Transcript Panitumumab ASCO 2006 Hecht

Final STEPP results of prophylactic versus reactive
skin toxicity (ST) treatment (tx) for panitumumab
(pmab)-related ST in patients (pts) with metastatic
colorectal cancer (mCRC)
Edith P. Mitchell,1 Mario Lacouture,2 Heather
Shearer,3 Nicholas Iannotti,4 Bilal Piperdi,5
Madhavan Pillai,6 Feng Xu,7 Mohamed Yassine7
1Kimmel
Cancer Center, Thomas Jefferson University, Philadelphia, PA;
2Northwestern University, Chicago, IL;
3Piedmont Hematology Oncology Associates PLLC, Winston-Salem, NC;
4Hematology Oncology Associates of Treasure Coast, Port Saint Lucie, FL;
5University of Massachusetts Medical Center, Worcester, MA;
6Virginia Oncology Care PC, Richlands, VA;
7Amgen Inc., Thousand Oaks, CA
American Society of Clinical Oncology 2009
Introduction
•
Colorectal cancer is the third most common cancer worldwide, with approximately
1 million new cases diagnosed annually1
•
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 and Canada as
monotherapy in patients with wild-type KRAS tumor status2,3
•
Skin toxicities are the most common treatment-related side effects of anti-EGFR
therapy3,4
•
The STEPP study is the first prospective study to examine differences between
prophylactic and reactive skin treatment for skin toxicities associated with any
EGFR inhibitor
•
This is the final analysis of STEPP on safety and efficacy of panitumumab by skin
treatment and KRAS status
American Society of Clinical Oncology 2009
Study Objectives
• To estimate the difference in the incidence of specific ≥
grade 2 skin toxicities of interest between patients
receiving prophylactic or reactive skin treatment arms
during the 6-week skin treatment period
• Secondary objectives:
– Assessments of other skin toxicity events during the
6-week skin treatment period
– Safety and efficacy of panitumumab plus irinotecanbased chemotherapy by KRAS status
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Methods: Study Design
•
Phase 2, multicenter, open-label, randomized clinical trial conducted in
the US
•
Patients received either pmab 6 mg/kg/FOLFIRI Q2W or pmab 9.0 mg/kg/
irinotecan chemotherapy Q3W by investigators choice
•
Tumor response was assessed by central review using modified
Response Evaluation Criteria in Solid Tumors (RECIST) at weeks 9 and
13, and Q8W thereafter for patients on the Q2W regimen, and at weeks
10, 14, 22, and then Q9W thereafter for patients on the Q3W regimen
•
Within each chemotherapy stratum, patients were randomized in a 1:1
ratio to either the prophylactic or reactive skin treatment
•
Patient-reported Quality of Life was assessed using the Dermatology Life
Quality Index (DLQI) at screening during weeks 2 to 7, and at the week 13
or 14 visit, depending on treatment schedule
•
Patients continued on-study until completion of the post-treatment
follow-up period, death, withdrawal of full consent, or lost to follow-up
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STEPP Study Schema
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1:1a
n=
95
Prophylactic Skin
Treatment
n = 48
Reactive Skin
Treatment
n = 47
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Q8W
or Q9W
by chemotherapy regimen (investigator choice): either FOLFIRI and
panitumumab Q2W regimen or irinotecan and panitumumab Q3W regimen
bSkin treatment period: Weeks 1 to 6 (start day - 1)
Skin assessment period: QW from weeks 1 to 7
P
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aStratified
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Skin Treatment
• Prophylactic skin treatment regimen administered weeks 1 to 6
(beginning day 1):
• 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
• Per investigator discretion, a reactive skin treatment was
administered anytime during weeks 1-6
• From week 7 and thereafter, investigators had the option to
continue patients on the assigned skin treatment regimen
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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 progression of disease or
toxicity-based from fluoropyrimidine, oxaliplatin, and/or
bevacizumab
• ECOG performance status of 0 or 1
• No prior irinotecan use for the treatment of mCRC
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Statistical Analysis
• This is the final analysis of the STEPP study
• Skin toxicity, anti-tumor efficacy, and safety endpoints were
analyzed on the primary analysis set including all randomized
patients
• Analyses by KRAS were defined as a subset of patients with
evaluable KRAS status
• Quality of life data were based on PRO analysis set defined as
a subset of patients with baseline and at least one postbaseline PRO results
• Logistic regression model was employed to estimate the
treatment effect on the binary endpoints of interest. The Odds
Ratio (OR) and 95% CI using the Wald method were provided
• AEs (adverse events) were grouped by using MedDRA 9.0.
The severity of AEs was coded according to the NCI CTCAE v.
3.0 with modification for Dermatology Toxicity Grading for
skin related toxicities
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Table 1: Patient Disposition
Prophylactic
Skin Treatment
N = 48
Reactive Skin
Treatment
N = 47
48 (100)
47 (100)
Disease progression
30 (63)
28 (60)
Adverse event
5 (10)
5 (11)
Patient request
5 (10)
6 (13)
Death
3 (6)
2 (4)
Other
5 (10)
6 (13)
31.0
40.7
Patients who ended second-line treatment – n (%)
Reason for ending treatment – n (%)
Median follow-up time1, weeks
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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Table 1: Demographics and Disease Characteristics
(cont’d)
Sex – n (%)
Men
Race – n (%)
White or Caucasian
Black or African American
Hispanic or Latino
Other
Age – years, median (min, max)
ECOG performance status – n (%)
0
1
2
Primary tumor type – n (%)
Colon
Rectal
Number of metastatic sites – n (%)
1
>1
Prophylactic Skin Treatment
N = 48
Reactive Skin Treatment
N = 47
32 (67)
26 (55)
34 (71)
6 (13)
5 (10)
3 (6)
60 (24, 84)
40 (85)
5 (11)
1 (2)
1 (2)
61 (40, 86)
34 (71)
12 (25)
2 (4)
30 (64)
17 (36)
0 (0)
34 (71)
14 (29)
28 (60)
19 (40)
18 (38)
30 (63)
17 (36)
30 (64)
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Primary Endpoint - Incidence of Grade 2 or Higher Skin
Toxicities1 in Prophylactic vs Reactive Skin Treatment Arms
(During the Skin Treatment Period, Final Analysis)
Patients with grade 2 or higher skin toxicity – n (%)2
Odds Ratio3 (95% CL)
Grade 2 – n (%)
Grade 3 – n (%)
Prophylactic
Reactive
Skin
Skin
Treatment
Treatment
N = 48
N = 47
14 (29)
29 (62)
0.3 (0.1, 0.6)
11 (23)
3 (6)
19 (40)
10 (21)
1 Specific
skin toxicities of interest per protocol
There were no grade 4 skin toxicities during the skin treatment period
3 Odds ratio is estimated from a logistic regression model including treatment (prophylactic vs reactive) that includes an
adjustment for chemotherapy stratum (Q2W vs Q3W)
2
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Probability of Grade 2 or Higher Skin Toxicity1 by Time on the
Study
1Specific
skin toxicities of interest per protocol
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Best Overall Response1 and Progression-free
Survival By Skin Treatment Group
Central Review
Prophylactic
N = 48
Reactive
N = 47
7 (15)
5 (11)
Complete response
0 (0)
0 (0)
Partial response
7 (15)
5 (11)
Stable disease
24 (50)
25 (53)
Disease control
31 (65)
30 (64)
Disease progression
9 (19)
10 (21)
Not done or unevaluable
8 (17)
7 (15)
4.7 (2.9 - 6.0)
4.1 (2.9 - 6.2)
Best overall response – n (%)
Progression free survival – KM
Median (95% CI) Months
1By
independent central review and confirmed by a follow-up assessment no less than 28 days after the criteria for response were first met
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Disposition: KRAS subsets
Patients enrolled n (%)
Wild-type
KRAS
N = 49
Mutant
KRAS
N = 38
49 (100)
38 (100)
23 (47)
28 (74)
Death
4 (8)
0 (0)
Protocol deviation
4 (8)
0 (0)
Adverse events
5 (10)
5 (13)
Patient request
8 (16)
3 (8)
Consent withdrawn
0 (0)
1 (3)
Administrative decision
3 (6)
1 (3)
Other
2 (4)
0 (0)
Median
39.3
33.2
Range
0.7, 96.4
1.7, 96.6
Total patients ended treatment – n (%)
Reason for ending treatment period – n (%)
Disease progression
Follow-up time (weeks)
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Best Overall Response by Central review: KRAS
subsets
Wild-type
KRAS
N = 49
Mutant
KRAS
N = 38
Complete response
0 (0)
0 (0)
Partial response
8 (16)
3 (8)
Stable disease
26 (53)
21 (55)
Disease control
34 (69)
24 (63)
Disease progression
10 (20)
6 (16)
4 (8)
6 (16)
Best overall response – n (%)a
Not done or unevaluable
aResponses
were confirmed at least 4 weeks after response criteria were first met
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Central Review of Progression Free Survival by
KRAS Status:
Events
N (%)
KRAS Wild-type
34 (69%)
KRAS Mutant
26 (68%)
HR = 0.8 (95% CI: 0.4 - 1.3)
100%
Median (months)
(95 % CI)
5.5 (4.0 - 6.8)
3.3 (2.9 - 5.2)
90%
Survival Distribution Function
80%
70%
60%
50%
40%
30%
20%
10%
KRAS Wild Type
KRAS Mutant
0%
0
4
8
12
16
20
Months
KRAS Wild Type N 49
Censored
0
KRAS Mutant N
Censored
38
0
32
2
15
3
7
0
1
2
0
1
17
3
6
1
2
1
1
0
0
0
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Best Overall Response1 and Progression-free Survival by
KRAS Status and Skin Treatment Group2
Central Review
Wild-type KRAS
Mutant KRAS
Prophylactic
N = 23
Reactive
N = 26
Prophylactic
N = 21
Reactive
N = 17
4 (17)
4 (15)
2 (10)
1 (6)
Complete response
0 (0)
0 (0)
0 (0)
0 (0)
Partial response
4 (17)
4 (15)
2 (10)
1 (6)
Stable disease
13 (57)
13 (50)
11 (52)
10 (59)
Disease control
17 (74)
17 (65)
13 (62)
11 (65)
Disease progression
3 (13)
7 (27)
5 (24)
1 (6)
Not done or unevaluable
3 (13)
2 (8)
3 (14)
5 (29)
6 (4 - 9)
5 (2 - 8)
3 (3 - 5)
3 (3 - 9)
Best overall response – n (%)
Progression free survival – KM
Median (95% CI) Months
1Responses
2This
were confirmed via central review and confirmed 28 days after the criteria for response was first met
was an unplanned analysis
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Adverse Events of Interest1 Week 1 Through the Safety
Follow-up
Prophylactic Skin Treatment - N = 48
Any
Grade
Grade 3
Pts with any event – n (%)
48 (100)
Dermatitis acneiform
Reactive Skin Treatment - N = 47
Grade 4
Any
Grade
Grade 3
Grade 4
20 (42)
5 (10)
47 (100)
25 (53)
10 (21)
37 (77)
2 (4)
0 (0)
40 (85)
10 (21)
0 (0)
Pruritus
30 (63)
1 (2)
0 (0)
32 (68)
5 (11)
0 (0)
Pustular rash
13 (27)
2 (4)
0 (0)
19 (40)
8 (17)
0 (0)
Paronychia
8 (17)
0 (0)
1 (2)
17 (36)
3 (6)
0 (0)
Nausea
32 (67)
3 (6)
0 (0)
26 (55)
4 (9)
0 (0)
Vomiting
22 (46)
3 (6)
0 (0)
17 (36)
4 (9)
0 (0)
Fatigue
29 (60)
5 (10)
0 (0)
27 (57)
5 (11)
0 (0)
Diarrhea
27 (56)
7 (15)
0 (0)
40 (85)
15 (32)
0 (0)
Neutropenia
9 (19)
3 (6)
1 (2)
20 (43)
8 (17)
4 (9)
Hypomagnesemia
7 (15)
1 (2)
1 (2)
13 (28)
2 (4)
1 (2)
Dehydration
6 (13)
3 (6)
0 (0)
16 (34)
8 (17)
0 (0)
1There
were no grade 5 adverse events of interest
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Treatment Exposure
Prophylactic Skin Treatment
Total number of panitumumab doses1
Total panitumumab doses delayed during
the study1 – n (%)
1Patients
Reactive Skin Treatment
325
333
12 (4)
21 (6)
who had changes in panitumumab during the study
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Dermatologic Toxicities – Grade 3
Prophylactic Skin Treatment
Reactive Skin Treatment
25%
% Patients
20%
15%
10%
5%
0%
Dermatitis
acneiform
Pruritus
Pustular rash
Paronychia
Of these commonly observed dermatologic toxicities, there were no grade 4
or 5 events for either skin treatment group
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Non-Dermatologic Toxicities – Grade 3 and 4
% Patients
Prophylactic Skin Treatment
Reactive Skin Treatment
35%
30%
25%
20%
15%
10%
5%
0%
Gr 3 Gr 4
Gr 3 Gr 4
Gr 3 Gr 4
Nausea
Vomiting
Fatigue
Gr 3 Gr 4
Gr 3 Gr 4
Gr 3
Gr 4
Gr 3 Gr 4
Diarrhea
Neutropenia Hypomagnesemia Dehydration
Of these commonly observed non-dermatologic toxicities, there were no grade 5
events for either skin treatment group
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Mean (SD) DLQI Score Change from Baseline to Week 3
and Week 71
Mean (SD) DLQI change from baseline to
week 3 – points
Mean (SD) DLQI change from baseline to
week 7 – points
1Based
Prophylactic Skin
Treatment
N = 46
Reactive Skin
Treatment
N = 44
1.3 (2.6)
4.2 (5.8)
2.0 (2.8)
2.6 (4.4)
on the PRO Analysis Set defined as patients who had a baseline and at least 1 post-baseline DLQI score
Patients in the prophylactic skin treatment group reported improved quality of life,
especially during weeks 2 to 3 when the median time to first ≥ grade 2 skin toxicity
of interest was reached in the reactive skin treatment group
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Conclusions
• The incidence of grade 2 or higher skin toxicities during
the 6-week skin treatment period was reduced by more
than 50% in the prophylactic treatment group compared
with the reactive treatment group
• Numerical differences in favor of the wild-type KRAS
group were observed for all efficacy endpoints
• Prophylactic and reactive skin treatment regimen had
no difference in efficacy based on skin toxicity regimen
• A phase 3 registrational study is currently ongoing to
investigate panitumumab with FOLFIRI by KRAS
mutational status in second-line mCRC
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References
1.
2.
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4.
Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J
Clin. 2005; 55:74-108.
Jakobovits A, et al. Nat Biotech. 2007; 25:1134-1143.
Vectibix® Prescribing Information, Amgen Inc. Thousand Oaks, CA; 2007.
Perez-Soler R, Saltz L. J Clin Oncol. 2005; 23:5235-5246.
American Society of Clinical Oncology 2009