ASPECCTA randomized, multicenter,

open-label, phase 3 study of panitumumab vs cetuximab for previously treated wild-type (WT) KRAS metastatic

colorectal cancer (mCRC)

Timothy Price,1 Marc Peeters,2 Tae Won Kim,3 Jin Li,4 Stefano Cascinu,5 Paul Ruff,6 Atilli Satya Suresh,7 Kathy Zhang,8

Swaminathan Murugappan,8 Roger Sidhu8

1The Queen Elizabeth Hospital and University of Adelaide, Woodville, Australia; 2Antwerp University Hospital and University of Antwerp, Edegem, Belgium; 3Asan Medical Center, University of Ulsan, Seoul, Korea; 4Fudan University

Cancer Hospital, Shanghai, P.R. China; 5Universita Politecnica delle Marche, Ancona, Italy; 6University of Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa; 7Apollo Hospital, Hyderabad, India;

8Amgen Inc., Thousand Oaks, CA, USA

Disclosures For Prof T. Price

Advisory Board: Amgen Inc. (uncompensated)

2

Therapeutic indication (EU)

Vectibix® Summary of Product Characteristics.

Panitumumab is indicated for the treatment of adult patients with wild-type RAS metastatic colorectal cancer (mCRC):

In first-line in combination with FOLFOX or FOLFIRIIn second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan)As monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens

The combination of panitumumab with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS mCRC or for whom RAS mCRC status is unknown

The recommended dose of panitumumab is 6 mg/kg of bodyweight given once every two weeks

Introduction

Anti-EGFR agents (panitumumab and cetuximab) are approved as monotherapy in the treatment of patients with chemorefractory WT KRAS mCRC

Cetuximab has demonstrated OS benefit prospectively in chemorefractory (3rd line) mCRC (CO.17 study; Jonker et al, 2007 NEJM)

Panitumumab has not prospectively demonstrated a statistically significant survival benefit in monotherapy setting in mCRC patients, potentially due to frequent use of anti-EGFR crossover treatment

ASPECCT is the first head-to-head, randomized phase 3 study evaluating the efficacy and safety of panitumumab vs cetuximab for the treatment of chemorefractory WT KRAS mCRC

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ASPECCT Study Schema

Stratification Factors:• North America and Western Europe and Australia vs rest of world (ROW) • ECOG PS (0 or 1 vs 2)

Crossover between arms during study treatment was not allowed

RANDOMISE

1:1

Panitumumab 6.0 mg/kg Q2W

Cetuximab 400 mg/m2 loading dose,

250 mg/m2 QW

PD

PD

SURVIVAL

Patients with previously

treated, WT KRAS mCRC

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Study Endpoints

Primary endpoint: Overall Survival (OS)

Key secondary endpoints:

Progression-Free Survival (PFS)

Objective response rate (ORR)

Safety

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Key Eligibility Criteria

Age ³ 18 years oldHistologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum Metastatic diseaseWT KRAS tumor status, assessed centrallyMeasurable or non-measurable disease per RECIST version 1.1 Disease progression or intolerability on irinotecan-, oxaliplatin- and fluorouracil-based therapy for mCRCAdequate hematologic, renal, hepatic, metabolic functionNo prior anti-EGFR therapyNo symptomatic brain metastasesSigned informed consent

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Statistical Considerations

Non-inferiority design: Compare the effect of panitumumab vs cetuximab on OS

Treatment effect of cetuximab compared to BSC was derived from the CO.17 trial (9.5 vs 4.8 months, HR=0.55) (CO.17 study; Karapetis et al 2008, NEJM)

Retention rate – what fraction of the treatment effect of cetuximab over BSC is preserved by panitumumab (point estimate and confidence interval)

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Statistical Considerations (cont.)

To satisfy the non-inferiority test at a 1-sided 2.5% significance level, panitumumab will demonstrate preservation of at least 50% of the cetuximab OS effect relative to Best Supportive Care (BSC).

A synthesis approach with an asymptotic standard normal test statistic will be used to test the OS inferiority null hypothesis

Non-inferiority is claimed if Zpc score is less than ‘-1.96’

Constancy – qualitative assessment that study population and assumptions are aligned in this study vs CO.17

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Demographics and Disease Characteristics

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Panitumumab(N = 499)

Cetuximab(N = 500)

Men 315 (63.1) 318 (63.6)

Race, white – n (%) 266 (53.3) 258 (51.6)

Age – years, median (range) 61.0 (19-86) 60.5 (20-89)

ECOG PS – n (%)

0 154 (30.9) 163 (32.6)

1 303 (60.7) 297 (59.4)

2 42 (8.4) 40 (8.0)

Region – n (%)

North America, Western EU, AUS 154 (30.9) 156 (31.2)

ROW 345 (69.1) 344 (68.8)

Primary diagnosis, colon cancer – n (%) 292 (58.5) 326 (65.2)

Prior chemotherapy – n (%) 499 (100) 499 (99.8)

Prior bevacizumab – n (%) 126 (25.3) 132 (26.4)

Sites of metastatic disease – n (%)Liver onlyLiver plus other sites

52 (10.4)447 (89.6)

50 (10)450 (90)

Median follow-up time – months (range) 9.5 (0.3, 35.6) 9.3 (0.1, 34.5)

Overall Survival

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0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Months

Pro

po

rtio

n E

ven

t-fr

ee

Patients at risk:CetuximabPanitumumab

500 462 398 349 283 221 181 151 122 94 70 54 37 24 16 8 1 0 0499 456 399 345 286 224 185 156 124 98 76 48 32 22 12 3 2 2 0

34 36

Hazard Ratio: 0.97, 95%CI: (0.84, 1.11)P-value: 0.0007Z-score: -3.19 Retention rate: 1.06, 95% CI: (0.82, 1.29)

Eventsn/N (%)

Median (95% CI)months

Panitumumab 383/ 499(76.8)

10.4 (9.4, 11.6)

Cetuximab 392 / 500(78.4)

10.0 (9.3, 11.0)

OS Subset Analysis

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0.1 1.0 10.0Hazard Ratio (Panitumumab / Cetuximab)

Favors Panitumumab Favors Cetuximab

All Patients 999 0.97 0.84-1.11Rest of World 689 1.00 0.84-1.19N America, Western EU and Aus 310 0.90 0.71-1.15ECOG PS Status: 0 or 1 917 0.98 0.85-1.14ECOG PS Status: 2 82 0.84 0.53-1.34Prior bevacizumab: No 741 1.05 0.89-1.24Prior bevacizumab: Yes 258 0.77 0.58-1.02Primary tumor: Colon 618 0.93 0.78-1.11Primary tumor: Rectal 381 1.06 0.84-1.34Metastatic: Liver only 102 1.19 0.75-1.90Metastatic: Other sites w/o liver 897 0.95 0.82-1.10

Factors

Age < 65 654 1.04 0.87-1.23Age ≥ 65 345 0.85 0.67-1.08Male 633 0.92 0.77-1.10Female 366 1.06 0.84-1.34

N HR 95% CI

Subsequent Therapies

Panitumumab(N=499)

Cetuximab(N=500)

Any anti-tumor therapy for colorectal cancer, n (%) 205 (41.1) 211 (42.2)

Chemotherapy 155 (31.1) 165 (33.0)

Anti-EGFR mAb• Cetuximab-based• Panitumumab-based

45 (9.0)39 (7.8)5 (1.0)

52 (10.4)41 (8.2)12 (2.4)

Anti-VEGF 35 (7.0) 33 (6.6)

Other 117 (23.4) 109 (21.8)

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Eventsn/N (%)

Median (95% CI)months

Panitumumab 477 / 499(95.6)

4.1 (3.2, 4.8)

Cetuximab 477 / 500(95.4)

4.4 (3.2, 4.8)

Hazard Ratio: 1.002, 95% CI: 0.882, 1.138

Progression-Free Survival

1414

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Months

Pro

po

rtio

n E

ven

t-fr

ee

500 355 247 155 86 41 23 15 9 4 3 1 1 0 0 0 0499 350 245 151 73 42 27 16 9 7 6 3 3 2 2 1 0

Patients at risk:CetuximabPanitumumab

Objective Response Rates

Panitumumab(N=486)

Cetuximab(N=485)

Best tumor response over the study – n (%)

Complete response 2 (0.4) 0 (0)

Partial response 105 (21.6) 96 (19.8)

Stable disease or Non CR/Non PD 226 (46.5) 236 (48.7)

Patients with objective response* – n (%) 107 (22.0) 96 (19.8)

Rate (95% CI) - %22.02

(18.41, 25.97)19.79

(16.34, 23.62)

Odds Ratio (95% CI) 1.15 (0.83, 1.58)

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*Objective response is defined as a best tumor response of complete or partial response. Baseline measurable patients only.

Summary of Adverse Events

Panitumumab(N=496)

Cetuximab(N=503)

Patients with any adverse events - n (%) 485 (97.8) 494 (98.2)

Worst grade 3 180 (36.3) 159 (31.6)

Worst grade 4 37 (7.5) 27 (5.4)

Worst grade 5 29 (5.8) 50 (9.9)

Any serious 151 (30.4) 169 (33.6)

Permanent discontinuation of study drug

69 (13.9) 61 (12.1)

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Includes only patients who received protocol treatment

Incidence of Grade 3 or Higher Adverse Events Of Interest

Adverse Event – n (%) PanitumumabN=496

CetuximabN =503

Fatal AE’sColon cancerOthers

29 (5.8)20 (4.0)9 (1.8)

50 (9.9)34 (6.8)16 (3.2)

Treatment-related fatal AE’s 0 (0) 1 (0.2)

Skin and Subcutaneous tissue AE’sAny gradeGrade 3Grade 4Serious

430 (86.7)60 (12.1)

2 (0.4)1 (0.2)

440 (87.5)48 (9.5)

0 (0)0 (0)

HypomagnesemiaAny gradeGrade 3Grade 4

143 (28.8)27 (5.4)9 (1.8)

95 (18.9)10 (2.0)3 (0.6)

Infusion reactionsAny gradeGrade 3Grade 4

14 (2.8)1 (0.2)0 (0)

63 (12.5)5 (1.0)4 (0.8)

DiarrheaAny gradeGrade 3Grade 4

91 (18.3)7 (1.4)3 (0.6)

89 (17.7)9 (1.8)0 (0.0)

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Conclusions

ASPECCT met its primary endpoint of non-inferiority for OS

Panitumumab retained 106% (95% CI 82-129) of the OS benefit of cetuximab over best supportive care in patients with WT KRAS mCRC

Observed safety profiles between the two treatment arms were consistent with previously reported studies for both agents

No new toxicities or safety signals were identified for panitumumab

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AcknowledgementsWe wish to thank the patients, their families and friends, and the study staffs

We wish to thank Amgen Inc.

The ASPECCT Investigators

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• N. M. A. Abdullah �• R. Adams• M. Aghmesheh• J. B. Ahn• B. Aleknaviciene• D. Amadori• S. Attili• Y. Ba• Y. Bai• J. Bennouna• V. M. K. Bhavaraju• S. Bondarde• C. Borg• D. Borg• P. Cao• G. Carlsson• A. Cheng• S. Chiara• G. Chong• J. Chovanec• L. Ciuffreda• G. Cohen

• B. Colwell• P. Cooray• G. Cruciani• D. Cunningham• S. Dakhil• G. de Lima Lopes Jr• A. Deptala• C. Deshmukh• N. Dobrovolskaya• F. Drudi• M. Ducreux• A. Dudov• S. Essapen• P. L. Etienne• M. Faedi• S. Falk• E. Fernebro• M. Foszczynska-Kloda• V. Gangadharan• M. R. A. Gentili• P. Gibbs• V. Gorbunova

• M. Goyal• E. Grincuka• S. Grumett• S. Gupte• J. Haux• H. Heleniak• G. F. Ho• E. Idelevich• C. Jacobs• R. Janciauskiene• D. Jovanovic• E. Kalbacher• T. W. Kim• Y. H. Kim• S. Y. Kim• T. Y. Kim• K. Krizan• M. Kubecova• K. D. Lee• H. Letocha• J. Li• R. K. LI 

• H. Liang• R. S.C. Lim• F. Lofts• C. Lozada Zingoni• B. Ma• J. Malan• S. Man• G. Manikhas• L. Manzyuk• G. Marx• B. Melichar• P. Montenegro Beltran• A. Mukhopadhyay• R. Nagarkar• W. Ng• T. Niederman• S. Nirni• J. Novotny• Z. Nowecki• P. Nygren• R. Orlova• H. Pan

• J. O. Park• R. Passalacqua• N. Pavlakis• M. Peeters• J. Pikiel• S. Plate• T. Price• S. Protsenko• G. Purkalne• S. Qin• P. Ruff• I. Ryniewicz-Zander• D. Sacdalan• J. F. Salas Sanchez• T. Salek• A. Scarfe• L. Shen• M. Smakal• S. Sonawane• K. Srinivasan• M. Stresko• W. C. Su

• C. J. Tai• S. Tamberi• N. Tebbutt• C. Y. Teoh• A. Thomas• S. Tjulandin• M. N. A Uy• D. Vorobiof• J. Wang• L. Wang• C-H Wang• G. Wilson• R. Wilson• E. Wojcik• F.C.S. Wong• L. Wong• K. Wozniak• J. Xu• T. S. Yang• D. Ygael

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