1
The Life Raft Group
The Life Raft Group
40 Galesi Drive
Wayne, NJ 07470
Phone 973-837-9092
Fax 973-837-9095
Email [email protected]
www.liferaftgroup.org
2
Life Raft Group Relapse Study
Disease Progression in Patients with Metastatic GIST Receiving Gleevec (Imatinib): The Effect of Drug Dosage
3
Study Criteria
Metastatic GIST patientsInitial response to Gleevec
was shrinkageOn Gleevec one year or more
4
Objectives Of Our Study
To determine whether there was a correlation between Gleevec dosage and the development of resistance, after one year, amongst metastatic GIST Patients who had initially experienced shrinkage on Gleevec.
To evaluate the difference between using starting dosage (intent to treat) and actual dosage (dosage delivered).
5
Data Notes
Based upon patient reporting Adjusted for patient compliance-7 non-
compliant patients in study May be biased by non random distribution May not be representative of all patients Some subjectivity in assessment of initial
shrinkage and time of relapse Were not able to distinguish between 600
mg and 800 mg dosage levels due to small numbers
6
Data Notes-2
Two patients who said that they had initial shrinkage (one of our study criteria) were excluded from study because the shrinkage was too marginal.
One patient, a clinical trial participant, was excluded from study because he was incorrectly categorized as metastatic GIST (another of our study criteria) when he actually had a cyst.
One patient, a clinical trial participant, has pediatric GIST.
7
n = 169
92 males 77 females
78 Relapsed 91 Stable
8
Starting Dose Distribution
Starting dose distributions were close to equal for males and females, with 43% of males and 36% of females on 600 mg or more.
9
Starting Dose Distributions
≥ 600 < 600
Males 43% 57%
Females 36% 64%
Totals 40% 60%
10
Starting Dose Relapse Rates
Although there was a higher relapse rate for the lower dose group (49.5% versus 41.2%) this was not statistically significant (p = 0.265).
11
Relapse Rates Starting Dosage
n= 169 No. Rate
Total 78 46.2%
< 600 50 49.5%
≥ 600 28 41.2%
Males 44 47.8%
< 600 27 51.9%
≥ 600 17 42.5%
Females 34 44.2%
< 600 23 46.9%
≥ 600 11 39.3%
12
Total Relapse Rates @ Starting Dosage
< 600
≥ 600
Total
Relapsed
Non-Relapsed
50.5%58.8%
53.8%
49.5%
41.2%46.2%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Relapsed Non-Relapsed
13
Male Relapse Rates @ Starting Dosage
< 600≥ 600
Total
Relapsed
Non-Relapsed
48.1%57.5%
52.2%51.9%
42.5%
47.8%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Relapsed Non-Relapsed
14
Female Relapse Rates @ Starting Dosage
< 600
≥ 600
Total
Relapsed
Non-Relapsed
53.1%
60.7%
55.8%
46.9%
39.3%44.2%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Relapsed Non-Relapsed
15
Dosage Change
38% of the total group had at least one dosage change.
A higher percentage of females (16%) had a net reduction from high to low dose than males (7%) although this was not statistically significant.
16
MaleFemale
Total
Up
Dow n
Total
37.0%39.0%
37.9%
27.2%
33.8%
30.2%
9.8%
5.2% 7.7%0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
% D
osag
e C
han
ge
Up Dow n Total
Dosage Change
17
Actual Dosage-Total
There was a significantly lower relapse rate overall for higher actual dose versus lower dose: p = .001
18
Actual Dosage-Gender
There was a significantly lower relapse rate for females alone for higher actual dose versus lower dose: p = .004
There was a non-significant lower relapse rate for males alone for higher actual dose versus lower dose: p = .116
19
Relapse Actual Dosage
n= 169 No. Rate
Total 78 46.2%
< 600 63 52.9%
≥ 600 15 30.0%
Males 44 47.8%
< 600 31 53.4%
≥ 600 13 38.2%
Females 34 44.2%
< 600 32 52.5%
≥ 600 2 12.5%
20
Total Relapse Rates @ Actual Dosage
< 600≥ 600
Total
Relapsed
Non-Relapsed
47.1%
70.0%
53.8%
52.9%
30.0%
46.2%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Relapsed Non-Relapsed
21
Male Relapse Rates @ Actual Dosage
< 600≥ 600
Total
Relapsed
Non-Relapsed
46.6% 61.8%
52.2%53.4%
38.2%
47.8%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Relapsed Non-Relapsed
22
Female Relapse Rate
While not statistically significant (due to small numbers), the actual dosage data does suggest a gender difference that needs to be watched in future studies.
23
Female Relapse Rates @ Actual Dosage
< 600≥ 600
Total
Relapsed
Non-Relapsed
47.5%
87.5%
55.8%
52.5%
12.5%
44.2%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
Relapsed Non-Relapsed
24
Actual vs. Starting Dosage
Lower dose group had an 8% higher relapse rate based upon starting dose
but a 23% higher relapse rate based upon actual dose.
25
Relapse Starting Dosage Actual Dosage
n= 169 No. Rate No. Rate
Total 78 46.2% 78 46.2%
< 600 50 49.5% 63 52.9%
≥ 600 28 41.2% 15 30.0%
Males 44 47.8% 44 47.8%
< 600 27 51.9% 31 53.4%
≥ 600 17 42.5% 13 38.2%
Females 34 44.2% 34 44.2%
< 600 23 46.9% 32 52.5%
≥ 600 11 39.3% 2 12.5%
26
Actual vs. Starting Dose Relapse Rates-Totals
Actual
Start
Total ≥ 600
Total < 600
52.9%
49.5%
30.0%
41.2%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%%
Re
lap
se
d
Total ≥ 600 Total < 600
27
Actual vs. Starting Dosage Relapse Rates-Males
Actual
Start
Male ≥ 600
Male < 600
53.4%
51.9%
38.2%42.5%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%%
Rel
apse
d
Male ≥ 600 Male < 600
28
Actual vs. Starting Dose Relapse Rates-Females
Actual
Start
Female ≥ 600
Female < 600
52.5%
46.9%
12.5%
39.3%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
% R
ela
ps
ed
Female ≥ 600 Female < 600
29
Six Month Time PeriodActual Dosage
Relapse rates were relatively consistent in five six month time periods starting with month 13, although the fifth period (37 – 42 months) numbers are still too small.
This brings us 42 months out from day one.
30
Relapse Over 6 Month Time Periods
n = 169 No. Relapsed/
No. Eligible
% Relapsed
13-18 months 25/169 14.8%
19-24 months 21/131 16.0%
25-30 months 15/93 16.1%
31-36 months 12/67 17.9%
37-42 months 5/34 14.7%
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Relapse Rates Over 6 Month Time Periods
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
14.0%
16.0%
18.0%
20.0%
13--18 19--24 25--30 31--36 37--42
Time Periods
Rela
pse R
ate
s
32
Relapse Over 6 Month Time Periods By Dosage
< 600 ≥ 600
13-18 months 22/119=18.5% 3/50 = 6.0%
19-24 months 17/88 = 19.3% 4/43 = 9.3%
25-30 months 11/61 = 18.0% 4/32 = 12.5%
31-36 months 9/44 = 20.5% 3/23 = 13.0%
37-42 months 4/23 = 17.4% 1/11 = 9.1%
33
Relapse Rates Over 6 Month Time Periods By Dosage
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
13--18 19--24 25--30 31--36 37--42
Time Periods
Rel
apse
Rat
e
Higher Dosage
≥ 600
Low er Dosage
< 600
34
Using the more traditional Kaplan-Meier analysis method
which takes into account length of treatment time
Relapse rates overall and separately by gender were significantly lower for higher dose
35
Relapse Curves: Effect of Dose Level
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 18 24 30 36 42 48 54
Ending Month
Perc
ent
Not
Rela
psed S
ince M
onth
12
Dose ≥ 600
Dose < 600
P=0.0037 one-tail (statistically significant)
36
Relapse Curves Dose Level for Males
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 18 24 30 36 42 48 54
Ending Month
Perc
ent
Not
Rela
psed S
ince M
onth
12
Dose ≥ 600
Dose < 600
P=0.00418 one-tail (statistically significant)
37
Relapse Curves Dose Level for Females
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 18 24 30 36 42 48 54
Ending Month
Perc
ent
Not
Rela
psed S
ince M
onth
12
Dose ≥ 600
Dose < 600
P=0.0089 one-tail (statistically significant)
38
Conclusions
When looking at actual dosage, patients on 600 mg or more of Gleevec are significantly more likely to have lower relapse rates than do patients on less than 600 mg.
Actual dosage produces substantially different results than starting dosage.
39
Our Relapse Study Team
Norman Scherzer, LRG Exec. DirectorJerry Call, Science CoordinatorPamela Barckett, Medical Rsch Asst.David Josephy, PhD, BiochemistMichael Josephy, MSc, MathematicianRichard Singleton, PhD, Statistician
40
Hold These Slides
41
7 Non Compliant Patients In Study
NC 1 Prescribed 600: took about 300-relapsed
NC 4 Prescribed 800: took about 400-relapsed
NC 5 Dr. raised dose from 400 to 600 after relapse; takes 400
NC 10 Prescribed 400: takes betw. 200 & 300-o.k.
NC 11 Prescribed 800: took betw. 400 & 600-relapsed
NC 12 Prescribed 600: took betw. 400 & 500-relapsed
NC 14 Prescribed 600: takes betw. 400 & 500-o.k.
42
Relapse No Relapse Totals
Total 78 46.2% 91 53.8% 169 100%
< 600 Start< 600 Actual
50 63
49.5%52.9%
51 56
50.5%47.1%
101 119
100%100%
≥ 600 Start≥ 600 Actual
28 15
41.2%30.0%
40 35
58.8%70.0%
68 50
100%100%
Males 44 47.8% 48 52.2% 92 100%
< 600 Start< 600 Actual
27 31
51.9%53.4%
25 27
48.1%46.6%
52 58
100%100%
≥ 600 Start≥ 600 Actual
1713
42.5%38.2%
2321
57.5%61.8%
4034
100%100%
Females 34 44.2% 43 55.8% 77 100%
< 600 Start< 600 Actual
2332
46.9%52.5%
2629
53.1%47.5%
4961
100%100%
≥ 600 Start≥ 600 Actual
11 2
39.3%12.5%
1714
60.7%87.5%
2816
100%100%
44
Actual Dosage
Relapse No Relapse Totals
Data needs to be revised
Total 71 43.9% 91 56.1% 162 100%
≤ 400 60 51.3% 57 48.7% 117 100%
≥ 600 11 24.4% 34 *
75.6% 45 100%
Males 42 46.2% 49 53.8% 91 100%
≤ 400 32 50.8% 31 49.2% 63 100%
≥ 600 10 35.7% 18 *
64.3% 28 100%
Females
29 40.8% 42 59.2% 71 100%
≤ 400 28 52.0% 26 48.0% 54 100%
≥ 600 1 5.9% 16 94.1% 17 100%
* Includes 1 patient at 500 mg
45
Relapse No Relapse Totals
Starting vs. Actual Data needs to be revised
Total 71 43.9% 91 56.1% 162 Δ
100%
≤ 400 48 60
48.5%51.3%
51 57
51.5%48.7%
99 117 + 18
100%100%
≥ 600 23 11
36.5%24.4%
40 34
63.5%75.6%
63 45 - 18
100%100%
Males 42 46.2% 49 53.8% 91 100%
≤ 400 27 32
49.1%50.8%
28 31
50.9%49.2%
55 63 + 8
100%100%
≥ 600 15 10
41.7%35.7%
21 18
58.3%64.3%
36 28 - 8
100%100%
Females 29 40.8% 42 59.2% 71 100%
≤ 400 21 28
47.7%52.0%
23 26
52.3%48.0%
44 54 + 10
100%100%
≥ 600 8 1
29.6% 5.9%
19 16
70.4%94.1%
27 17 -10
100%100%
46
Singleton Slides
47
Relapse Curves (Effect of I nteraction)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 18 24 30 36 42 48 54
Ending Month
Perc
ent
Not
Rela
psed S
ince
Month
12
F≥600 & M<600
F<600 & M≥600
P=0.927 two-tail (not statistically significant)
48
Relapse Curves (Gender for Dose ≥ 600 mg/ day)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 18 24 30 36 42 48 54
Ending Month
Perc
ent
Not
Rela
psed S
ince
Month
12
Female
Male
P=0.1464 (not statistically significant)
49
Relapse Curves (Gender for Dose < 600 mg/ day)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 18 24 30 36 42 48 54
Ending Month
Perc
ent
Not
Rela
pse
d S
ince
Month
12)
Female
Male
P=0.7574 two-tail (not statistically significant)
50
Relapse Curves (Gender for Dose < 600 mg/ day)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 18 24 30 36 42 48 54
Ending Month
Perc
ent
Not
Rela
pse
d S
ince
Month
12)
Female
Male
51
Kaplan-Meier Relapse Curves (Dose)
0%
20%
40%
60%
80%
100%
120%
12 18 24 30 36 42 48
Ending Month
Perc
en
t N
ot
Rela
psed S
ince M
on
th 1
2
Dose >500
Dose ≤500
All Doses
P = 0.0037 one-tail) statistically significant)
52
Kaplan-Meier Relapse Curves (Dose)
0%
20%
40%
60%
80%
100%
120%
12 18 24 30 36 42 48
Ending Month
Perc
en
t N
ot
Rela
psed
Sin
ce M
on
th 1
2
Dose ≥600
Dose ≤500
All Doses
P = 0.0037 (one-tail) statistically significant
53
Kaplan-Meier Relapse Curves (Gender)
0%
20%
40%
60%
80%
100%
120%
12 18 24 30 36 42 48
Ending Month
Perc
ent
Not
Rela
psed S
ince
Month
12
Female
Male
Total
P = 0.7334 two-tail (not statistically significant)
54
Kaplan-Meier Relapse Curves (Dose/ Gender I nteraction)
0%
20%
40%
60%
80%
100%
120%
12 18 24 30 36 42 48
Ending Month
Perc
ent
Not
Rela
psed S
ince
Month
12
F>500 & M≤500
F≤500 & M>500
Total
P = 0.927 two-tail (not statistically significant)
55
Kaplan-Meier Relapse Curves (Gender)
0%
20%
40%
60%
80%
100%
120%
12 18 24 30 36 42 48
Ending Month
Perc
ent
Not
Rela
pse
d S
ince
Month
12
Female
Male
Total
56
Kaplan-Meier Relapse Curves (Dose/ Gender I nteraction)
0%
20%
40%
60%
80%
100%
120%
12 18 24 30 36 42 48
Ending Month
Perc
ent
Not
Rela
psed S
ince
Month
12
F>500 & M≤500
F≤500 & M>500
Total
P = 0.927 two-tail (not statistically significant)
57
Relapse Starting Dosage
n= 169 No. Rate
Total 78 46.2%
≥ 600 28 41.2%
Males 44 47.8%
≥ 600 17 42.5%
Females 34 44.2%
≥ 600 11 39.3%
58
Relapse Actual Dosage
n= 169 No. Rate
Total 78 46.2%
≥ 600 15 30.0%
Males 44 47.8%
≥ 600 13 38.2%
Females 34 44.2%
≥ 600 2 12.5%
59
Relapse Starting Dosage Actual Dosage
n= 169 No. Rate No. Rate
Total 78 46.2% 78 46.2%
≥ 600 28 41.2% 15 30.0%
Males 44 47.8% 44 47.8%
≥ 600 17 42.5% 13 38.2%
Females 34 44.2% 34 44.2%
≥ 600 11 39.3% 2 12.5%
60
Relapse Starting Dosage Actual Dosage
n= 169 No. Rate No. Rate
Total 78 46.2% 78 46.2%
< 600 50 49.5% 63 52.9%
≥ 600 28 41.2% 15 30.0%
Males 44 47.8% 44 47.8%
< 600 27 51.9% 31 53.4%
≥ 600 17 42.5% 13 38.2%
Females 34 44.2% 34 44.2%
< 600 23 46.9% 32 52.5%
≥ 600 11 39.3% 2 12.5%
61
% On 600 mg or More
T otal
Male
Female
Actual
Star ting
40%43%
36%
30%
37%
21%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Actual Star ting
62
Dosage Change
Down Up None
Male 25 9 58
Female 26 4 47
Total 51 13 105
63
Dosage Change
Dose < 600 ≥ 600 Totals % ≥ 600 Change
Start 101 68 169 40% N.A.
Male 52 40 92 43% N.A.
Female 49 28 77 36% N.A.
Actual 119 50 169 30% - 10%
Male 58 34 92 37% -6%
Female 61 16 77 21% -15%
64
65
Relapse Curves Effect of Gender
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
12 18 24 30 36 42 48 54
Ending Month
Perc
ent
Not
Rela
psed S
ince M
onth
12
Female
Male
P=0.7334 two-tail (not statistically significant)