Transcript Slide 1

A pooled analysis of the final results of the
two randomized phase II studies comparing
Gemcitabine (G) vs Gemcitabine + Docetaxel
(G+D) in patients (pts) with
metastatic/relapsed leiomyosarcoma (LMS)
F.Duffaud, P. Pautier, B. Bui, M.L Hensley, A.Rey,
N.Penel, D.Reinke, A. Le Cesne, J.Y Blay, R.G Maki
Disclosure
 Consultant for Novartis Pharma, Pfizer
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Introduction and Study Rationale
 Gemcitabine and Docetaxel have been studied in STS with
mixed results
 Gemcitabine (G) – limited single agent activity
 Phase II studies - 30 min infusion: only low-response rates (RR: 3-18%)
Fixed-dose rate (10 mg/m2/min): a pharmacologic advantage*
 Docetaxel (D) – limited single agent activity (RR: 0 -18%)
 Combination G (fixed-dose-rate infusion) + D
 Impressive activity in LMS:
 Response Rate 53% (2/5 extra uterine LMS, 16/25 uterine)**
 Hypotheses of activity for combination:
 prolonged G infusion and synergy between combination of these drugs
 2 randomized trials compared the activity of G versus G+D in metastatic
soft tissue sarcomas
Patel S 2001*, Hensley 2002**
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Introduction and Study Rationale
 The SARC002 trial compared G vs G+D as 1st to 4th line
therapy for metastatic soft tissue sarcomas (mSTS) of many
subtypes. Maki RG et al. JCO 2007
 “Synergy of G+D accounts for the bulk of the combination’s arm activity,
rather than the fixed-dose rate infusion of G”
 The French TaxoGem study compared the activity of G vs G+D
in LMS exclusively, as 2d-line therapy for metastatic disease
after a 1st line anthracycline based regimen, with stratification
by primary site (uterus vs extra-uterus)
 G+D failed to demonstrate any advantage (OR, PFS) compared to G in
uterine OR extra-uterine LMS
 Although well tolerated, G+D was more toxic than G alone
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Methods
 SARC002 study
 A Bayesian adaptive randomization procedure was used
 based on the estimated probabilities of treatment success (RECIST)
 TaxoGem study
 Stratification: by primary tumor location (uterine LMS vs. others)
 Each stratum considered as an independent phase II study
The Simon method was used (ASCO 2008 abstr. 10511, ASCO 2009 abstr 10527)
 “Uterus” study, 20 evaluable pts/arm
 for a 74% probability of selecting the best arm with a RR of 50%, Baseline RR= 40%
 “Extra-uterus” study, 20 evaluable pts/arm
 for a 91.8% probability of selecting the best arm with a RR of 40%, Baseline RR = 20%
 Pooled analysis
 Analysis of the primary data from all evaluable LMS patients
included in both studies
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Main eligibility criteria
 SARC002 study
 Patients with mSTS recurrent/progressive disease,
 0-3 prior chemotherapy regimen(s)
 Age > 10
 TaxoGem study
 Patients with histologically-proven LMS, metastatic or with
unresectable local relapse,
 Only one prior doxorubicin based regimen,
 Age ≥18
 Both studies
 Measurable disease (per RECIST),
 ECOG PS ≤ 2,
 Adequate organ function
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SARC002 and TAXOGEM – study objectives
• Primary end-point :
Objective Response Rate (RECIST1.0)
– SARC002: Tumor response (CR+PR within 24 weeks) and
also defined DISEASE CONTROL AS “response”
(SD lasting > 24 weeks), tumor evaluation every 2 cycles
– TaxoGem: Best response during treatment,
tumor evaluation every 2 cycles,
• Secondary end-points :
PFS, duration of response, toxicity, OS
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SARC002 and TaxoGem – treatment
Treatment schedule
• G arm: G delivered as a fixed dose rate of 10 mg/m2/min, 1200mg/m2 IV
over 120 min (d1+d8) q21 days in the SARC002 study, and 1000 mg/m2 IV
over 100 min (d1+d8+d15) q21 days in the TaxoGem study.
• G+D arm, both studies: G 900 mg/m2 over 90 min (d1+d8) + D 100
mg/m2 over 60 min d8 + lenograstim (G-CSF) 150 µg/m2/d d9-d15
Gemcitabine
D1
D8
D15
G
G
G
Randomization
D1=D29
G
CYCLE N
D8
G
D15
G
CYCLE N+1
TAGOGEM study
G
Gemcitabine +
Docetaxel
D1
G+D
G
D8
D1=D22
Lenograstim
D9-D15
G+D
D8
Lenograstim
D9-D15
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Pooled analysis- population analysed
 121 evaluable LMS patients from both studies
 SARC002 trial: 38 patients
 treated between May 2003 – October 2005
 9 in the G arm, 29 in the G+D arm
 TaxoGem trial: 83 patients
 treated between April 2006 – March 2009
 43 in the G arm, 40 in the G+D arm
 Previous lines of chemotherapy for metastic disease
 0 for 15 (12%) patients, 1 for 100 (83%) pts, 2 for 4 pts and 3 for 2 pts
 → 100 pts received G or G+D as second line of chemotherapy
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Patient characteristics - Extra uterine LMS
Gemcitabine
CHARACTERISTICS
n
%
30
100
Age (years)
-
-
Female sex
15
50
-
-
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Gemcitabine + Docetaxel
Median
(min-max)
n
%
39
100
-
-
18
54
-
-
30
10
26
15
50
21
54
Trunk
1
3.5
4
10
Other
5
16
7
18
Grade FNCLCC 2/3
28
93
36
92
Prior
chemotherapy
for
metastatic disease
Previous lines of chemotherapy
1st (2d+ 3d)
Prior radiation (primary tumor)
27
90
32
82
Number of patients randomized
ECOG PS
64 (36-76)
1 (0-2)
Median
(min-max)
55 (23-78)
0 (0-2)
Primary site
Extremity
Retroperitoneal/ abdominal/ GI
26 (1+0)
12
28 (3+1)
40
15
38
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Patient characteristics - Uterine LMS
Gemcitabine
CHARACTERISTICS
n
%
Number of patients randomised
22
100
Age (years)
-
-
ECOG PS
-
-
Gemcitabine + Docetaxel
Median
(min-max)
%
30
100
54 (41-80)
-
-
56 (37-76)
0 (0-2)
-
-
0 (0-2)
0
15
21
1
5
9
2
2
0
Prior
chemotherapy
for
metastatic disease
previous lines of chemotherapy
1st (2d+3d)
Prior radiation (primary tumor)
21
95
21
21
Median
(min-max)
n
26
87
25 (0+1)
95
24
80
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Pooled analysis – toxicity
TOXICITY nb of
cycles
Gemcitabine
N = 52
Gemcitabine + Docetaxel
N = 69
Nb of cycles : 258
Nb of cycles : 330*
G3
G4
G3
G4
Neutrophils
39
11
14
10
Platelets
15
6
44
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Hemoglobin
3
1
20
-
Asthenia
5
-
14
1
Myalgia
-
-
4
-
Fever / infection
3
-
2
1
Cutaneous
-
-
2
-
Oedema
2
-
3
-
Cardiac toxicity
-
1
-
1
Neurotoxicity
-
-
2
-
Pulmonary toxicity
2
2
2
1
*
Toxicity known for only 288 cycles out of 330 delivered cycles
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Pooled analysis – Progression-free survival
EXTRA UTERINE - PFS
100%
80%
median PFS
G : 5.5 months (CI95%: 3 - 8.5)
G + D : 7months(CI95%: 2.8 - 10.5)
67%
60%
56%
59%
50%
40%
30%
20%
26%
G+D
G
0%
0
3
6
9 12 15 18 21
Months since 1st course
30
39
20
23
15
19
At risk
8
11
7
9
4
7
3
6
3
5
24
3
2
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Pooled analysis – Progression-free survival
UTERINE - PFS
100%
80%
63%
60%
median PFS
G : 4.9 months (CI95%:1.8 - 10.4)
G + D : 6 months (CI95%:2.3 - 10.4)
50%
55%
40%
46%
28%
20%
G+D
18%
G
0%
0
3
22
30
12
19
At risk
6
9 12 15 18 21
Months since 1st course
10
14
7
10
4
7
2
5
1
4
1
3
24
3
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Responses: Extra - uterine LMS
Gemcitabine
n = 30
BEST RESPONSE
Assessable patients
Complete/partial response
Stable
Progression
Objective response [95%-CI]
Non progression rate [95%-CI]
Gemcitabine +
Docetaxel n= 39
n
30
%
-
n
39
%
-
4
13
4
10
19
63
23
59
7
23
12
31
13% [4 - 31%]
10% [3 - 24%]
77% [58 - 90%]
66% [52 - 83%]
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Responses: Uterine LMS
Gemcitabine
n = 22
BEST RESPONSE
Gemcitabine +
Docetaxel n= 30
n
22
%
-
n
30
%
-
4
18
7
23
Stable
9
41
14
47
Progression
9
41
9
30
Assessable patients
Complete/partial response
Objective response [95%-CI]
18% [5 - 40%]
23% [10 - 42%]
Non progression rate [95%-CI]
59% [36 - 79%]
70% [51 - 85%]
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Pooled analysis – Overall survival
Median follow-up: 25.2 months [ 0.7 - 37.8 ]
EXTRA UTERIN - OS
100%
97%
87%
86%
80%
71%
78%
60%
59%
G
40%
G+D
20%
0%
0
3
6
9 12 15 18 21 24
Months since 1st course
30
39
29
31
26
25
At risk
20
21
16
20
15
19
11
16
11
13
9
7
27
5
3
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Pooled analysis – Overall survival
Median follow-up: 28 months [ 2.7 – 37.4 ]
100%
UTERIN - OS
96%
82%
93%
80%
73%
60%
64%
58%
G+D
40%
G
20%
0%
0
3
At risk
22
30
21
27
6
9
12 15 18 21 24
Months since 1st course
18
20
17
18
14
13
10
13
10
11
7
10
7
7
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Pooled analysis – conclusions
 High rates of progression-free survival
- 3 months PFS of 67% (G) and 59% (G+D) in extra uterine LMS, and of
55% (G) and 63% (G+D) in uterine LMS
- 6 months PFS ≥ 46% in both arms and both groups support the
hypothesis that both G alone and G+D are active regimens in uterine and
extra uterine LMS according to EORTC STBSG
 EORTC EJC 2002, Active agents 2d line in mSTS: 3mo PFR ≥ 40% and 6mo PFR ≥14%
 G+D failed to demonstrate any advantage (OR, PFS) compared
to G alone in uterine and in extra-uterine LMS
 Maki et al.2007: median PFS of 3 and 6.2 mo in G and G+D in all mSTS
 TaxoGem median PFS of 5.5 and 4.6 mo in G and G+D for uterine LMS
and 5.5 and 3.4 mo in G and G + D in extra-uterine LMS
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Pooled analysis – conclusions
 Even well tolerated, G+D is more toxic than G
 one toxic death in G+D arm; haematotoxicity, asthenia,
neurotoxicity,…
 It is reasonable to offer G alone as therapy for metastatic LMS
 PFS curves do not show differences between G and
G+D in metastatic LMS (mLMS) and are superimposable
 Although G and G+D are active to some degree in uterine and
extra-uterine LMS new agents of greater efficacy are needed for
all metastatic LMS
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Acknowledgments
 Patients and families
 French and US Centers and trial investigators
 Sponsor : FNCLCC, Paris : M Jimenez, Gosse, V. Bénavent, P. Nezan,
C. Delavault, C. Mahier
 DM and Statistics, Institut Gustave Roussy, Villejuif : G. Danton,
A. Laplanche, A. Mauguen
With the support of :
Institut National du Cancer (INCa), Ligue Nationale Contre le Cancer
Chugai Pharma France, Sanofi-Aventis France
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