Gefitinib IRESSA versus docetaxel in patients with locally advanced or metastatic nonsmall cell lung

1
Gefitinib (IRESSA) versus docetaxel in patients
with locally advanced or metastatic non-small
cell lung cancer pre-treated with platinum-based
chemotherapya randomized, open-label Phase III
study (INTEREST)

• Douillard JY,1 Kim ES,2 Hirsh V,3 Mok T,4
  Socinski M,5 Gervais R,6 Wu YL,7 Li L,8 Sellers
  M,9 Lowe E,10
• 1Centre René Gauducheau, Nantes, France
  2University of Texas, MD Anderson Cancer Center,
  Houston, USA 3McGill University Health Centre,
  Montreal, Canada 4Department of Clinical
  Oncology, Prince of Wales Hospital, School of
  Public Health, The Chinese University of Hong
  Kong, Hong Kong, China 5Lineberger Comprehensive
  Cancer Center, University of North Carolina at
  Chapel Hill, NC, USA 6Centre Regional de Lutte
  Contre le Cancer Baclesse, Caen, France 7Lung
  Cancer Research Institute and Cancer Center,
  Guangdong Provincial Peoples Hospital,
  Guangzhou, China 8Peking Union Medical College
  Hospital, Beijing, China 9AstraZeneca,
  Macclesfield, UK 10AstraZeneca, Wilmington, USA

2
Study design

Endpoints

• Patients
• Age 18 years
• Life expectancy 8 weeks
• Progressive or recurrent disease following CT
• Considered candidates for further CT with
  docetaxel
• 1 or 2 CT regimens(1 platinum)
• PS 0-2

• Primary
• Overall survival(co-primary analysesa of
  non-inferiority in all patients and superiority
  in patients with high EGFR gene copy number)
• Secondary
• Progression-free survival
• Objective response rate
• Quality of life
• Disease related symptoms
• Safety and tolerability
• Exploratory
• Biomarkers

amodified Hochberg procedure applied to control
for multiple testingCT, chemotherapy PS,
performance status EGFR, epidermal growth factor
receptor
JY Douillard and ES Kim et al. WCLC 2007
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Study conduct

• 149 centers in 24 countries worldwide
• 1466 patients randomized
• Randomization period March 2004 to February 2006
  
• 1169 deaths from 1433 patients (81.6) in
  per-protocol population
• Mean time on treatment
• gefitinib 4.4 months
• docetaxel 3.0 months
• Median number (range) of docetaxel cycles 4
  (1-24)
• 82.2 given at full dose

JY Douillard and ES Kim et al. WCLC 2007
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Post-discontinuation treatments(ITT population)
Gefitinib
Other chemotherapy without docetaxel 15
Docetaxel
Other chemotherapy without EGFR TKI 10
aPatients may have also received other
chemotherapy and/or erlotinib during the
study Radiotherapy, surgery, medical procedures
and other treatment excluded ITT,
intent-to-treat EGFR TKI, EGFR tyrosine kinase
inhibitor
JY Douillard and ES Kim et al. WCLC 2007
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Demography (ITT population)
Docetaxel, (N733)
Gefitinib, (N733)
Age lt 65 years Female WHO PS 0 / 1 / 2a Never
smokera 2nd-linea Asian origin Adenocarcinomaa Sin
ce diagnosis lt6 / 6-12 / gt12 months Prior
platinum refractoryb / receiveda Prior paclitaxel
refractoryb / received / nonea Best response to
previous CT (CRPR) / SD / PD Locally advanced
disease
61 36 30 / 58 / 12 20 84 21 54 26 / 38 / 35 54 /
45 9 / 9 / 81 27 / 41 / 26 14
67 33 25 / 63 / 12 20 83 23 55 27 / 37 / 35 56 /
42 8 / 9 / 82 31 / 38 / 25 13
WHO, World Health Organization CR, complete
response PR, partial responseSD, stable
disease PD, progressive disease a1 of the 6
stratification factors bprogressed during or
within 3 months of completing therapy
JY Douillard and ES Kim et al. WCLC 2007
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Objective tumor response (RECIST)(EFR population)
Patients ()
(n659)
(n657)
OR gt 1 implies a greater chance of response on
gefitinib OR and p-value from logistic
regression with covariates
RECIST, response evaluation criteria in solid
tumorsEFR, evaluable for response OR, odds
ratio CI, confidence interval
JY Douillard and ES Kim et al. WCLC 2007
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Quality of life and symptom improvement rates
(EFQ population)
patients with sustained clinically relevant
improvement
p lt 0.0001
p 0.0026
p 0.1329
p-values from logistic regression with
covariates. Clinically relevant improvement
pre-defined as6 point improvement for FACT-L and
TOI 2 point improvement for LCS, maintained for
at least 21 days
EFQ, evaluable for quality of life, FACT-L,
Functional Assessment of Cancer
Therapy-LungTOI, Trial Outcome Index LCS, Lung
Cancer Subscale
JY Douillard and ES Kim et al. WCLC 2007
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Adverse event summary
All AEs
Treatment-relateda
Gefitinib(N729) 687 (94.2) 161 (22.1) 31
(4.3) 59 (8.1) 272 (37.3)
Docetaxel(N715) 668 (93.4) 210 (29.4) 28
(3.9) 102 (14.3) 400 (55.9)
Gefitinib(N729) 527 (72.3) 28 (3.8) 6 (0.8) 30
(4.1) 62 (8.5)
Docetaxel(N715) 588 (82.2) 130 (18.2) 15
(2.1) 78 (10.9) 291 (40.7)
n () AE SAE AE leading to death AE leading to
discontinuation CTC Grade 3 or 4 AE
aInterpret with caution due to open-label study
designAE, adverse event SAE, serious adverse
event CTC, common toxicity criteria
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Most common AEs ?10 incidence in any treatment
groupby decreasing frequency of all AEs in
overall population (1)
Docetaxel All AEs (N715)
Gefitinib Grade 3/4 AEs (N729)
Docetaxel Grade 3/4 AEs (N715)
Gefitinib All AEs (N729)
AE, n ()
35 (5.0)b 9 (1.2) 360 (49.4) 182 (25.0) 255
(35.0) 148 (20.3) 159 (21.8) 23 (3.2) 120
(16.5) 109 (15.0)
514 (73.7)b 72 (10.1) 73 (10.2) 334 (46.7) 177
(24.8) 187 (26.2) 151 (21.1) 254 (35.5) 117
(16.4) 123 (17.2)
Neutropeniaa Febrile neutropenia Rash/acned Asthe
nic conditionsd Diarrhea Nausea Anorexiad Alopecia
Dyspnoea Vomiting
15 (2.2)c 9 (1.2) 15 (2.1) 32 (4.4) 18 (2.5) 3
(0.4) 11 (1.5) - 45 (6.2) 4 (0.5)
406 (58.2)c 72 (10.1) 4 (0.6) 64 (9.0) 22 (3.1) 9
(1.3) 7 (1.0) - 55 (7.7) 8 (1.1)
aData from lab reports. Calculations only include
patients with a baseline and gt one post-baseline
value bWorsening in lab value from baseline
cWorsening in lab value from baseline to CTC
grade 3/4. N697 for neutropenia with gefitinib
and docetaxel dGrouped term (sum of several
preferred terms)
Difference in overall incidence is ? 3 greater
on gefitinib Difference in overall incidence is
? 3 greater on docetaxel
JY Douillard and ES Kim et al. WCLC 2007
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Most common AEs ?10 incidence in any treatment
groupby decreasing frequency of all AEs in
overall population (2)
Docetaxel All AEs (N715)
Gefitinib Grade 3/4 AEs (N729)
Docetaxel Grade 3/4 AEs (N715)
Gefitinib All AEs (N729)
AE, n ()
Neurotoxicitya Cough Constipation Pyrexia Fluid
retentiona Stomatitisa Lower RTI and lung
infectionsa Myalgia Dry skin Anaemia Interstitial
lung diseasea
49 (6.7) 108 (14.8) 79 (10.8) 69 (9.5) 48
(6.6) 67 (9.2) 71 (9.7) 24 (3.3) 111 (15.2) 34
(4.7) 10 (1.4)
171 (23.9) 102 (14.3) 121 (16.9) 118 (16.5) 112
(15.7) 93 (13.0) 74 (10.3) 113 (15.8) 10 (1.4) 84
(11.7) 8 (1.1)
1 (0.1) 6 (0.8) 6 (0.8) 2 (0.3) 0 0 23 (3.2) 1
(0.1) 0 11 (1.5) 5 (0.7)
17 (2.4) 5 (0.7) 13 (1.8) 4 (0.6) 5 (0.7) 3
(0.4) 25 (3.5) 4 (0.6) 0 15 (2.1) 5 (0.7)
aGrouped term (sum of several preferred
terms) RTI, respiratory tract infection
Difference in overall incidence is ? 3 greater
on gefitinib Difference in overall incidence is
? 3 greater on docetaxel
JY Douillard and ES Kim et al. WCLC 2007
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Overall survival in overall PP population
1.0
Probabilityof survival
0.8
0.6
0.4
0.2
0.0
0
4
8
12
16
20
24
28
32
36
40
Months
At risk
723
336
225
131
83
50
31
14
0
0
518
Gefitinib
710
339
228
139
89
46
24
7
0
0
503
Docetaxel
Pre-specified NI limit in HR terms (translates to
? 50 effect retention Rothmann 2003) 1.154
96 of historical docetaxel advantage over BSC
from TAX-317 retained by gefitinib (96 CI 52,
129) Indirect comparison of gefitinib to BSC HR
(96 CI) 0.63 (0.42, 0.92), p0.0137 PP,
per-protocol NI, non-inferiority HR, hazard
ratio OS, overall survival BSC, best supportive
care
JY Douillard and ES Kim et al. WCLC 2007
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Progression-free survival(EFR population)
Probabilityof PFS
1.0
0.8
0.6
0.4
0.2
0.0
0
4
8
12
16
20
24
28
32
36
40
Months
At risk
Gefitinib
659
77
34
18
9
5
3
0
0
0
194
Docetaxel
657
42
16
4
2
1
0
0
0
0
208
HR lt 1 implies a lower risk of progression on
gefitinib PFS, progression-free survival
JY Douillard and ES Kim et al. WCLC 2007
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Overall survival in patients with highEGFR gene
copy number (ITT population)
Probabilityof survival
1.0
0.8
0.6
0.4
0.2
0.0
0
4
8
12
16
20
24
28
32
36
40
Months
At risk
85
44
26
13
10
6
4
3
0
0
66
Gefitinib
89
42
31
22
14
7
4
1
0
0
63
Docetaxel
FISH, fluorescence in situ hybridization
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Overall survival in pre-planned
subgroups(overall PP population)
Treatment-by-subgroup interaction test p-value
Overall
Adenocarcinoma
Non-adenocarcinoma
PS 0 or 1
PS 2
Prior platinum - refractory
all p gt 0.05
Prior platinum - received
Ever smoked
Never smoked
Prior paclitaxel - refractory
Prior paclitaxel - received
Prior paclitaxel - none
p 0.0311 for prior regimens
1 prior regimen
2 prior regimens
Male
Female
Asian
Non-asian
Aged lt65
Aged 65
all p gt 0.05
Diag to random lt6 months
Diag to random 6-12 months
Diag to random gt12 months
Best response to prior CT CR/PR
Best response to prior CT SD
Best response to prior CT PD
Best response to prior CT unknown
0.5
1.0
1.5
2.0
HR (gefitinib vs docetaxel) and 95 CI
Cox analysis without covariates
JY Douillard and ES Kim et al. WCLC 2007
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Overall survival by biomarkers(ITT population)
Overall
EGFR FISH
EGFR FISH -
EGFR expression
EGFR expression -
EGFR mutation
EGFR mutation -
K-RAS mutation
K-RAS mutation -
0.5
1.0
1.5
2.0
0
HR (gefitinib vs docetaxel) and 95 CI
Cox analysis without covariates
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Conclusions

• The study met the primary objective of
  demonstratingnon-inferiority of gefitinib
  relative to docetaxel in terms of overall
  survival
• There was no evidence from the co-primary
  analysis to support the hypothesis that EGFR FISH
  positive patients have superior overall survival
  on gefitinib compared to docetaxel
• PFS, objective response rate and disease-related
  symptom improvements were similar for gefitinib
  and docetaxel
• Gefitinib had a more favourable tolerability
  profile than docetaxel
• Significantly more gefitinib-treated patients
  experienced a clinically relevant improvement in
  quality of life compared to docetaxel

JY Douillard and ES Kim et al. WCLC 2007
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Acknowledgements

• Thank you to all the patients, their families
  and investigators for their support in this trial