Disclosure InformationRelationships Relevant to this Session

Maria Di Bartolomeo

Nordic Pharma

Please note, all disclosures are reported as submitted to ASCO, and are always available at chicago2012.asco.org

ITACA-SIntergroup Trial of Adjuvant Chemotherapy

in Adenocarcinoma of the Stomach

Comparison of a sequential treatment

with irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV)

followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment

for radically resected gastric cancerE.Bajetta, I.Floriani, M.Di Bartolomeo, R.Labianca,

A.Santoro, R.Casaretti, E.Pasquini, F.Di Fabio, G.Pinotti, P.Bidoli, G.Rosati, A.Mambrini, A.Ciarlo, S.Ricci,

L. Frassinetti, F.Di Costanzo, AM.Bochicchio

PRESENTED BY MARIA DI BARTOLOMEO

on behalf of ITACA-S group

• The standard recommendation for resectable gastric cancer was surgery (D1 dissection)

• Meta-analysis of literature data showed a small but significant benefit with chemotherapy1

• Large, patient-level meta-analysis2 confirmed that 5-FU-based chemotherapy is associated with a statistically significant benefit:

OS HR 0.82 (95% CI 0.76-0.90; P< .001)

DFS HR 0.82 (95% CI 0.75-0.90; P< .001)

• Our choice of 5-FU/LV regimen as control arm was based on the results of meta-analysis of randomized clinical trials

Background

(1 Mari, Ann Oncol,2000; 2GASTRIC, JAMA 2010)

ITACA-S

Bajetta, Ann Oncol, 2002

Cascinu, JNCI, 2007

Di Costanzo,JNCI, 2008

De Vita,Ann Oncol, 2007

Stage T3-4/N+ T3-4/N+ T3-4/N+ I-IIIB

Pts 137/137 196/201 128/130 112/113

Experimental Arm EAPFU/LV PELFwk PELF ELFE

Control arm Follow-up FU/LV Follow-up Follow-up

HR 0.93 0.95 0.90 0.91

5-y OS control arm 49% 50% 48.7% 43.5%

Italian contribution

ITACA-S

• FOLFIRI -> less hematological, renal and neurological toxicity and less stomatitis than cisplatin combinations

• Docetaxel (TXT), CDDP and 5-FU regimen is active in terms of objective response and OS, but several grade 3-4 AEs

• Treatment sequence FOLFIRI TXT/CDDP• Minimize AEs by considering each drug toxicity

profile • Feasibility of the sequence was documented in the

ITMO trial2

• Could more active drugs improve the benefit of FU/LV chemotherapy in patients radically resected with extended lymph nodes dissection?

Rationale for Experimental arm

ITACA-S

(1 Di Bartolomeo, Oncology 2006;)

Study Design

Independent, not for profit,multicenter, randomized, superiority trial

Adenocarcinoma of the stomach or GEJ

Stratification for:CenterLymph-node involvement (N-/N+)

Q2wks, 4 administrations

Control arm

5-FU:400-600mg/m2d1,2-14LV:100mg/m2d1,2-14 9 cycles

ITACA-S

CPT-11:180mg/m2d1-14 5-FU:400/600mg/m2d1,2-14LV:100mg/m2d1,2-14

TXT:75mg/m2d1-21CDDP:75mg/m2d1-21

3 cycles

Experimental arm

4 cycles

• Histologically proven carcinoma of the stomach or gastroesophageal junction

• Total/subtotal gastrectomy with at least D1 dissection (D2 recommended )

• pN+ or pT2b-3-4

• No previous radiation and/or chemotherapy

• Complete recovery from surgery. The first infusion administered 3 to 8 weeks after surgery

Eligibility criteria

ITACA-S

• Primary endpoint: Disease-Free Survival (DFS)

• 636 events (1100 patients) required:

• to detect a 20% relative reduction of recurrence/death

(HR 0.80)

• assuming 3-year DFS in control arm to be 50%

• to provide 80% power

• with 5% two-sided significance level

• Interim analyses for monitoring study conduction

Statistical considerations

ITACA-S

• 6 excluded for major violations:• 3 control arm• 3 experimental arm

Recruitment1106 Randomized

541 control arm 565 experimental arm

1100 ITT population538 control arm

562 experimental arm

1072 Safety population520 control arm

552 experimental arm

• 28 never started treatment:• 16 control arm• 12 experimental arm

• 6 crossed group• 4 control-> experimental• 2 experimental -> control

ITACA-S

Feb/2005-Aug/2009

Total (n.1100)

Experimental arm (n.562)

Controlarm (n.538)

Age (yrs) % median (range) > 70 yrs

62 (24-77) 16

62 (30-76) 17

61 (24-77) 15

Sex % Male

63 62 65

ECOG % 0 1

90 10

91 9

88 12

Histology (acc. Lauren) % Diffuse Intestinal MixedOther classification (WHO)

40351114

40361014

40351114

Baseline characteristics

ITACA-S

Characteristics Total (n.1100)

Experimental arm (n.562)

Control arm (n.538)

Node dissection % D1 D2 D3

25723

24733

27712

Examined node % median <15 15-24 > 25

271133 56

27123355

26 11 3257

Tumor site % GE junction Proximal Distal Multicenter

12 3

59 26

13 3

57 26

11 2 59 26

Surgical report

ITACA-S

Total (n.1100)

Experimental arm (n.562)

Control arm(n.538)

Stage (UICC6th) %IbIIIIIaIIIbIV

832 271417

8

32251419

831291417

N (UICC7th) % N0 N1(1-2) N2 (3-6) N3a (7-15) N3b (>15)

919263016

1019262817

820263214

TNM stage

ITACA-S

Completed: 76%- per protocol: 17% - modified: 59%

Discontinued: 24% - Adverse events 15%- Death 1% - Withdrawal 7%- Progressive disease 1%

Completed: 86%- per protocol: 36% - modified: 50%

Discontinued: 14%- Adverse events 6%- Death 1%- Withdrawal 4%- Progressive disease 3%

Treatment compliance

ITACA-S

Experimental arm Control arm

Experimental arm

Control arm

Treatment completed 76% 86%

9 cycles 86%

8 cycles 90%

7 cycles 76% 93%

6 cycles 83% 94%

5 cycles 89% 95%

4 cycles 92% 97%

3 cycles 94% 98%

2 cycles 97% 99%

1 cycle 100% 100%

Treatment received

FOLFIRI CDDP +TXT

ITACA-S

leukopenia neutropenia anemia max hematological0

5

10

15

20

25

30

35

40

45

50

0.89

0.29

17

46

0.9

48

control experimental

percen

tage

Grade 3-4 hematological toxicity

*All p<0.001

*

*

*

*

ITACA-S

diarrhoea vomiting stomatitis fever/infection asthenia0

2

4

6

8

10

12

14

16

18

3 3 20.6000000000000

033

10

16

4

2

14

control experimental

percen

tage

Grade 3-4 non hematological toxicity

*All p<0.001

*

*

*

*

*

ITACA-S

Events Overall(n.1100)

Experimental arm (n.562)

Control arm (n.538)

Relapse/Deaths % 558 (51) 283 (50) 275 (51)

Deaths % 440 (40) 222 (39) 218 (40)

Relapse site**: % locoregional both distant

108

82

109

81

107

83

Events and Relapses

median follow up: 48 mos (range IQ35.5-62.2)

**% calculated on the total of relapses

ITACA-S

Disease-free survival

HR:0.98 95%CI: 0.83-1.16

p=0.83Median DFS: 41.3 months

5-year DFS: 44.8%

ITACA-S

538 418 328 273 194 127 71

562 438 347 270 201 129 74

ControlExperimental

Dis

ease

Fre

e S

urvi

val

0 10 20 30 40 50 600,0

0,2

0,4

0,6

0,8

1,0

Months from randomizationPatients at risk

ExperimentalControl

Events

275

283

Totals

538

562

Overall survival

ITACA-S

538 477 401 321 222 149 79

562 492 404 328 230 149 81

Control

Experimental

Ove

rall

Sur

viva

l

0 10 20 30 40 50 600,0

0,2

0,4

0,6

0,8

1,0

Months from randomizationPatients at risk

ExperimentalControl

Events

218

222

Totals

538

562

HR:1.0 95%CI: 0.83-1.20

p=0.986Median OS: 69.8 months

5-year OS: 52.2%

Hazard Ratio for deaths

ITACA-S

p=0.371

Test for interaction

p=0.602

p=0.733

p=0.928

p=0.371

Test for interaction

• ITACA-S is the largest western trial to compare two different types of adjuvant chemotherapy in gastric cancer

• Patients received adequate surgery and D2 dissection in more than 75%

• Sequential irinotecan/FU-CDDP/TXT is feasible in the adjuvant setting. However it is:

- not more effective than FU/LV- more toxic than FU/LV

• According to these results there is no indication to use polychemotherapy regimen in adjuvant setting for any stage of gastric cancer

Conclusions

ITACA-S

Sponsor •Istituto Farmacologico Mario Negri Milano

Steering committee

• E.Bajetta (PI), B.Daniele, D.Nitti, R. Labianca, A.Martoni, E.Mini, F.Di Costanzo, A,Falcone, D. Amadori, G.Tortora, G.Comella

DSMC

• MG. Valsecchi, M. Tonato, E. Zucca

ITACA-S

Financial Support by: Sanofi Aventis-Italy & Pfizer- Italy

ITACA-S

Bajetta, MilanoPinotti, VareseRosati, PotenzaBordonaro, CataniaBochicchio, RioneroFazio, MilanoMarini, BresciaBuscarino,CataniaMassidda, CagliariIsa, Gorgonzola Bartolini, SondrioReguzzoni, Busto ArsizioIop, LatisanaVilla, MilanoUcci, LeccoTumolo, PordenoneFrustaci, AvianoLombardo, PescaraSbalzarini, CasalpusterlengoVerusio, SaronnoBonetti, LegnagoMonfadini, PadovaAgostara, PalermoBonciarelli, EsteMarchetti, RomaZagonel, RomaCicero, CastrovillariMantovani, CagliariDuro, ComoOliani, Montecchio MaggiorePorcile, AlbaBobbio Pallavicini, CremaGebbia, PalermoRepetto, Roma

Labianca, Bergamo Bidoli, MonzaFoa, MilanoAitini, MantovaBarni, TreviglioGiordano, ComoMartignoni, MilanoCatalano, PesaroZaniboni, BresciaAglietta, CandioloPiazza, MilanoBeretta, BresciaMenichetti, SenigalliaCortesi, RomaSilva, FabrianoNardi, Reggio CalabriaCascinu, AnconaLuporini, MilanoFicarella, Urbino

Falcone, Livorno Cantore, CarraraDi Leo, PratoRicci, PisaMagnanini, ArezzoSozzi, BiellaFea, CuneoChiara, GenovaAlabiso, NovaraFioretto, AntellaDecensi, GenovaCiuffreda, TorinoBarsani, lucca

Fiorentini, EmpoliMazzanti, Firenze

Montesarchio, NapoliDaniele, BeneventoGenua, Ariano Irpino

Martoni, BolognaBrandes, BolognaLelli, Ferrara

Nitti, PadovaTiberio, BresciaDe Manzoni, Verona

De Placido, NapoliCartenì, Napoli

ITMO GISCAD

GOIRC

GONO

ONCOTECH

APRIC

GOCCI

GIRCG

IRST

SICOG

GOAM

Thanks to:

Santoro, RozzanoBoni, Reggio EmiliaDi Costanzo, FirenzeCavanna, PiacenzaMattioli, FanoPucci, ParmaBravi, Città di CastelloArtioli, CarpiPassalacqua, CremonaContu, SassariRossetti, Marsciano

Fiorentini, EmpoliMazzanti, Firenze

Casaretti, NapoliFarris, SassariFilippelli, PaolaGraco, Lamezia TermeRoselli , RomaNatale, PenneBuzzi, TerniTafuto, PozzuoliMasullo, Vallo della Lucania

Ravaioli, RiminiAmadori, ForlìMarangolo, RavennaGambi, FaenzaCruciani, Lugo

……..the patients and their families