mapie vs map in patients with a poor response to pre-operative chemotherapy for newly-diagnosed...

MAPIE vs MAP in patients with a Poor Response to pre-operative chemotherapy for newly-diagnosed osteosarcoma:

Results from EURAMOS-1

CTOS 2014, Berlin17-Oct-2014

Neyssa Marina, Sigbjørn Smeland, Stefan S Bielack, Mark Bernstein, Gordana Jovic,Jane M Hook, Mark D Krailo, Trüde Butterfass-Bahloul, Thomas Kühne, Mikael Eriksson,Lisa Teot, Hans Gelderblom, Leo Kager, Kirsten Sundby Hall, Richard Gorlick, R. Lor Randall, Pancras W Hogendoorn , Gabriele Calaminus, Matthew R Sydes, Jeremy S Whelanon behalf of the EURAMOS-1 investigators

E UROPEANO STEOSARCOMAI NTERGROUP

Abstract ID: 2055690

Design and eligibility

Biopsy-proven diagnosis of resectable osteosarcoma

REGISTER

MAP (induction)

Surgery

Histological response assessment

Poor Good

RANDOMIZE RANDOMIZE

MAP MAPIE MAP MAPifn

Registration

• Resectable high-grade osteosarcoma

• Extremity or axial

• Localized or metastatic

• Age ≤40yr

• No pretreatment for osteosarcoma

• No previous chemo for any disease

• No contraindication to treatment

• Registration & chemo ≤30day after biopsy

• Written informed consent

Design

Primary tumor

resectionRAP MM

IE M

A MM

wk 1-10 wk 11

wk 12-40

Ai M

wk 12-29

x2

AP MM A MMAP MM

AP MM IE M AP MM IE M Ai MM

MAPIE

MAP

Induction MAP

Eligibility for randomisation• Poor histological response to induction MAP

≥10% viable tumor in resected specimen

• Complete resection of primary tumor

• No progression

• Recovered from prior therapy

Poor Response

Dosing

M Methotrexate 12gm/m2

A Doxorubicin 75mg/m2

P Cisplatin 120mg/m2

I Ifosfamide 14g/m2

i ifosfamide 9g/m2

E Etoposide 500mg/m2

Outcome measures

• Primary

Event-free survival (EFS)• Local recurrence• Progression of existing metastases• New metastatic disease• Secondary malignancy• Death

• Secondary includeOverall survival (OS)Short & long-term toxicityQuality of life

Sample sizeAssumptions• 3yr EFS 45% (MAP) 55% (MAPIE)• Target HR = 0.75• Power 80%• Type I error 0.05

Targets• ≥ 378 EFS events• 693 Poor Response randomizations over 5 years ~ 2000 registrations

Randomisation• Permuted blocks• Stratification factors: data center, metastases status, site and

location of tumor on bone

Analyses• Treatment effect estimated with

1. Hazard Ratio (HR) from adjusted Cox model • Proportionality of hazards tested

Hazards not proportional

2. Restricted Mean Survival Time (RMST)• RMST measures average time event-free

up to a specified time point 5 yearsi.e. area under the curve

Rationale for releasing data now

• Analysis planned at ≥378 EFS events

• Fewer poor responders randomised (618/693)• Event rate is lower than predicted• Results unlikely to change in near future

• IDMC recommended early release and dissemination– After routine review of the data (Jun-2014)– Data released by the Trial Steering Committee

• Analysis includes 300 EFS events (median FU 4.5y)

Recruitment: Apr2005 – Nov2011

Registration2260

Confirmed Poor Responder

1059

Randomized 618

MAP310

MAPIE 308

1201 Not Poor Responder 1041 Confirmed Good Response 160 Response not reported

441 Not Randomized 208 (47%) Non-consent 102 (23%) Progression (local or distant) 51 (12%) Histology reported outside trial timelines 44 (10%) Not 2 cycles induction MAP 17 ( 4%) Other 15 ( 4%) No removal of mets/unresectable disease 4 ( 1%) Reason missing 1 (<1%) Good responder, entered PR rand (MAP)

COG; 313

COSS; 157

EOI; 115

SSG; 33

Baseline characteristicsMAP MAPIE

Age at randomisationMedian (IQR)(min-max) 15

4(11-18)- 40

15 5

(12-17)- 40

SexMaleFemale

174 136

(56%)(44%)

191 117

(62%)(38%)

Site of tumorProximal femur/humerusOther limb siteAxial/Skeletal

43 253

14

(14%)(82%)( 5%)

34 256

17

(11%)(83%)( 6%)

Primary metastases*YesNo

45265

(15%)(86%)

32274

(10%)(90%)

Total 310 308

*metastases status missing for 2 patients on MAPIE arm

Cumulative standardised dose

Median (IQR)Target MAP MAPIE

Number of courses

% Received targetTarget MAP MAPIE

M methotrexate (g/m2)

96 8

A doxorubicin (mg/m2)

300 4

P cisplatin (mg/m2)

240 2

I ifosfamide 14g(g/m2)

52 3

i ifosfamide 9g(g/m2)

18 2

E etoposide(g/m2)

1.5 3

Postoperative chemotherapyreceived doses



Number of courses



96 94 (80-97)

88(68-97)

8


300 296 (284-303)

299(233-305)

4

P cisplatin (mg/m2)

240 239(235-241)

240(230-244)

2


52 n/a 41 (27-42)

3


18 n/a 17 (9-18)

2

E etoposide(g/m2)

1.5 n/a 1.5 (1.0-1.5)

3




Number of courses



96 94 (80-97)

88(68-97)

8 73% 58%


300 296 (284-303)

299(233-305)

4 83% 78%

P cisplatin (mg/m2)

240 239(235-241)

240(230-244)

2 92% 84%


52 n/a 41 (27-42)

3 n/a 74%


18 n/a 17 (9-18)

2 n/a 64%

E etoposide(g/m2)

1.5 n/a 1.5 (1-1.5)

3 n/a 75%


Worst postoperative toxicity

*neutrophils and platelets excluded

Worst toxicityGrade 3

MAPGrade 4 Grade 5 Grade 3

MAPIEGrade 4 Grade 5

Worst non-haem* postoperative

177(59%)

59(20%)

1(<1%)

172(58%)

88(30%)

1(<1%)

Overall 237 / 300 (79%) 261 / 297 (88%)

Fisher’s test p=0.004

Worst toxicity(includes all toxicities)

Grade 3MAP

Grade 4 Grade 5 Grade 3MAPIE

Grade 4 Grade 5

Worst postoperativetoxicity

26 (9%) 259(86%)

1(<1%)

20(7%)

259(87%)

1(<1%)

Overall 286 / 300 (95%) 280 / 297 (94%)

Fisher’s test p=0.585

137

181

11

35

0

50

100

150

200

Num

ber

of

patients

3 4toxicity grade

Febrile neutropenia

MAP MAPIE

48

57

1

9

1

0

20

40

60

Num

ber

of

patients

3 4 5toxicity grade

Infection normal ANC

MAP MAPIE

103

135

4

23

0

50

100

150

Num

ber

of

patients

3 4toxicity grade

Infection documented clinically

MAP MAPIE

39

58

4

13

0

20

40

60

Num

ber

of

patients

3 4toxicity grade

Hypophosphataemia

MAP MAPIE

2

5

1

2

0

1

2

3

4

5

Num

ber

of

patients

3 4toxicity grade

Creatinine

MAP MAPIE

2

4

0

1

2

3

4

Nu

mb

er

of

pa

tient

s

3toxicity grade

Typhlitis

MAP MAPIE

Secondary malignancies (SMN)

MAP (310 pts)

MAPIE (308 pts)

Number of SMNs 2 (0.6%) Between 7 (2.3%) and 9 (2.9%)

TypesAcute Myeloid LeukaemiaAcute Monocytic LeukaemiaMDS

1-1

412

Additional reports under review* 2

• Higher rate of SMNs expected with MAPIE (vs. MAP)• Expected rate with MAPIE: <5%• Observed SMNs with MAPIE arm: 2.3% (95%CI 0.9%-4.6%) potentially 2.9% (95%CI 1.3%-5.5%)

• These are preliminary data; cleaning is ongoing. Additional 2 events reported as SMN, without any other information.

0.00

0.25

0.50

0.75

1.00

307 245(53) 181(57) 124(30) 88(7) 52(2) 22(3) 8(0) 0(0)MAPIE308 225(81) 175(45) 133(12) 95(5) 64(3) 28(2) 8(0) 0(0)MAP

0 12 24 36 48 60 72 84 96months

MAP MAPIE

Event-Free Survival

54% (49%-60%)

52% (46%-58%)

Main resultsHR=1.01 (0.80-1.26) p=0.99Target HR=0.75

Hazards are not proportional (p=0.0001) HR difficult to interpret

MAP: lower event rate than predicted Expected EFS: 45% at 3yrObserved EFS: 54% at 3yr (49%-60%)

3-year EFS

Reported: 300 EFS events 148 MAP, 152 MAPIE

Target: 378 EFS events

0.00

0.25

0.50

0.75

1.00

307 245(53) 181(57) 124(30) 88(7) 52(2) 22(3) 8(0) 0(0)MAPIE308 225(81) 175(45) 133(12) 95(5) 64(3) 28(2) 8(0) 0(0)MAP

0 12 24 36 48 60 72 84 96months

MAP MAPIE

Event-Free Survival

54% (49%-60%)

52% (46%-58%)

RMST To 5yr 95%CI

MAP 37.5m 34.9 to 40.1MAPIE 38.1m 35.6 to 40.5

Diff. 0.6m -3.1 to 4.4 P = 0.738

MAP: lower event rate than predicted Expected EFS: 45% at 3yrObserved EFS: 54% at 3yr (49%-60%)

3-year EFS

Reported: 300 EFS events 148 MAP, 152 MAPIE

Target: 378 EFS events

No difference

MAPIE increases average EFS time by 0.6 months (p=0.738)

Overall survival

MAP arm: lower event rate than predictedExpected 5-year OS: 45%Observed 5-year OS: 66% (61%-73%)

0.00

0.25

0.50

0.75

1.00

307 286(12) 241(35) 184(21) 129(13) 77(4) 34(1) 11(1) 0(0)MAPIE308 282(23) 238(38) 182(21) 132(7) 86(5) 39(0) 9(1) 0(0)MAP

0 12 24 36 48 60 72 84 96months

MAP MAPIE

66% (60-71%)

68% (61%-73%)

5-year OS

Reported: 182 deaths 95 MAP 87 MAPIE

Target: 378 deathsTarget not reached

Conclusions

• Data reported earlier than planned: 300 / 378 events

• No evidence of advantage of MAPIE over MAP in EFS or OS

• Fewer patients on MAPIE received the intended dose

• MAPIE associated with greater toxicity

• MAPIE associated with higher risk of secondary malignancy

• Investigators & research staff at all 326 trial sites & data centers

• National co-ordinating investigators– N Marina, M Bernstein, S Bielack, L Kager, Z Papai, T Kühne, J Starý, J Whelan, C Dhooge,

M Capra, H Gelderblom, S Smeland, M Ericcson, O Johansson, M Tarkkanen, O Nielsen

• Members of the IDMC, TSC, TMG and trial advisory panels

• Funding bodies– National Cancer Institute, USA ; European Science Foundation (ESF) under the EUROCORES Program

European Clinical Trials (ECT), through contract No. ERASCT-2003-980409 of the European

Commission, DG Research, FP6 (Ref No MM/NG/EMRC/0202); Fonds National de la Recherche

Scientifique & Fonds voor Wetenschappelijk Onderzoek-Vlaanderen; Danish Medical Research Council;

Academy of Finland; Deutsche Forschungsgemeinschaft; Deutsche Krebshilfe; Federal Ministry of

Education and Research, Germany, BMBF 01KN1105; Semmelweis Foundation; Netherlands Council for

Medical Research; Research Council of Norway; Scandinavian Sarcoma Group; Swiss Paediatric

Oncology Group; Cancer Research UK, CRUK/05/013; UK Medical Research Council

• All patients who participated in EURAMOS-1

Acknowledgments

www.euramos.org

EFS in localised disease subgroup

M0 – includes patients with no mets or possible mets

0.00

0.25

0.50

0.75

1.00

32 9(21) 3(4) 1(0) 0(0)MAPIE M1273 170(89) 84(33) 21(5) 0(0)MAPIE M045 11(33) 6(1) 3(0) 0(0)MAP M1263 164(93) 89(16) 25(5) 0(0)MAP M0

0 12 24 36 48 60 72 84 96months

MAP M0 MAP M1

MAPIE M0 MAPIE M1

539 patients

241 EFS events: 114 MAP, 127 MAPIETarget: 270 EFS events

ResultsHR=1.06 (0.83-1.37), p=0.63Target HR=0.71

Hazards are not proportional, p=0.002 HR difficult to interpret

3-year EFS59% (53%-65%)

56% (49%-61%)



Number of courses



96 94 (80-97)

88(68-97)

8


300 296 (284-303)

299(233-305)

4

P cisplatin (mg/m2)

240 239(235-241)

240(230-244)

2

I ifosfomide 14g(g/m2)

52 n/a 41 (27-42)

3

i ifosfomide 9g(g/m2)

18 n/a 17 (9-18)

2

E etoposide(g/m2)

1.5 n/a 1.5 (1.0-1.5)

3


39

58

4

13

0

20

40

60

Num

ber

of

patients

3 4toxicity grade

Hypophosphataemia

MAP MAPIE

2

5

1

2

0

1

2

3

4

5

Num

ber

of

patients

3 4toxicity grade

Creatinine

MAP MAPIE

2

4

0

1

2

3

4

Num

ber

of

patients

3toxicity grade

Thyhlitis

MAP MAPIE

2

9

3 3

0

2

4

6

8

10

Num

ber

of

patients

3 4toxicity grade

Mood alteration

MAP MAPIE

1

6

0

2

4

6N

um

ber

of

patients

3toxicity grade

Somnolance

MAP MAPIE

2

3

1

0

1

2

3

Num

ber

of

patients

3 5toxicity grade

LVSD

MAP MAPIE

50

100

150

g /

m2

Methotrexate

MAP MAPIE

0

200

400

600

mg

/ m2

Doxorubicin

MAP MAPIE

0

50

100

150

200

250

mg /

m2

Cisplatin

MAP MAPIE

EFS in localised disease subgroupRMST To 5yr 95%CI

MAP 40.15m 37.3 to 43.0MAPIE 40.09m 37.4 to 42.7

Diff. -0.06m -3.9 to 3.7 P > 0.999

0.00

0.25

0.50

0.75

1.00

32 9(21) 3(4) 1(0) 0(0)MAPIE M1273 170(89) 84(33) 21(5) 0(0)MAPIE M045 11(33) 6(1) 3(0) 0(0)MAP M1263 164(93) 89(16) 25(5) 0(0)MAP M0

0 12 24 36 48 60 72 84 96months

MAP M0 MAP M1

MAPIE M0 MAPIE M1

Overall survival

MAP arm: lower event rate than predictedExpected 5-year OS: 45%Observed 5-year OS: 66% (61%-73%)

0.00

0.25

0.50

0.75

1.00

307 286(12) 241(35) 184(21) 129(13) 77(4) 34(1) 11(1) 0(0)MAPIE308 282(23) 238(38) 182(21) 132(7) 86(5) 39(0) 9(1) 0(0)MAP

0 12 24 36 48 60 72 84 96months

MAP MAPIE

66% (60-71%)

68% (61%-73%)

5-year OS

Main resultsHR=0.99 (0.74-1.32) p=0.81Target HR=0.75

No evidence against proportionality of hazards (p=0.08)

mapie vs map in patients with a poor response to pre-operative chemotherapy for newly-diagnosed...

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