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

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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/armUterus” 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/armExtra-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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• 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

SARC002 and TAXOGEM SARC002 and TAXOGEM – study objectives study objectives

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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

SARC002 and TaxoGem SARC002 and TaxoGem – treatment treatment

G G G G G

Randomization TAGOGEM study

G G

D1 D8 D15 D1=D29 D8 D15

D1 D8

Gemcitabine

Gemcitabine + Docetaxel

G

Lenograstim D9-D15

D8

CYCLE N CYCLE N+1

Lenograstim D9-D15

G+D G+D

D1=D22

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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

CHARACTERISTICS n %Median

(min-max) n %Median

(min-max)

Number of patients randomized 30 100 39 100

Age (years) - - 64 (36-76) - - 55 (23-78)

Female sex 15 50 18 54

ECOG PS - - 1 (0-2) - - 0 (0-2)

Primary site

Extremity 9 30 10 26

Retroperitoneal/ abdominal/ GI 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 formetastatic disease

27 90 32 82

Previous lines of chemotherapy1st (2d+ 3d)

26 (1+0) 28 (3+1)

Prior radiation (primary tumor) 12 40 15 38

Gemcitabine Gemcitabine + Docetaxel

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Patient characteristics - Uterine LMSPatient characteristics - Uterine LMS

CHARACTERISTICS n %Median

(min-max) n %Median

(min-max)

Number of patients randomised 22 100 30 100

Age (years) - - 54 (41-80) - - 56 (37-76)

ECOG PS - - 0 (0-2) - - 0 (0-2)

0 15 21

1 5 9

2 2 0

Prior chemotherapy formetastatic disease

21 95 26 87

previous lines of chemotherapy1st (2d+3d)

21 25 (0+1)

Prior radiation (primary tumor) 21 95 24 80

Gemcitabine Gemcitabine + Docetaxel

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Pooled analysis – toxicity

TOXICITY nb of cycles

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

GemcitabineN = 52

Nb of cycles : 258

Gemcitabine + DocetaxelN = 69

Nb of cycles : 330*

*Toxicity known for only 288 cycles out of 330 delivered cycles

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Pooled analysis – Progression-free survival

EXTRA UTERINE - PFS

3334781520302567911192339

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15 18 21 24Months since 1st courseAt risk

56%

30%

G + D

G

50%

26%

median PFSG : 5.5 months (CI95%: 3 - 8.5)

G + D : 7months(CI95%: 2.8 - 10.5)

67%

59%

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Pooled analysis – Progression-free survival

UTERINE - PFS

11247101222

3345710141930

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15 18 21 24Months since 1st courseAt risk

46%

18%

50%

28%

G + D

G

median PFSG : 4.9 months (CI95%:1.8 - 10.4)

G + D : 6 months (CI95%:2.3 - 10.4)55%

63%

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Responses: Extra - uterine LMS

BEST RESPONSE n % n %

Assessable patients 30 - 39 -

Complete/partial response 4 13 4 10

Stable 19 63 23 59

Progression 7 23 12 31

Objective response [95%-CI]

Non progression rate [95%-CI]

Gemcitabine n = 30

Gemcitabine + Docetaxel n= 39

13% [4 - 31%]

77% [58 - 90%]

10% [3 - 24%]

66% [52 - 83%]

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Responses: UResponses: Uterine terine

LMSLMS

BEST RESPONSE n % n %

Assessable patients 22 - 30 -

Complete/partial response 4 18 7 23

Stable 9 41 14 47

Progression 9 41 9 30

Objective response [95%-CI]

Non progression rate [95%-CI]

Gemcitabine n = 22

Gemcitabine + Docetaxel n= 30

18% [5 - 40%]

59% [36 - 79%]

23% [10 - 42%]

70% [51 - 85%]

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Pooled analysis – Overall survivalMedian follow-up: 25.2 months [ 0.7 - 37.8 ]

EXTRA UTERIN - OS

591111151620262930371316192021253139

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15 18 21 24 27

Months since 1st courseAt risk

78% 71%

87%

59%

G

G + D

97%

86%

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Pooled analysis – Overall survivalMedian follow-up: 28 months [ 2.7 – 37.4 ]

UTERIN - OS

7710101417182122

71011131318202730

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15 18 21 24Months since 1st courseAt risk

82%

64%

G

73%

58%

G + D

93%

96%

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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 CancerChugai Pharma France, Sanofi-Aventis France