land mark trials gastric cancer
TRANSCRIPT
Land mark studies inMetastatic Gastric Cancer
Prof.Ahmed M Badheeb, MD.
Professor Of Oncology and Internal Medicine
TAX 325
Role of Docetaxel: V 325 Phase III
RANDOMIZE
Stratification Factors: Liver Involvement
Prior Gastrectomy
Measurable vs
Evaluable Disease
Weight Loss (>5%) inPrior 3 Months
Centers
Adequate hydration and anti-emetics required, No Prophylactic Growth FactorsResponse assessment every 8 weeks independent of treatment schedule
Cisplatin 100 mg/m2/IV over 1-3 hrs
Cycles repeated every 4 weeks
Docetaxel 75 mg/m2 IV over 1 hr Cisplatin 75 mg/m2 IV over 1-3 hrsboth on Day 1 only
5-FU 750 mg/m2/day by CIV over5 days Days 1-5
Cycles repeated every 3 weeks
5-FU 1000 mg/m2/day by CIV over5 days Days 1-5
CF (230)
DCF EOX FC-T =ToGA
RR 25.4%
36.7%
48%4% CR
TTP 3.7 M
5.6 m 7
OS 8.6 M
9.2 m 11.2
1-yr. OS
31.6%
40.2%
2-yr.OS
8.8%
18.4%
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 %
DCF is too toxic- and not worth itmDCF vs DCFShah 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?
REAL 2
Advanced Gastric Cancer: REAL-2 Cunningham, NEJM 2008, v 358, p. 36
1002 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)
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
Cunningham, NEJM 2008, v358, p. 42
Cunningham, NEJM 2008, v 358, p. 41
Cunningham, NEJM 2008, v358, p 44
CALGB 80403 / ECOG E1206
CALGB 80403 / ECOG E1206: Schema
Stratification:ECOG 0-1 vs 2ADC vs. SCC
ARM A: (ECF + cetuximab); 1 cycle = 21 days
Cetuximab 400 250mg/m2 IV, weeklyEpirubicin 50 mg/m2 IV, day 1Cisplatin 60mg/m2 IV, day 1Fluorouracil 200mg/m2/day, days 1-21
ARM B: (IC + cetuximab); 1 cycle = 21 days
Cetuximab 400 250mg/m2 IV, weeklyCisplatin 30 mg/m2 IV, days 1 and 8Irinotecan 65 mg/m2 IV, days 1 and 8
ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days
Cetuximab 400 250mg/m2 IV, weeklyOxaliplatin 85 mg/m2 IV, day 1Leucovorin 400 mg/m2, day 1Fluorouracil 400 mg/m2 IV bolus, day 1Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)
CALGB 80403/ECOG 1206: Response
ECF-C N=64
IC-C N=68
FOLFOX-C N=69
Response CR 0 1 ( 1%) 2 ( 3%) PR 37 (58%) 30 (44%) 35 (51%) SD 15 (23%) 23 (34%) 19 (28%) PD 4 ( 6%) 10 (15%) 8 (12%)
Not eval / unknown 5 / 3 (8% /5%) 2 / 2 (3% /3%) 3 / 2 (4% /3%) Objective Response Rate*
(CR+PR)/total 57.8 45.6 53.6 (90% C.I.) 46.8 68.3 35.2 56.3 43.1 64.0 p vs. H0<0.25 <.0001 <.0001 <.0001 Response duration (mos) median 6.1 5.3 5.7 range 0.5 - 22.7 0.5 - 20.1 2.4 - 18.2
*RECIST - confirmed; restaging every 6 weeks
0 5 10 15 20 25
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Prop
ortio
n Su
rviv
ing ECF-C (n=67)
IC-C (n=71)FOLFOX-C (n=72)
CALGB 80403/ECOG 1206: Overall Survival by Arm
ToGA
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
HER2 and trastuzumab mechanism of action
HER2 receptortrastuzumab
Trastuzumab Inhibits HER2-mediated signalling in HER2-positive tumors Prevents HER2 activation by blocking extracellular
domain cleavage Activates antibody-dependent cellular cytotoxicity
The Rules for EGFR Targeting
Breast- HER2 overexpression
Colon- KRAS
Lung- ATP binding site mutations
Gastric- Do we actually know?
HER2 testingHER2 testing in breast cancer is
well establishedRecent evidence shows that same
techniques with some modifications are also valid for assessing HER2 status in stomach cancer
1. Hoffmann 2008
HER2 testing – 2 main methods1. Immunohistochemistry (IHC)
– Shows how much of the HER2 protein is present in the tumour sample
HER2-negative HER2-positive
HER2 testing – 2 main methods2. Fluorescence in-situ hybridization (FISH)
– Measures the amount of the HER2/neu gene in each cell
HER2-negative HER2-positive
ToGA trial design
HER2-positiveadvanced GC
(n=584)
5-FU or capecitabinea + cisplatin(n=290)
R
aChosen at investigator’s discretion GEJ, gastroesophageal junction
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
Phase III, randomized, open-label, international, multicenter study
1Bang et al; Abstract 4556, ASCO 2009
3807 patients screened1
810 HER2-positive (22.1%)
Treatment regimens
Capecitabine1000 mg/m2 bid d1-14 q3w x 6
5-Fluorouracil 800 mg/m2/day continuous iv infusion d1-5 q3w x 6
Cisplatin 80 mg/m2 q3w x 6
Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg q3w until PD
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
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
Patient demographics and baseline characteristics
Characteristic F+Cn=290
F+C + trastuzumabn=294
Sex, %Male / Female 75 / 25 77 / 23
Age, median (range) years 59.0 (21-82) 61.0 (23-83)
Weight, median (range) kg 60.3 (28-105) 61.5 (35-110)
Region, n (%)AsiaC/S AmericaEuropeOther
166 (56)26 (9)95 (32)9 (3)
158 (53)27 (9)
99 (33)14 (5)
Type of GC (central assessment)IntestinalDiffuseMixed
74.2a
8.7a
17.1a
76.8b
8.9b
14.3b
Prior gastrectomy 21.4 24.1
Highest recruitment was from Korea, Japan, China and Russia F, fluoropyrimidine; C, cisplatin an=287; bn=293
Primary end point: OS
Time (months)
294290
277266
246223
209185
173143
147117
11390
9064
7147
5632
4324
3016
2114
137
126
65
40
10
00
No. at risk
11.1 13.8
0.00.10.20.30.40.50.60.70.80.91.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Event
FC + TFC
Events
167182
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
MedianOS
13.811.1
T, trastuzumab
Secondary end point: PFS
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Event
294290
258238
201182
14199
9562
6033
4117
287
215
133
93
82
62
61
61
40
20
00
5.5 6.7
No. at risk
0.00.10.20.30.40.50.60.70.80.91.0
Time (months)
FC + TFC
Events
226235
HR
0.71
95% CI
0.59, 0.85
p value
0.0002
MedianPFS
6.75.5
Secondary end point: tumor response rate
2.4%5.4%
32.1%
41.8%
34.5%
47.3%
Intent to treat
ORR= CR + PRCR, complete response; PR, partial response
p=0.0599
p=0.0145F+C + trastuzumabF+C
p=0.0017Patients (%)
CR PR ORR
113
OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)
1.0
0.8
0.6
0.4
0.2
0.0
363432302826242220181614121086420Time (months)
11.8 16.0
FC + TFC
Events
120136
HR
0.65
95% CI
0.51, 0.83
MedianOS
16.011.8
Event
0.1
0.3
0.5
0.7
0.9
218 198
40
53
124
2011
228 218
196 170
170 141
142 112
12296
10075
8453
6539
5128
10
00
No. at risk
3920
2813
Safety: non-hematological AEs
AE, %F+C
n=290F+C + trastuzumab
n=294All Grade 3/4 All Grade 3/4
NauseaVomitingFatigueDiarrheaConstipationAstheniaStomatitisWeight decreaseAbdominal pain
634628283218151414
782423221
675035372619242316
7649
<14
<121
AEs occurring in >10% of patients
Safety: cardiac AEs
aMeasured at baseline and every 12 weeks; MI, myocardial infarction
Cardiac event, n (%) F+C(n=290)
F+C + trastuzumab (n=294)
All Grade 3/4 All Grade 3/4
Cardiac AEs, total 18 (6) 9 (3) 17 (6) 4 (1)
Cardiac failure 2 (<1) 2 (<1) 1 (<1) 1 (<1)
Asymptomatic LVEF dropsa
<50% <50% and by 10%
2 (1.1)2 (1.1)
14 (5.9)11 (4.6)
Cardiac AEs leading to death 2 (<1)Cardiac arrest;
cardio-respiratory arrest
2 (<1)Acute MI; angina unstable and
cardiac failure
Cardiac AEs related to treatment 2 (<1) 2 (<1)
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
AVAGASTAvastinPFS +, OS not
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/m2 oral bid, d1–14, 1-week rest
Cisplatin 80 mg/m2 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
Patient Characteristics (I)
Number of patients N=774 (%)XP + Placebo
N=387XP + Bev
N=387Gender Male 258 (67) 257 (66)
Age, years Median (range) 59 (22–82) 58 (22–81)
ECOG PS 0–1≥2
367 (95)20 (5)
365 (94)22* (6)
Region AsiaEuropePan-America
188 (49)124 (32)75 (19)
188 (49)125 (32)74 (19)
Fluoropyrimidine Capecitabine5-FU
365 (94)22 (6)
364 (94)23 (6)
Disease status Locally advancedMetastatic
9 (2)378 (98)
20 (5)367 (95)
*1 additional patient had an ECOG PS of 4
Patient Characteristics (II)
Number of patients N=774 (%)XP + Placebo
N=387XP + Bev
N=387
Primary site StomachGEJ
338 (87)49 (13)
333 (86)54 (14)
Histologic typeIntestinalDiffuseMixed
135 (35)206 (53)
26 (7)
155 (40)176 (46)
35 (9)
Disease measurability
MeasurableEvaluable
297 (77)90 (23)
311 (80)76 (20)
Metastatic sites, n01≥2
8 (2)131 (34)247 (64)
8 (2)131 (34)247 (64)
Prior gastrectomy Yes 107 (28) 110 (28)Liver metastasis Yes 126 (33) 130 (34)
Overall Survival
387387
343355
271291
204232
146178
98104
1519
XP + PlaceboXP + Bev
Number at risk
5450
00
XP + Placebo
XP + Bev
HR = 0.8795% CI 0.73–1.03 p = 0.1002
Survival rate
3 9 15 18 21 240
0.0
0.10.2
0.30.40.5
0.6
0.70.80.91.0
6 12Study month
10.1
12.1
Progression-Free Survival
387387
279306
145201
86123
5571
3238
33
1511
00
XP + PlaceboXP + Bev
Number at risk
XP + Placebo
XP + Bev
HR = 0.8095% CI 0.68–0.93 p = 0.0037
Progression-free survival rate
0.0
0.10.2
0.30.40.5
0.6
0.70.80.91.0
3 9 15 18 21 240 6 12
5.36.7
Study month
Conclusion and Questions
FOLFOX or XELOX- a new standard?
Established role of HerceptinNew role of Avastin?
– PFS +, OS not
– Should we use Avastin beyond progression