, p. 42

14 Cunningham, NEJM 2008, v 358, p. 41

15 Cunningham, NEJM 2008, v358, p 44

16 CALGB / ECOG E1206: Schema Stratification: ECOG 0-1 vs 2 ADC vs. SCC ARM A: (ECF + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Epirubicin 50 mg/m2 IV, day 1 Cisplatin 60mg/m2 IV, day 1 Fluorouracil 200mg/m2/day, days 1-21 ARM B: (IC + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Cisplatin 30 mg/m2 IV, days 1 and 8 Irinotecan 65 mg/m2 IV, days 1 and 8 ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days Cetuximab 400  250mg/m2 IV, weekly Oxaliplatin 85 mg/m2 IV, day 1 Leucovorin 400 mg/m2, day 1 Fluorouracil 400 mg/m2 IV bolus, day 1 Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

17 CALGB 80403/ECOG 1206: Response *RECIST - confirmed; restaging every 6 weeks

18 CALGB 80403/ECOG 1206: Overall Survival by Arm

19 The ToGA trial: A phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer

20 HER2 and trastuzumab mechanism of action HER2 receptor trastuzumab Trastuzumab Inhibits HER2-mediated signalling in HER2-positive tumors Prevents HER2 activation by blocking extracellular domain cleavage Activates antibody-dependent cellular cytotoxicity

21 The Rules for EGFR Targeting Breast- HER2 overexpression Colon- KRAS Lung- ATP binding site mutations Gastric- Do we actually know?

22 HER2 testing HER2 testing in breast cancer is well established Recent evidence shows that same techniques with some modifications are also valid for assessing HER2 status in stomach cancer 1. Hoffmann 2008

23 HER2 testing – 2 main methods 1.Immunohistochemistry (IHC) –Shows how much of the HER2 protein is present in the tumour sample HER2-negative HER2-positive

24 HER2 testing – 2 main methods 2.Fluorescence in-situ hybridization (FISH) –Measures the amount of the HER2/neu gene in each cell HER2-negative HER2-positive

25 ToGA trial design HER2-positive advanced GC (n=584) 5-FU or capecitabine a + cisplatin (n=290) R a Chosen at investigator’s discretion GEJ, gastroesophageal junction 5-FU or capecitabine a + 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 Phase III, randomized, open-label, international, multicenter study 1 Bang et al; Abstract 4556, ASCO patients screened HER2-positive (22.1%)

26 Treatment regimens Capecitabine 1000 mg/m 2 bid d1-14 q3w x 6 5-Fluorouracil 800 mg/m 2 /day continuous iv infusion d1-5 q3w x 6 Cisplatin 80 mg/m 2 q3w x 6 Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg q3w until PD

27 ToGA trial end points Primary end point: −overall survival Secondary end points −PFS, TTP, ORR, Clinical Benefit Rate, Duration of Response, QoL, safety, pain intensity, analgesic consumption, weight change, pharmacokinetics Sample size assumptions −median OS improvement from 10 to 13 months (HR 0.77) −α-level = 0.05, 80% power −required sample size: 584 patients randomized 1:1 Analyses −1st pre-planned interim analysis after 230 events (50%) −2nd interim analysis after 345 events (75%) considered final by Independent Data Monitoring Committee

28 Main patient selection criteria Exclusion criteria Previous adjuvant chemotherapy within 6 months Chemotherapy for advanced disease Congestive heart failure or baseline LVEF <50% Creatinine clearance <60 mL/min IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction Inclusion criteria Adenocarcinoma of stomach or GEJ Inoperable locally advanced and/or metastatic disease Measurable (RECIST), or non-measurable evaluable disease HER2-positive tumor (centrally assessed) –IHC 3+ and/or FISH+ Adequate organ function and ECOG performance status ≤2 Written informed consent

29 Patient demographics and baseline characteristics CharacteristicF+C n=290 F+C + trastuzumab n=294 Sex, % Male / Female75 / 2577 / 23 Age, median (range) years59.0 (21-82)61.0 (23-83) Weight, median (range) kg60.3 (28-105)61.5 (35-110) Region, n (%) Asia C/S America Europe Other 166 (56) 26 (9) 95 (32) 9 (3) 158 (53) 27 (9) 99 (33) 14 (5) Type of GC (central assessment) Intestinal Diffuse Mixed 74.2 a 8.7 a 17.1 a 76.8 b 8.9 b 14.3 b Prior gastrectomy Highest recruitment was from Korea, Japan, China and Russia F, fluoropyrimidine; C, cisplatin a n=287; b n=293

30 Primary end point: OS Time (months) No. at risk Event FC + T FC Events HR % CI 0.60, 0.91 p value Median OS T, trastuzumab

31 Secondary end point: PFS Event No. at risk Time (months) FC + T FC Events HR % CI 0.59, 0.85 p value Median PFS

32 Secondary end point: tumor response rate 2.4% 5.4% 32.1% 41.8% 34.5% 47.3% Intent to treat ORR= CR + PR CR, complete response; PR, partial response p= p= F+C + trastuzumab F+C p= Patients (%) CRPRORR

33 11 3 OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) Time (months) FC + T FC Events HR % CI 0.51, 0.83 Median OS Event No. at risk

34 Safety: non-hematological AEs AE, % F+C n=290 F+C + trastuzumab n=294 AllGrade 3/4AllGrade 3/4 Nausea Vomiting Fatigue Diarrhea Constipation Asthenia Stomatitis Weight decrease Abdominal pain <1 4 <1 2 1 AEs occurring in >10% of patients

35 Safety: cardiac AEs a Measured at baseline and every 12 weeks; MI, myocardial infarction Cardiac event, n (%)F+C (n=290) F+C + trastuzumab (n=294) AllGrade 3/4AllGrade 3/4 Cardiac AEs, total18 (6)9 (3)17 (6)4 (1) Cardiac failure2 (<1) 1 (<1) Asymptomatic LVEF drops a <50% <50% and by  10%2 (1.1) 14 (5.9) 11 (4.6) Cardiac AEs leading to death2 (<1) Cardiac arrest; cardio-respiratory arrest 2 (<1) Acute MI; angina unstable and cardiac failure Cardiac AEs related to treatment2 (<1)

36 Summary ToGA met the primary end point −trastuzumab reduces the risk of death by 26% when combined with a reference chemotherapy (HR 0.74) −prolongs the median survival by nearly 3 months (11.1 to 13.8 months; p=0.0046) in patients with HER2-positive advanced GC All secondary efficacy parameters (PFS, TTP, ORR, CBR, DoR) were also significantly improved Addition of trastuzumab to chemotherapy was well tolerated: there was no difference in overall safety profile, including cardiac AEs, between treatment arms

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

38 Patient Characteristics (I) Number of patients N=774 (%) XP + Placebo N=387 XP + Bev N=387 GenderMale258 (67)257 (66) Age, yearsMedian (range)59 (22–82)58 (22–81) ECOG PS0–1 ≥2 367 (95) 20 (5) 365 (94) 22 * (6) RegionAsia Europe Pan-America 188 (49) 124 (32) 75 (19) 188 (49) 125 (32) 74 (19) FluoropyrimidineCapecitabine 5-FU 365 (94) 22 (6) 364 (94) 23 (6) Disease statusLocally advanced Metastatic 9 (2) 378 (98) 20 (5) 367 (95) *1 additional patient had an ECOG PS of 4

39 Patient Characteristics (II) Number of patients N=774 (%) XP + Placebo N=387 XP + Bev N=387 Primary site Stomach GEJ 338 (87) 49 (13) 333 (86) 54 (14) Histologic type Intestinal Diffuse Mixed 135 (35) 206 (53) 26 (7) 155 (40) 176 (46) 35 (9) Disease measurability Measurable Evaluable 297 (77) 90 (23) 311 (80) 76 (20) Metastatic sites, n 0 1 ≥2 8 (2) 131 (34) 247 (64) 8 (2) 131 (34) 247 (64) Prior gastrectomyYes107 (28)110 (28) Liver metastasisYes126 (33)130 (34)

40 Overall Survival XP + Placebo XP + Bev Number at risk XP + Placebo XP + Bev HR = % CI 0.73–1.03 p = Survival rate Study month

41 Progression-Free Survival XP + Placebo XP + Bev Number at risk XP + Placebo XP + Bev HR = % CI 0.68–0.93 p = Progression-free survival rate Study month

42 Conclusion and Questions FOLFOX or XELOX- a new standard? Established role of Herceptin New role of Avastin? –PFS +, OS not –Should we use Avastin beyond progression


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