1. Updated results of STEPP, a phase 2, open‑label study of pre-emptive versus reactive skin toxicity treatment in metastatic colorectal cancer (mCRC) patients receiving panitumumab + FOLFIRI or irinotecan‑only chemotherapy as second-line treatment
Edith P. Mitchell,1 Mario LaCouture,2 Heather Shearer,3 Nicholas Iannotti,4 Bilal Piperdi,5 Madhavan V. Pillai,6 Feng Xu,7 Mohamed Yassine7
1Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; 2Northwestern University, Chicago, IL, USA; 3Piedmont Hematology Oncology Associates PLLC, Winston-Salem, NC, USA; 4Hematology Oncology Associates of Treasure Coast, Port Saint Lucie, FL, USA; 5University of Massachusetts Medical Center, University Campus, Worcester, MA, USA; 6Virginia Oncology Care PC, Richlands, VA, USA; 7Amgen Inc., Thousand Oaks, CA, USA
STEPP ASCO GI DRAFT - CONFIDENTIAL

2. Introduction
Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is approved in the US as monotherapy for mCRC after disease progression on standard chemotherapy and in the EU as monotherapy in patients with wild-type KRAS tumor status1,2
Skin toxicities are the most common treatment‑related side effects of anti‑EGFr therapy2,3
The STEPP study is first prospective study to examine differences between pre‑emptive and reactive skin treatment for skin toxicities associated with panitumumab in combination with FOLFIRI or single-agent irinotecan chemotherapy
In addition, efficacy by KRAS mutational status was evaluated
Reminder- this is an interim analysis of STEPP. It is the final analysis of the primary endpoint.
Jakobovits A, et al. Nat Biotech. 2007; 25:
Vectibix® Prescribing Information, Amgen Inc. Thousand Oaks, CA; 2007.
Perez-Soler R, Saltz L. J Clin Oncol. 2005; 23:
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3. Study Objectives, and Pre-Emptive Skin Treatment Regimen
Primary objective:
To estimate the difference in incidence rates of specific ≥ grade 2 skin toxicities of interest between patients in the pre-emptive and reactive skin treatment arms during the 6-week skin treatment period
Other objectives:
Safety and efficacy of panitumumab plus Q2W or Q3W chemotherapy by skin treatment and KRAS status
Pre-emptive skin treatment regimen administered weeks 1 to 6:
Skin moisturizer – apply to face, hands, feet, neck, back, and chest daily in the morning upon rising
Sunscreen (PABA free, SPF ≥ 15, UVA/UVB protection) – apply to exposed skin areas before going outdoors
Topical steroid (1% hydrocortisone cream) – apply to face, hands, feet, neck, back, and chest at bedtime
Doxycycline 100 mg BID
STEPP ASCO GI DRAFT - CONFIDENTIAL

4. STEPP Study Schema n = 48 n = 47 n = 95 TUMOR SKIN OVER AL L TOXICITY
RESPONSE
EVALUATION
SKIN
TOXICITY
EVALUATION
OVER AL L
SURVIVAL
FOLLOW UP
SAFETY
FOLLOW UP
RANDOMI ZAT I ON
PROGRESS ION
SCREEN I NG
Pre-Emptive Skin
Treatment
n = 48
Reactive Skin
Treatment
Patients (planned N = 95) received either:
FOLFIRI Q2W + pmab 6.0 mg/kg Q2W (n = 55), or
Irinotecan Q3W + pmab 9.0 mg/kg Q3W (n = 40)
Within each stratum, patients were randomized 1:1 to either:
Pre‑emptive skin treatment during weeks 1 to 6
Reactive skin treatment
Pre-emptive skin treatment included the administration of:
Skin moisturizer
Sunscreen (PABA free, SPF ≥ 15, UVA/UVB protection)
1% hydrocortisone cream
Doxycycline 100 mg BID
n = 47
n = 95
Q8W or Q9W
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5. Key Eligibility Criteria
≥ 18 years of age
Unresectable metastatic adenocarcinoma of the colon or rectum that cannot, per investigator, be cured by surgical resection at the time of randomization
Measurable disease per modified RECIST
Failure of first-line treatment containing fluoropyrimidine and oxaliplatin-based chemotherapy with or without bevacizumab for mCRC
Treatment failure was defined as toxicity-based from fluoropyrimidine, oxaliplatin, and/or bevacizumab or progression of disease
ECOG performance status of 0 or 1
No prior irinotecan use for the treatment of mCRC
STEPP ASCO GI DRAFT - CONFIDENTIAL

6. Statistical Considerations and Analysis Set
This is an interim analysis of STEPP consisting of:
The final analysis of the primary endpoint (N = 95)
Analysis sets from this interim analysis included:
Primary analysis set: all randomized patients (N = 95) that had the opportunity to complete the first tumor response assessment at week 13 or week 14
KRAS primary analysis set: all patients who had known KRAS status from the primary analysis set (N = 87; 8 patients were excluded)
Safety analysis set: all patients who received at least 1 dose of investigational drug (N = 95)
This is an interim analysis of STEPP consisting of the final analysis of the primary endpoint as described earlier.
Analysis sets from this interim analysis included:
Primary analysis set….
KRAS primary analysis set
STEPP ASCO GI DRAFT - CONFIDENTIAL

7. Pre-Emptive Skin Treatment Reactive Skin Treatment
Patient Disposition
Pre-Emptive Skin Treatment
(n = 48)
Reactive Skin Treatment
(n = 47)
Patients who ended second-line treatment – n (%)
47 (98)
41 (87)
Reason for ending treatment – n (%)
Disease progression
30 (63)
25 (53)
Adverse event
5 (10)
5 (11)
Patient request
4 (8)
4 (9)
Death
3 (6)
2 (4)
Other
5 (12)
Median (Q1, Q3) follow-up time1, weeks
26.9 (13, 39.9)
30.6 (17.7, 51)
1 Follow-up time is calculated as the randomization date to the last on-study or long-term follow-up visit
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8. Baseline Demographics and Disease Characteristics
Pre-Emptive Skin Treatment
(n = 48)
Reactive Skin Treatment
(n = 47)
Sex – n (%)
Men
32 (67)
26 (55)
Race – n (%)
White or Caucasian
34 (71)
40 (85)
Black or African American
6 (13)
5 (11)
Hispanic or Latino
5 (10)
1 (2)
Other
3 (6)
Age – years, median (min, max)
60 (24, 84)
61 (40, 86)
ECOG performance status – n (%)
30 (64) 1
12 (25)
17 (36) 2
2 (4)
0 (0)
Primary tumor type – n (%)
Colon
28 (60)
Rectal
14 (29)
19 (40)
Number of metastatic sites – n (%)
18 (38)
> 1
30 (63)

9. Primary Endpoint: Incidence of Grade 2 or Higher Skin Toxicities1 in Pre-Emptive vs Reactive Skin Treatment Arms (During the Skin Treatment Period, Final Analysis)
Pre-Emptive Skin
Treatment
(n = 48)
Reactive Skin
(n = 47)
Patients with grade 2 or higher skin toxicity – n 14 29
Percentage (95% CL)
29 (16, 42)
62 (48, 76)
Odds Ratio2 (95% CL)
0.3 (0.1, 0.6)
Most Severe with grade 2 or higher skin toxicity3
Grade 2 – n 11 19
23 (11, 35)
40 (26, 54)
Grade 3 – n 3 10
Percentage (95% CL)
6 (0, 13)
21 (10, 33)
1 Specific skin toxicities of interest per protocol
2 Odds ratio is estimated from a logistic regression model including treatment (pre-emptive vs reactive) that includes an adjustment for chemotherapy stratum (Q2W vs Q3W).
3 There were no grade 4 skin toxicities of interest during the skin treatment period.
NR = not reached

10. Time to First Occurrence of Grade 2 or Higher Skin Toxicity (Kaplan-Meier Estimate)
Events Median (95% CI)
N (%) Weeks
Pre-emptive 14 (29) NR
Reactive 29 (62) (2.1, 6.3)
HR = 0.4 (95% CI: )

11. Investigator Assessment
Interim Best Overall Response by Pre-Emptive and Reactive Skin Treatment Group
Investigator Assessment
Central Review
Pre-Emptive
(n = 48)
Reactive
(n = 47)
Best overall response – n (%)
8 (17)
7 (15)
4 (9)
Complete response
2 (4)
3 (6)
0 (0)
Partial response
6 (13)
Stable disease
23 (48)
25 (53)
24 (50)
26 (55)
Disease control
31 (65)
32 (68)
30 (64)
Disease progression
10 (21)
9 (19)
Not done or unevaluable

12. Panitumumab + Irinotecan
Interim Efficacy by Panitumumab Plus FOLFIRI or Irinotecan Chemotherapy Regimen
Panitumumab + FOLFIRI
(n = 55)
Panitumumab + Irinotecan
(n = 40)
Investigator Review
Central
Review
Central Review
Best overall response –
% (95% CI)
24 (12, 35)
16 (7, 26)
5 (0, 12)
Progression free survival – months (95% CI)
6.1 (4.6, 7.4)
4.6 (3.1, 6.2)
3.5 (2.3, 5.2)
4.0 (2.3, 6.0)
Overall survival –
months (95% CI)
13.3 (10.9, -)
9.2 (7.0, 13.8)

13. Investigator Assessment
Interim Best Overall Response by KRAS Status (KRAS Primary Analysis Set)
Investigator Assessment
Central Review
Wild-Type KRAS
(n = 49)
Mutant KRAS
(n = 47)
Best overall response – n (%)
10 (20)
4 (11)
7 (14)
3 (8)
Complete response
3 (6)
2 (5)
0 (0)
Partial response
Stable disease
27 (55)
19 (50)
21 (55)
Disease control
37 (76)
23 (61)
34 (69)
24 (63)
Disease progression
9 (24)
6 (16)
Not done or unevaluable
5 (10)
8 (21)

14. Interim Progression-Free Survival by KRAS Status (KRAS Primary Analysis Set)
Local Review
Central Review
Events Median (95% CI)
N (%) Months
Wild-type 36 (73) (4.6, 8.2)
Mutant 29 (76) (2.3, 5.2)
HR = 0.7 (95% CI: )
Events Median (95% CI)
N (%) Months
Wild-type 34 (69) (4.0, 6.8)
Mutant 25 (66) (2.8, 5.2)
HR = 0.7 (95% CI: )

15. Summary of Adverse Events
Pre-Emptive
Skin
Treatment
(n = 48)
Reactive
(n = 47)
Patients with any adverse event – n (%)
48 (100)
47 (100)
Maximum grade 3 or higher
29 (60)
38 (81)
Serious adverse events
13 (27)
23 (49)
Skin treatment-related adverse events
10 (21)
3 (6)
Panitumumab discontinued due to adverse events
9 (19)
11 (23)
Ended second-line treatment due to adverse events
6 (13)
7 (15)
All deaths on study1
17 (35)
18 (38)
1 No panitumumab-related deaths were reported within 30 days of the last panitumumab administration.

16. Adverse Events of Interest1
Pre-Emptive Skin Treatment (n = 48)
Reactive Skin Treatment
(n = 47)
Any
Grade
Grade 3
Grade 4
Patients with any adverse event – n (%)
48 (100)
19 (40)
5 (10)
47 (100)
25 (53)
9 (19)
Dermatitis acneiform
37 (77)
2 (4)
0 (0)
40 (85)
10 (21)
Nausea
31 (65)
3 (6)
26 (55)
4 (9)
Fatigue
29 (60)
27 (57)
5 (11)
Diarrhea
27 (56)
7 (15)
15 (32)
Vomiting
22 (46)
17 (36)
Pustular rash
13 (27)
8 (17)
Neutropenia
1 (2)
20 (43)
Hypomagnesemia
13 (28)
Dehydration
6 (13)
1 There were no grade 5 adverse events of interest.

17. Conclusions
In this analysis of STEPP, the incidence of specific grade 2 or higher skin toxicities during the 6 week skin treatment period was reduced by more than 50% in the pre-emptive treatment group compared with the reactive treatment group
Numerical differences in favor of the wild-type KRAS group were observed for all efficacy endpoints
The combination of panitumumab and irinotecan based chemotherapy was well tolerated
The STEPP study continues per protocol for safety and efficacy
A phase 3 registrational study is currently ongoing to investigate panitumumab with FOLFIRI by KRAS mutational status in second-line mCRC
STEPP ASCO GI DRAFT - CONFIDENTIAL