Results of a Randomized Phase III Trial (MPACT) of Weekly nab-Paclitaxel PlusGemcitabine vs Gemcitabine Alone for

Patients With Metastatic Adenocarcinoma of the Pancreas With PET and CA19-9

Correlates

Daniel D. Von Hoff,1 Thomas Ervin,2 Francis P. Arena,3 E. Gabriela Chiorean,4 Jeffrey Infante,5 Malcolm Moore,6 Thomas Seay,7 Sergey A. Tjulandin,8 WenWee Ma,9 Mansoor N. Saleh,10 Marion Harris,11 Michele Reni,12 Ramesh K. Ramanathan,1 Josep Tabernero,13 Manuel Hidalgo,14 Eric Van

Cutsem,15 David Goldstein,16 Xinyu Wei,17 Jose Iglesias,18 Markus F. Renschler 17

1TGen, Scottsdale Healthcare, AZ, USA; 2Florida Cancer Specialists/Sarah Cannon Research Institute, Englewood, FL; 3Arena Oncology Associates, Lake Success, NY, USA; 4University of Washington, Seattle, WA, USA; 5Sarah Cannon Research Institute/Tennessee Oncology,

PLLC, Nashville, TN; 6Princess Margaret Hospital, Toronto, Canada; 7Atlanta Cancer Care, GA, USA; 8Blokhin Cancer Research Center, Moscow, Russia; 9Roswell Park Cancer Institute, Buffalo, NY, USA; 10Cancer Specialists, Atlanta, GA, USA; 11Southern Health, East Bentleigh,

VIC, Australia; 12San Raffaele Scientific Institute, Milan, Italy; 13Vall d'Hebron University Hospital, Barcelona, Spain; 14Centro Integral Oncológico Clara Campal, Madrid, Spain; 15Leuven University, Belgium; 16Prince of Wales Hospital, Sydney, NSW, Australia; 17Celgene

Corporation, Summit, NJ, USA; 18Bionomics, Thebarton, Australia

Disclosures

2Von Hoff et al. ASCO 2013.

This study was sponsored by Celgene Corporation

Von Hoff: consultant or advisory role, honoraria, and research funding, Celgene; Ervin: research funding, Celgene; Arena: research funding, Clinical Research Alliance and Celgene; Chiorean: research funding, Celgene; Moore: consultant or advisory role and research funding, Celgene; Seay: research funding, Celgene; Tjulandin: research funding, Celgene; Ma: research funding, Celgene; Saleh: research funding, Celgene; Reni: consultant or advisory role, honoraria, and research funding, Celgene; Ramanathan: consultant or advisory role, honoraria, and research funding, Celgene; Tabernero: consultant or advisory role and honoraria, Celgene; Hidalgo: consultant or advisory role, honoraria, and research funding, Celgene; Van Cutsem: research funding, Celgene; Goldstein: consultant or advisory role and research funding, Celgene; Wei: employment or leadership position and stock ownership, Celgene; Iglesias: employment or leadership position at Bionomics and stock ownership, Celgene; Renschler: employment or leadership position and stock ownership, Celgene; Infante, Harris: nothing to disclose.

nab-Paclitaxel + Gemcitabine in Pancreatic Cancer

1. Preclinical models1,2:• nab-Paclitaxel (nab-P) active as single agent• Synergizes with gemcitabine (Gem)

2. In a 67-patient phase I/II trial of nab-P + Gem1

• MTD: nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 every 28 days

• Promising activity at MTD• ORR: 48%• Median PFS: 7.9 months• Median OS: 12.2 months

1. Von Hoff DD, et al. J Clin Oncol. 2011;29:4548-4554. 2. Frese KK, et al. Cancer Discov. 2012;2:260-269. 3Von Hoff et al. ASCO 2013.

Study Design

1:1, stratified by KPS, region, liver metastasis

Planned N = 842

• Stage IV• No prior treatment for

metastatic disease• KPS ≥ 70 • Measurable disease• Total bilirubin ≤ ULN• No age limitation

nab-P125 mg/m2 IV qw 3/4

+

Gem1000 mg/m2 IV qw 3/4

Gem1000 mg/m2 IV qw 7/8

then qw 3/4

4

Primary endpoint– OS

Secondary endpoints– PFS and ORR by

independent review (RECIST)

Safety and tolerability– By NCI CTCAE v3.0

• With 608 events, 90% power to detect OS; HR = 0.769 (2-sided α = 0.049)

• Treat until progression• CT scans every 8 weeks• PET scans in an initial cohort of

patients at baseline and weeks 8 and 16• CA19-9 measurements at baseline and

every 8 weeks

Von Hoff et al. ASCO 2013.

Country nab-P + Gem, n Gem, n All, n (%)

USA 235 241 476 (55)Australia 61 59 120 (14)Russia 50 50 100 (12)Canada 33 30 63 (7)Italy 21 16 37 (4)Ukraine 14 12 26 (3)Spain 6 10 16 (2)Germany 3 5 8 (1)Austria 3 3 6 (1)France 4 2 6 (1)Belgium 1 2 3 (< 1)Total 431 430 861 (100)

MPACT (CA046) Phase III Trial

Total of 151 sites enrolled 861 patients between May 8, 2009, and April 17, 20125Von Hoff et al. ASCO 2013.

Baseline Characteristics

Variablenab-P + Gem

(n = 431)Gem

(n = 430)

All Patients(N = 861)

AgeMedian years (min, max) 62 (27, 86) 63 (32, 88) 63 (27, 88)

≥ 65 years old, % 41 44 42

Sex Male, % 57 60 58

KPS90-100, % 58 62 60

70-80, % 42 38 40

Pancreatic primary location

Head, % 44 42 43

Body, % 31 32 31

Tail, % 24 26 25

Current site(s) of metastasis

Lung, % 35 43 39

Liver, % 85 84 84

No. of metastatic sites

1, % 8 5 6

2, % 47 48 47

≥ 3, % 45 47 46

Previous Whipple Yes, % 7 7 7

Biliary stent Yes, % 19 16 17

CA19-9a

Normal, % 14 13 13

> ULN-< 59 ×ULN, % 28 28 28

≥ 59 × ULN, % 46 45 46

ULN, upper limit of normal.a CA19-9 at baseline was unknown in 13% of patients. 6Von Hoff et al. ASCO 2013.

Overall Survival

Months

Pro

po

rtio

n o

f S

urv

ival

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1.0

0.00 3 6 9 12 15 18 21 24 27 30 33 36 39

Pts at risknab-P + Gem:

Gem:

431

430

357

340

269

220

169

124

108

69

67

40

40

26

27

15

16

7

9

3

4

1

1

0

1

0

0

0

nab-P + Gem

Gem

OS, months

Events/n (%) Median (95% CI)75th

Percentile

333/431 (77) 8.5 (7.89-9.53) 14.8

359/430 (83) 6.7 (6.01-7.23) 11.4

HR = 0.7295% CI (0.617-0.835)P = 0.000015

7Von Hoff et al. ASCO 2013.

• Subsequent therapy: 38% for nab-P + Gem and 42% for Gem• OS censored at time of secondary therapy: 9.4 vs 6.8 months; HR 0.68; P = 0.00007• Trial conclusions not impacted by secondary therapies

Overall Survival Rate

nab-P + Gem Gem

Time Points,months Survival, % Survival, % Increase, % P Value

6 67 55 22 0.00074

9 48 36 33 0.00067

12 35 22 59 0.00020

18 16 9 78 0.00803

24 9 4 125 0.02123

8Von Hoff et al. ASCO 2013.

OS—Prespecified SubgroupsGroup

0.125 0.25 0.5 1.0 2.0

HR

All patients

nab-P + GemEvents/n

GemEvents/n HR

333/431 359/430 0.72

188/254 209/242 0.65

145/177 150/188 0.81

138/186 141/173 0.72

195/245 218/257 0.72

142/179 146/161 0.61

187/248 212/268 0.75

142/191 155/180 0.59188/237 201/246 0.80

290/365 309/360 0.69

43/66 50/70 0.86

21/33 16/21 0.41

159/202 163/206 0.75

104/136 121/140 0.79

49/60 59/63 0.50

47/60 43/56 1.07

96/122 95/120 0.83

151/197 171/195 0.6150/61 53/59 0.6762/64 59/62 0.8414/38 17/38 0.72

207/268 230/271 0.68

Age < 65 yearsAge ≥ 65 years

FemaleMale

KPS 70-80KPS 90-100

Australia

Western EuropeNorth America

Eastern Europe

Primary tumor location: head Primary tumor location: other

No liver metastases

Liver metastases

Normal CA19-9

CA19-9 ULN to < 59 x ULNCA19-9 ≥ 59 x ULN

> 3 metastatic sites

1 metastatic site

3 metastatic sites

2 metastatic sites

9Favors GemFavors nab-P + Gem Von Hoff et al. ASCO 2013.

PFS by Independent Review

Months

Pro

po

rtio

n o

f P

rog

ress

ion

-Fre

e S

urv

ival

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1.0

0.00 3 6 9 12 15 18 21 24

Pts at Risknab-P + Gem:

Gem:

431

430

281

209

122

51

62

23

24

10

8

6

4

4

2

0

0

0

nab-P + Gem

Gem

PFS, months

Events/n (%) Median (95% CI)75th

Percentile

277/431 (64) 5.5 (4.47-5.95) 9.2

265/430 (62) 3.7 (3.61-4.04) 5.9

HR = 0.6995% CI (0.581-0.821)P = 0.000024

10

PFS Rate at nab-P + Gem Gem Increase

6 months 44% 25% 76%

12 months 16% 9% 78%Von Hoff et al. ASCO 2013.

Response Rates

Variable nab-P + Gem(n = 431)

Gem(n = 430)

P Value

Overall response rate Independent review, % (95% CI) Investigator assessment, % (95% CI)

23 (19.1-27.2)

29 (25.0-33.8)

7 (5.0-10.1)

8 (5.3-10.6)

1.1 x 10−10

3.3 x 10−16

Disease control rate by independent review,a % (95% CI)

48(43.0-52.6)

33(28.4-37.5)

7.2 x 10−6

11

a Includes CR + PR + SD ≥ 16 weeks.

Von Hoff et al. ASCO 2013.

Variablenab-P + Gem

(n = 421)Gem

(n = 402)

Treatment duration, median months (min, max) ≥ 6 months, %

3.9 (0.1, 21.9)32

2.7 (0.1, 21.5)15

Relative dose intensity (%), median (min, max) nab-P Gem

80.6 (16.7, 100.0)75.2 (14.3, 97.7)

--84.6 (14.1, 100.0)

Cumulative dose, median mg/m² nab-P Gem

1425.011,400.0

--9000.0

nab-P doses at 125 mg/m², n (%)Gem doses at 1000 mg/m², n (%)

4116.0 (71)3731.0 (63)

--3762.0 (79)

Treatment Exposure

12Von Hoff et al. ASCO 2013.

Preferred Termnab-P + Gem

(n = 421)Gem

(n = 402)Pts with at least 1 AE leading to death, % 4 4

Grade ≥ 3 hematologic AEs,a % Neutropenia Thrombocytopenia Anemia

381313

279

12

Pts who received growth factors, % 26 15

Febrile neutropenia,b % 3 1

Grade ≥ 3 nonhematologic AEsb in > 5% pts, % Fatigue Peripheral neuropathyc

Diarrhea

17176

7< 11

Grade ≥ 3 neuropathy Time to onset, median days Time to improvement by 1 grade, median days Time to improvement to grade ≤ 1, median days Pts who resumed nab-P, %

140212944

11329----

Safety

a Based on laboratory values; b Based on investigator assessment of treatment-related events; c Grouped term.

13Von Hoff et al. ASCO 2013.

Metabolic Response by PET by Independent Review

• PET scans were performed in the first 257 patients randomized to receive treatment at PET-equipped centers

14

Outcome nab-P + Gem(n = 130)a

Gem(n = 127)a HR P Value

Metabolic response by PET,b %

63 38 - 0.000051

ORR by CT scan, % 31 11 - 0.0001

Median OS in PET cohort, mo

10.5 8.3 0.71 0.0096

a Follow-up scans at 8 weeks (n = 222) and 16 weeks (n = 134).b PET evaluated by EORTC criteria (Young H, et al. Eur J Cancer. 1999;35:1773-1782).

Von Hoff et al. ASCO 2013.

CA19-9 Best Response and Landmark OS Analyses

15Von Hoff et al. ASCO 2013.

• Best Decrease in CA19-9 During Study

Decrease in CA19-9 level nab-P + Gem(n = 379)

Gem(n = 371) P Value

Patients with a ≥ 20% decrease, n (%) 230 (61) 162 (44) < 0.0001

Patients with a ≥ 90% decrease, n (%) 117 (31) 51 (14) < 0.0001

• Predictive Value of CA19-9 Response at Week 8 on OS: Landmark Analyses

Decrease in CA19-9 Level at Week 8

nab-P + Gem Gem HR P Value

n Median OS, mo n Median OS, mo

≥ 20% 197 13.2 141 9.4 0.59 < 0.0001

≥ 90% 59 13.4 34 9.8 0.47 0.0053

Detailed analysis presented by Chiorean et al. (abstract 4058)

Conclusions from MPACT

1. MPACT study – a large, multi-center, international study performed at community and academic centers

2. OS, PFS, and ORR were superior for nab-P + Gem vs Gem

a) Improvement in OS across the entire curve, including median, 1-year, and 2-year survival rates

3. Metabolic response rate by PET and CA19-9 response rates were higher for nab-P + Gem vs Gem alone

a) Both were predictors for longer OS

16Von Hoff et al., ASCO 2013

Conclusions from MPACT (cont)

4. Serious life threatening toxicity not increased; AEs acceptable and manageable

5. nab-P + Gem, a new standard for the treatment of patients with metastatic pancreatic cancer, is superior to Gem alone and could become the backbone for new regimens

6. A phase III study of nab-P + Gem in the adjuvant setting is currently in development

17Von Hoff et al., ASCO 2013

MPACT Team

18Von Hoff et al. ASCO 2013.