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
11
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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