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MN&'(T800 1200_r=
MN&'(T800-1200_r=`
AF
none

CMF

n+')zK045%1y{ER1PgR|D}~'060%Ge=G1E')n+')zK045%
y{ER PgR|D}~'060%Ge=G E')s'DEe=zKT0.45*0.40=18%GO=`DF=zK03040%Ge=G13f_ 0e=IpDMNOfC(T1(8001200)/3/(0 18*(0 30 0 40))=3700 7400GO=
1200)/3/(0.18*(0.30-0.40))=3700-7400GO=`

AC

wi
.817 .832 .858 .870 .874 .885 .900
.652 .678 .722 .745 .771 .791 .800
.505 .538 .595 .624 .633 .661 .700

53

Disease-free Survival (DFS)

54

90

ACP

ACD

PTX

DTX

260

258

261

260

No. of pts

Hazard ratio (AC + a taxane as standard)

1.19

90.3% CI

1.00 - 1.41

p value

0.31

60
ACP
ACD
PTX
DTX

50
40

Hypothesis 2: Whether PTX or DTX is more effective
Hazard ratio (PTX as standard)

0.74

95.2% CI

0.60 - 0.91

p value0.0037

0
0

1

2

3

4

5

6

7

Time from randomization (year)
260
258
261
260

239
246
239
237

220
225
203
218

197
205
178
201

184
186
162
187

150
156
134
165

105
117
94
114

Comparison of four arms (DFS
64
67
45
70

patients at risk
100
90
80
70
60
50

AC Taxane
TaxaneHR1.19 (90.3%CI:1.00-1.41)

40

Hazard ratio
95! CI

Percennt Probability

Percennt Probability

ACP
ACD
PTX
DTX

100

Summary of events (OS)Hypothesis 1: A taxane alone is not inferior to AC + a taxane

70

ACP

ACD

PTX

DTX

reference

0.89
0.66-1.20

1.40
1.06-1.84

0.86
0.64-1.17

AC Taxane 518
Taxane 521

1

2

485
476

445
421

70
60
50

ACP
ACD
PTX
DTX

40
0
ACP
ACD
PTX
DTX

50

ACD+DTX
ACP+PTX
HR0.74 (95.2%CI:0.60-0.91)

5

6

7

0

402
379

370
349

306
297

222
208

131
115

DTX 518
PTX 521

1

2

483
478

443
423

3

4

5

6

7

406
375

373
346

319
284

231
199

137
109

Time from randomization (year)
patients at risk

ACD

PTX

DTX

262

263

263

261

1

2

262
263
263
261

256
258
259
258

248
250
248
248

Hazard ratio(AC + a taxane
as standard)

1.06

90.3% CI

0.83 - 1.36

p value

0.14

Hypothesis 2:
Whether PTX or DTX is more effective

3

4

5

6

7

Time from randomization (year)

70
60

ACP

Hypothesis 1:
A taxane alone is not inferior to AC + a taxane

80

4patients at risk

80

90

3

Time from randomization (year)

No. of pts

0

0
0

90

100

40

0

Perrcent Probability

Percent Probability
P

Summary of events (DFS)80

Overall Survival (OS)SABCS2011

100

235
241
229
239

222
226
214
230

187
195
183
202

139
151
130
144

84
88
70
91

Hazard ratio(PTX asstandard))

0.73

95.2% CI

0.54 - 0.98

p value

0.035

patients
ti t att risk
i k
55

56
AKA-9984-55

AKA-9984-56

Summary

Conclusion

8 cycles of a taxane is not ‘non-inferior’ to 4 cycles of AC followed by
4 cycles of a taxane in all analyzed patients in terms of disease-freedisease freesurvival.

As compared with paclitaxel, docetaxel is associated withimproved efficacy given in tri-weekly
tri weekly schedule.
schedule The results are
consistent with a study of metastatic breast cancer1. The efficacy
of taxanes seems to be schedule
schedule-dependent.
dependent. Docetaxel is suitable
for tri-weekly schedule but paclitaxel is more efficacious whenadministerd in weekly dose-dense schedule. Our observations inthis study are in a very good agreement with those in ECOG 1199
Trial2.

Docetaxel (75 mg/m2) is superior to paclitaxel (175 mg/m2) when
given every three weeks in terms of disease-free survival and overall
survival.
Regarding adverse events:
Incidences of nausea and vomiting were higher with 4 cycles of AC
followed by 4 cycles of a taxane than with 8 cycles of a taxane.

Eight cycles of Docetaxel (75 mg/m2 ) is an alternative regimen inpatients who are intolerance for, or reluctance to treatment withanthracyclines because of concern of cardiac malfunction or fearof nausea and vomiting.

Incidences of edema and febrile neutropenia
pwere highergwith docetaxel(75 mg/m2) than with paclitaxel (175 mg/m2) .
Incidence of sensory neuropathy was higher with paclitaxel (175 mg/m2)
than with docetaxel (75 mg/m2) .

1. Jones SE et al. J Clin Oncol 2005;23:5542
58
2. Sparano JA et al. N Engle J Med 2008;358:1663

57

AKA-9984-58

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IPASS: Studyy design
g
Endpoints
Patients• Chemonaïve

IPASS34Tg"hij]klmnoBCR]Wpqr"34Tg"hi• Age !18 years• Adenocarcinoma• Life expectancy!12 weeks• PS 0-2• Measurable stage IIIB /IV disease81

Gefitinib((250 mgg / day)y)• Progression-free survival(non-inferiority)

Secondaryhistology• Never or light ex-

smokers*

stuvwKKK

Primary

1:1 randomisation

Carboplatin(AUC 5 or 6) /paclitaxel(200 mg / m2)
3 weekly#• Objective response rate
• Overall survival
y of life• Quality• Disease-related symptoms• Safety and tolerability

Exploratory• Biomarkers• EGFR mutation• EGFR-gene-copy number• EGFR protein expression*Never smokers, <100 cigarettesgin lifetime; lightg ex-smokers, stopped
pp !15 yyears agog and smoked"10 pack years; #limited to a maximum of 6 cycles
Carboplatin / paclitaxel was offered to gefitinib patients upon progression
82
PS, performance status; EGFR, epidermal growth factor receptor
AstraZeneca data on file

IPASSx Study conduct
IPASS
"

"

1217 patients randomised"

Randomisation period: March
2006 to October 2007"

Data cut
cut-off:
off: 14 April 2008–"

Tony S.
S Mok et alal.
NEJM 2009;
361:947-57.

China, Hong Kong, Indonesia, Japan,
Malaysia, Philippines, Singapore,
Taiwan, Thailand""

IPASS: Results

87 centres in 9 countries in Asia

Hong Kong
Myanmar

950 PFS events observed in ITT
population (78% maturity)

M
Mean
time
ti
on treatmentttt–

gefitinib, 6.4 months–

carboplatin / paclitaxel, 3.4 months(median number of cycles#: 6)

Final survival data (944 events)
expected mid-2010#limited to a maximum of 6 cycles

83
AstraZeneca data on file

PFS, progression-free survival; ITT, intent-to-treat

84

Objective response rate in EGFR mutation
positive and negative patients
Overall
response
rate (%)

Gefitinib
Carboplatin / paclitaxel

71.2%

EGFR M+ odds ratio (95% CI) = 2.75
(1 65 4(1.65,
4.60),
60) p=0p=0.0001
0001

47.3%

Lancet Oncol 2010; 11: 121
121–2828

EGFR M- odds ratio (95% CI) = 0.04
(0.01, 0.27), p=0.0013

First-line trial withcisplatin+docetaxel
EGFR muted 86+86 pts
EGFR-mutedpts.
PFS 9.2 vs 6.3 months
HR 0.49 (95%CI0.34-0.71)

23.5%

1.1%
(n=132) (n=129)

Odds ratio >1 implies greater chance of response on gefitinib(n=91)(n=85)

85
AstraZeneca data on file

86!
NEJM 2010; 362: 2380-8.

trial withcisplatin+docetaxelii
EGFR-muted 114+110 pts.
PFS 10.8 vs 5.4 months
HR 0.30 (95%CI0.22-0.41)87"#$%&'()$%&MEGA*+,-+(&'./01
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