1

The Life Raft Group

The Life Raft Group

40 Galesi Drive

Wayne, NJ 07470

Phone 973-837-9092

Fax 973-837-9095

Email liferaft@liferaftgroup.org

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%

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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)