1. 1 The Life Raft Group 40 Galesi Drive Wayne, NJ 07470 Phone 973-837-9092 Fax 973-837-9095 Email liferaft@liferaftgroup.orgliferaft@liferaftgroup.org www.liferaftgroup.org

2. 2 Life Raft Group Relapse Study Disease Progression in Patients with Metastatic GIST Receiving Gleevec (Imatinib): The Effect of Drug Dosage

3. 3 Study Criteria Metastatic GIST patients Initial response to Gleevec was shrinkage On Gleevec one year or more

4. 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. 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. 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. 7 n = 169 92 males 77 females 78 Relapsed 91 Stable

8. 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. 9 Starting Dose Distributions ≥ 600< 600 Males43%57% Females36%64% Totals40%60%

10. 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. 11 Relapse RatesStarting Dosage n= 169No.Rate Total7846.2% < 6005049.5% ≥ 6002841.2% Males4447.8% < 6002751.9% ≥ 6001742.5% Females3444.2% < 6002346.9% ≥ 6001139.3%

12. 12 Total Relapse Rates @ Starting Dosage

13. 13 Male Relapse Rates @ Starting Dosage

14. 14 Female Relapse Rates @ Starting Dosage

15. 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. 16 Dosage Change

17. 17 Actual Dosage-Total There was a significantly lower relapse rate overall for higher actual dose versus lower dose: p =.001

18. 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. 19 RelapseActual Dosage n= 169No.Rate Total7846.2% < 6006352.9% ≥ 6001530.0% Males4447.8% < 6003153.4% ≥ 6001338.2% Females3444.2% < 6003252.5% ≥ 600212.5%

20. 20 Total Relapse Rates @ Actual Dosage

21. 21 Male Relapse Rates @ Actual Dosage

22. 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. 23 Female Relapse Rates @ Actual Dosage

24. 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. 25 RelapseStarting DosageActual Dosage n= 169No.RateNo.Rate Total7846.2%7846.2% < 6005049.5%6352.9% ≥ 6002841.2%1530.0% Males4447.8%4447.8% < 6002751.9%3153.4% ≥ 6001742.5%1338.2% Females3444.2%3444.2% < 6002346.9%3252.5% ≥ 6001139.3%212.5%

26. 26 Actual vs. Starting Dose Relapse Rates- Totals

27. 27 Actual vs. Starting Dosage Relapse Rates- Males

28. 28 Actual vs. Starting Dose Relapse Rates- Females

29. 29 Six Month Time Period Actual 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. 30 Relapse Over 6 Month Time Periods n = 169No. Relapsed/ No. Eligible % Relapsed 13-18 months25/16914.8% 19-24 months21/13116.0% 25-30 months15/9316.1% 31-36 months12/6717.9% 37-42 months5/3414.7%

31. 31 Relapse Rates Over 6 Month Time Periods

32. 32 Relapse Over 6 Month Time Periods By Dosage < 600 ≥ 600 13-18 months22/119=18.5%3/50 = 6.0% 19-24 months17/88 = 19.3%4/43 = 9.3% 25-30 months11/61 = 18.0%4/32 = 12.5% 31-36 months9/44 = 20.5%3/23 = 13.0% 37-42 months4/23 = 17.4%1/11 = 9.1%

33. 33 Relapse Rates Over 6 Month Time Periods By Dosage

34. 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. 35 P=0.0037 one-tail (statistically significant)

36. 36 P=0.00418 one-tail (statistically significant)

37. 37 P=0.0089 one-tail (statistically significant)

38. 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. 39 Our Relapse Study Team Norman Scherzer, LRG Exec. Director Jerry Call, Science Coordinator Pamela Barckett, Medical Rsch Asst. David Josephy, PhD, Biochemist Michael Josephy, MSc, Mathematician Richard Singleton, PhD, Statistician

40. 40 Hold These Slides

41. 41 7 Non Compliant Patients In Study NC 1Prescribed 600: took about 300-relapsed NC 4Prescribed 800: took about 400-relapsed NC 5Dr. raised dose from 400 to 600 after relapse; takes 400 NC 10Prescribed 400: takes betw. 200 & 300-o.k. NC 11Prescribed 800: took betw. 400 & 600- relapsed NC 12Prescribed 600: took betw. 400 & 500- relapsed NC 14Prescribed 600: takes betw. 400 & 500-o.k.

42. 42 RelapseNo RelapseTotals Total7846.2%9153.8%169100% < 600 Start < 600 Actual 50 63 49.5% 52.9% 51 56 50.5% 47.1% 101 119 100% ≥ 600 Start ≥ 600 Actual 28 15 41.2% 30.0% 40 35 58.8% 70.0% 68 50 100% Males4447.8%4852.2%92100% < 600 Start < 600 Actual 27 31 51.9% 53.4% 25 27 48.1% 46.6% 52 58 100% ≥ 600 Start ≥ 600 Actual 17 13 42.5% 38.2% 23 21 57.5% 61.8% 40 34 100% Females3444.2%4355.8%77100% < 600 Start < 600 Actual 23 32 46.9% 52.5% 26 29 53.1% 47.5% 49 61 100% ≥ 600 Start ≥ 600 Actual 11 2 39.3% 12.5% 17 14 60.7% 87.5% 28 16 100%

43. 43 Start DoseRelapseNo RelapseTotals Date needs to be revised Total7143.9%9156.1%162100% ≤ 4004848.5%5151.5%99100% ≥ 6002336.5%4063.5%63100% Males4246.2%4953.8%91100% ≤ 4002749.1%2850.9%55100% ≥ 6001541.7%2158.3%36100% Females2940.8%4259.2%71100% ≤ 4002147.7%2352.3%44100% ≥ 600829.6%1970.4%27100%

44. 44 Actual Dosage RelapseNo RelapseTotals Data needs to be revised Total7143.9%9156.1%162100% ≤ 4006051.3%5748.7%117100% ≥ 6001124.4% 34 *75.6%45100% Males4246.2%4953.8%91100% ≤ 4003250.8%3149.2%63100% ≥ 6001035.7% 18 *64.3%28100% Females2940.8%4259.2%71100% ≤ 4002852.0%2648.0%54100% ≥ 6001 5.9%1694.1%17100% * Includes 1 patient at 500 mg

45. 45 RelapseNo RelapseTotals Starting vs. Actual Data needs to be revised Total7143.9%9156.1%162 Δ100% ≤ 40048 60 48.5% 51.3% 51 57 51.5% 48.7% 99 117 + 18 100% ≥ 60023 11 36.5% 24.4% 40 34 63.5% 75.6% 63 45 - 18 100% Males4246.2%4953.8%91100% ≤ 40027 32 49.1% 50.8% 28 31 50.9% 49.2% 55 63 + 8 100% ≥ 60015 10 41.7% 35.7% 21 18 58.3% 64.3% 36 28 - 8 100% Females2940.8%4259.2%71100% ≤ 40021 28 47.7% 52.0% 23 26 52.3% 48.0% 44 54 + 10 100% ≥ 6008181 29.6% 5.9% 19 16 70.4% 94.1% 27 17 -10 100%

46. 46 Singleton Slides

47. 47 P=0.927 two-tail (not statistically significant)

48. 48 P=0.1464 (not statistically significant)

49. 49 P=0.7574 two-tail (not statistically significant)

50. 50

51. 51 P = 0.0037 one-tail) statistically significant)

52. 52 P = 0.0037 (one-tail) statistically significant

53. 53 P = 0.7334 two-tail (not statistically significant)

54. 54 P = 0.927 two-tail (not statistically significant)

55. 55

56. 56 P = 0.927 two-tail (not statistically significant)

57. 57 RelapseStarting Dosage n= 169No.Rate Total7846.2% ≥ 6002841.2% Males4447.8% ≥ 6001742.5% Females3444.2% ≥ 6001139.3%

58. 58 RelapseActual Dosage n= 169No.Rate Total7846.2% ≥ 6001530.0% Males4447.8% ≥ 6001338.2% Females3444.2% ≥ 600212.5%

59. 59 RelapseStarting DosageActual Dosage n= 169No.RateNo.Rate Total7846.2%7846.2% ≥ 6002841.2%1530.0% Males4447.8%4447.8% ≥ 6001742.5%1338.2% Females3444.2%3444.2% ≥ 6001139.3%212.5%

60. 60 RelapseStarting DosageActual Dosage n= 169No.RateNo.Rate Total7846.2%7846.2% < 6005049.5%6352.9% ≥ 6002841.2%1530.0% Males4447.8%4447.8% < 6002751.9%3153.4% ≥ 6001742.5%1338.2% Females3444.2%3444.2% < 6002346.9%3252.5% ≥ 6001139.3%212.5%

61. 61 % On 600 mg or More

62. 62 Dosage Change DownUpNone Male25958 Female26447 Total5113105

63. 63 Dosage Change Dose< 600≥ 600Totals% ≥ 600Change Start1016816940%N.A. Male52409243%N.A. Female49287736%N.A. Actual1195016930%- 10% Male58349237%-6% Female61167721%-15%

64. 64

65. 65 P=0.7334 two-tail (not statistically significant)