1. ASPECCT A 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

2. Disclosures For Prof T. Price
Advisory Board: Amgen Inc. (uncompensated)

3. Therapeutic indication (EU)
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 FOLFIRI
In 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
Vectibix® Summary of Product Characteristics.

4. 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, 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

5. ASPECCT Study Schema Panitumumab 6.0 mg/kg Q2WR A N D O M I S E
1:1
SURV I
VAL
Panitumumab 6.0 mg/kg Q2W PD
Patients with previously treated, WT KRAS mCRC
Cetuximab
400 mg/m2 loading dose, 250 mg/m2 QW PD
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

6. Study Endpoints Primary endpoint: Overall Survival (OS)
Key secondary endpoints:
Progression-Free Survival (PFS)
Objective response rate (ORR)
Safety

7. Key Eligibility Criteria
Age ³ 18 years old
Histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum
Metastatic disease
WT KRAS tumor status, assessed centrally
Measurable or non-measurable disease per RECIST version 1.1
Disease progression or intolerability on irinotecan-, oxaliplatin- and fluorouracil-based therapy for mCRC
Adequate hematologic, renal, hepatic, metabolic function
No prior anti-EGFR therapy
No symptomatic brain metastases
Signed informed consent

8. 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)

9. 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

10. Demographics and Disease Characteristics
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 (%)
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
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 only
Liver 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)

11. Proportion Event-free
Overall Survival
Events n/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)
100%
80%
Hazard Ratio: 0.97, 95%CI: (0.84, 1.11)
P-value:
Z-score: -3.19
Retention rate: 1.06, 95% CI: (0.82, 1.29)
60%
Proportion Event-free
40%
20% 0% 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Months
Patients at risk:
Cetuximab
500
462
398
349
283
221
181
151
122 94 70 54 37 24 16 8 1
Panitumumab
499
456
399
345
286
224
185
156
124 98 76 48 32 22 12 3 2 2

12. OS Subset Analysis Favors Panitumumab Favors Cetuximab Factors
N HR % CI
All Patients
Rest of World
N America, Western EU and Aus
ECOG PS Status: 0 or 1
ECOG PS Status: 2
Prior bevacizumab: No
Prior bevacizumab: Yes
Primary tumor: Colon
Primary tumor: Rectal
Metastatic: Liver only
Metastatic: Other sites w/o liver
Age < 65
Age ≥ 65
Male
Female
0.1
1.0
10.0
Hazard Ratio (Panitumumab / Cetuximab)

13. 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)

14. Progression-Free Survival
Events n/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)
100%
80%
Hazard Ratio: 1.002, 95% CI: 0.882, 1.138
60%
Proportion Event-free
40%
20% 0% 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Months
Patients at risk:
Cetuximab
500
355
247
155 86 41 23 15 9 4 3 1 1
Panitumumab
499
350
245
151 73 42 27 16 9 7 6 3 3 2 2 1 14

15. 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)
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)
*Objective response is defined as a best tumor response of complete or partial response. Baseline measurable patients only.

16. 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)
Includes only patients who received protocol treatment

17. Incidence of Grade 3 or Higher Adverse Events Of Interest
Adverse Event – n (%)
Panitumumab N=496
Cetuximab N =503
Fatal AE’s
Colon cancer
Others
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’s
Any grade
Grade 3
Grade 4
Serious
430 (86.7) 60 (12.1) 2 (0.4)
440 (87.5)
48 (9.5) 0 (0) 0 (0)
Hypomagnesemia
Grade 3 Grade 4
143 (28.8) 27 (5.4) 9 (1.8)
95 (18.9) 10 (2.0) 3 (0.6)
Infusion reactions Any grade Grade 3 Grade 4
14 (2.8) 1 (0.2) 0 (0)
63 (12.5) 5 (1.0) 4 (0.8)
Diarrhea
91 (18.3)
7 (1.4)
3 (0.6)
89 (17.7)
9 (1.8)
0 (0.0)

18. Conclusions
ASPECCT met its primary endpoint of non- inferiority for OS
Panitumumab retained 106% (95% CI ) 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

19. Acknowledgements
We wish to thank the patients, their families and friends, and the study staffs
We wish to thank Amgen Inc.
The ASPECCT Investigators
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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