Results of a Randomized Phase III Trial (MPACT) of Weekly nab-Paclitaxel Plus Gemcitabine vs Gemcitabine Alone for Patients With Metastatic Adenocarcinoma of the Pancreas With PET and CA19-9 Correlates

Daniel D. Von Hoff, 1 Malcolm Moore, 6 Thomas Ervin, Thomas Seay, 7 2 Francis P. Arena, 3 Sergey A. Tjulandin, 8 E. Gabriela Chiorean, WenWee Ma, 9 4 Jeffrey Infante, 5 Mansoor N. Saleh, 10 Marion Harris, 11 Michele Reni, Cutsem, 15 12 Ramesh K. Ramanathan, 1 David Goldstein, 16 Xinyu Wei, 17 Josep Tabernero, Jose Iglesias, 18 13 Manuel Hidalgo, 14 Markus F. Renschler 17 Eric Van 1 TGen, Scottsdale Healthcare, AZ, USA; 2 Florida Cancer Specialists/Sarah Cannon Research Institute, Englewood, FL; 3 Arena Oncology Associates, Lake Success, NY, USA; 4 University of Washington, Seattle, WA, USA; 5 Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; 6 Princess Margaret Hospital, Toronto, Canada; 7 Atlanta Cancer Care, GA, USA; 8 Blokhin Cancer Research Center, Moscow, Russia; 9 Roswell Park Cancer Institute, Buffalo, NY, USA; 10 Cancer Specialists, Atlanta, GA, USA; 11 Southern Health, East Bentleigh, VIC, Australia; 12 San Raffaele Scientific Institute, Milan, Italy; 13 Vall d'Hebron University Hospital, Barcelona, Spain; 14 Centro Integral Oncológico Clara Campal, Madrid, Spain; 15 Leuven University, Belgium; 16 Prince of Wales Hospital, Sydney, NSW, Australia; 17 Celgene Corporation, Summit, NJ, USA; 18 Bionomics, Thebarton, Australia

Disclosures

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; Renschler: ownership, Celgene; Infante, Harris : Iglesias : employment or leadership position at Bionomics and stock ownership, Celgene; employment or leadership position and stock nothing to disclose.

Von Hoff et al. ASCO 2013.

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nab-Paclitaxel + Gemcitabine

in Pancreatic Cancer

1. Preclinical models 1,2 :

• •

nab-Paclitaxel (nab-P) active as single agent Synergizes with gemcitabine (Gem) 2. In a 67-patient phase I/II trial of nab-P + Gem 1

•

MTD: nab-P 125 mg/m 2 + Gem 1000 mg/m 2 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.

2.

Von Hoff DD, et al.

J Clin Oncol

. 2011;29:4548-4554. Frese KK, et al.

Cancer Discov

. 2012;2:260-269. Von Hoff et al. ASCO 2013.

3

Planned N = 842

• • • • • •

Stage IV No prior treatment for metastatic disease KPS ≥ 70 Measurable disease Total bilirubin ≤ ULN No age limitation

  

Primary endpoint

–

OS Secondary endpoints

–

PFS and ORR by independent review (RECIST) Safety and tolerability

–

By NCI CTCAE v3.0

Study Design

nab-P 125 mg/m 2 IV qw 3/4 + Gem 1000 mg/m 2 IV qw 3/4 1:1, stratified by KPS, region, liver metastasis

• • • • •

Gem 1000 mg/m 2 IV qw 7/8 then qw 3/4 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.

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MPACT (CA046) Phase III Trial

Country nab-P + Gem, n Gem, n USA Australia Russia Canada Italy Ukraine Spain Germany Austria France Belgium Total 235 6 3 3 4 1 61 50 33 21 14 431 241 10 5 3 2 2 59 50 30 16 12 430 All, n (%) 476 (55) 120 (14) 100 (12) 63 (7) 37 (4) 26 (3) 16 (2) 8 (1) 6 (1) 6 (1) 3 (< 1) 861 (100) Total of 151 sites enrolled 861 patients between May 8, 2009, and April 17, 2012

Von Hoff et al. ASCO 2013.

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Baseline Characteristics

Variable Age Sex KPS Median years (min, max) ≥ 65 years old, % Male, % 90-100, % 70-80, % Pancreatic primary location Current site(s) of metastasis No. of metastatic sites Previous Whipple Biliary stent Head, % Body, % Tail, % Lung, % Liver, % 1, % 2, % ≥ 3, % Yes, % Yes, % CA19-9 a Normal, % > ULN-< 59

×

ULN, % ≥ 59

×

ULN, %

ULN, upper limit of normal.

a CA19-9 at baseline was unknown in 13% of patients.

nab-P + Gem (n = 431) 62 (27, 86) 41 57 58 42 44 31 24 35 85 8 47 45 7 19 14 28 46 Gem (n = 430) 63 (32, 88) 44 60 62 38 42 32 26 43 84 5 48 47 7 16 13 28 45 All Patients (N = 861) 63 (27, 88) 42 58 60 40 43 31 25 39 84 6 47 46 7 17 13 28 46

Von Hoff et al. ASCO 2013.

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Overall Survival

1.0

0.9

0.8

0.7

0.6

Events/n (%) nab-P + Gem Gem 333/431 (77) 359/430 (83) OS, months Median (95% CI) 8.5 (7.89-9.53) 6.7 (6.01-7.23) 75th Percentile 14.8

11.4

0.5

0.4

0.3

0.2

0.1

HR = 0.72

95% CI (0.617-0.835) P = 0.000015

0.0

0 Pts at risk nab-P + Gem: Gem: 431 430 3 357 340 6 269 220 9 169 124 12 108 69 15 67 40 18 Months 40 26 21 27 15 24 16 7 27 9 3 30 4 1 33 1 0 36 1 0 39 0 0

• 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

• Trial conclusions not impacted by secondary therapies = 0.00007

Von Hoff et al. ASCO 2013.

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Overall Survival

Rate

Time Points, months 6 9 12 18 24 nab-P + Gem Survival, % Gem Survival, % Increase, % P Value 67 48 35 16 9 55 36 22 9 4 22 33 59 78 125 0.00074

0.00067 0.00020

0.00803

0.02123

Von Hoff et al. ASCO 2013.

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OS —Prespecified Subgroups

Group All patients Age < 65 years Age ≥ 65 years Female Male KPS 70-80 KPS 90-100 Primary tumor location: head Primary tumor location: other Liver metastases No liver metastases 1 metastatic site 2 metastatic sites 3 metastatic sites > 3 metastatic sites Normal CA19-9 CA19-9 ULN to < 59 x ULN CA19 9 ≥ 59 x ULN Australia Eastern Europe Western Europe North America 0.125

HR nab-P + Gem Events/n 333/431 188/254 145/177 138/186 195/245 142/179 187/248 142/191 188/237 290/365 43/66 21/33 159/202 104/136 49/60 47/60 96/122 151/197 50/61 62/64 14/38 207/268 0.25

0.5

Favors nab-P + Gem 1.0

2.0

Favors Gem Gem Events/n 359/430 209/242 150/188 141/173 218/257 146/161 212/268 155/180 201/246 309/360 50/70 16/21 163/206 121/140 59/63 43/56 95/120 171/195 53/59 59/62 17/38 230/271

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HR 0.72

0.65

0.81

0.72

0.72

0.61

0.75

0.59

0.80

0.69

0.86

0.41

0.75

0.79

0.50

1.07

0.83

0.61

0.67

0.84

0.72

0.68

PFS by Independent Review

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 Pts at Risk nab-P + Gem: Gem: 431 430 PFS Rate at 6 months 12 months 3 281 209 Events/n (%) nab-P + Gem 277/431 (64) Gem 265/430 (62) PFS, months Median (95% CI) 5.5 (4.47-5.95) 3.7 (3.61-4.04) 75th Percentile 9.2

5.9

6 9 122 51 nab-P + Gem 44% 16% 62 23 12 Months 24 10 Gem 25% 9% 15 HR = 0.69

95% CI (0.581-0.821) P = 0.000024 18 21 24 8 6 4 4 2 0 0 0 Increase 76% 78%

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Response Rates

Variable nab-P + Gem (n = 431) Gem (n = 430) P Value Overall response rate

Independent review, % (95% CI) Investigator assessment, % (95% CI)

Disease control rate by independent review, a %

(95% CI) a Includes CR + PR + SD ≥ 16 weeks.

23 (19.1-27.2) 29 (25.0-33.8) 48 (43.0-52.6) 7 (5.0-10.1) 8 (5.3-10.6) 1.1 x 10 −10 3.3 x 10 −16 33 (28.4-37.5) 7.2 x 10 − 6

Von Hoff et al. ASCO 2013.

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Treatment Exposure

Variable Treatment duration, median months (min, max)

≥ 6 months, %

Relative dose intensity (%), median (min, max)

nab

-P Gem

Cumulative dose, median mg/m ²

nab

-P Gem

nab-P

doses at 125 mg/m², n (%) Gem doses at 1000 mg/m², n (%) nab-P + Gem (n = 421) 3.9

(0.1, 21.9) 32 1425.0

11,400.0

4116.0 ( 71 ) 3731.0 (63) Gem (n = 402) 2.7

(0.1, 21.5) 15 80.6

(16.7, 100.0) 75.2 (14.3, 97.7) - 84.6 (14.1, 100.0) - 9000.0

- 3762.0 (79)

Von Hoff et al. ASCO 2013.

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Safety

Preferred Term Pts with at least 1 AE leading to death, % Grade ≥ 3 hematologic AEs,

a Neutropenia Thrombocytopenia Anemia

% nab-P + Gem (n = 421) 4 38 13 13 Gem (n = 402) 4 27 9 12 Pts who received growth factors, % Febrile neutropenia,

b

% Grade ≥ 3 nonhematologic AEs

b Fatigue Peripheral neuropathy c Diarrhea

in > 5% pts, % 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, %

26 3 17 17 6 140 21 29 44 15 1 7 < 1 1 113 29 - --

a Based on laboratory values; b Based on investigator assessment of treatment-related events; c Grouped term. Von Hoff et al. ASCO 2013.

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Metabolic Response by PET by Independent Review

•

PET scans were performed in the first 257 patients randomized to receive treatment at PET-equipped centers Outcome nab-P + Gem (n = 130) a Gem (n = 127) a HR P Value Metabolic response by PET, b % 63 38 ORR by CT scan, % 31 11 Median OS in PET cohort, mo 10.5

8.3

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).

0.71

0.000051

0.0001

0.0096

Von Hoff et al. ASCO 2013.

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CA19-9

Best Response and Landmark OS Analyses

•

Best Decrease in CA19-9 During Study Decrease in CA19-9 level nab-P + Gem (n = 379) Patients with a decrease, n (%) ≥ 20% Patients with a decrease, n (%) ≥ 90% 230 (61) 117 (31) Gem (n = 371) 162 (44) 51 (14) P Value < 0.0001

< 0.0001

•

Predictive Value of CA19-9 Response at Week 8 on OS: Landmark Analyses nab-P + Gem Gem HR P Value Decrease in CA19-9 Level at Week 8 n Median OS, mo n Median OS, mo ≥ 20% ≥ 90% 197 59 13.2

13.4

141 34 9.4

9.8

0.59

0.47

< 0.0001

0.0053

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

Von Hoff et al. ASCO 2013.

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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

Von Hoff et al., ASCO 2013 16

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

Von Hoff et al., ASCO 2013 17

MPACT Team

Von Hoff et al. ASCO 2013.

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