2. Surviving GIST: Connecting the Dots Life Fest 2006 Norman Scherzer & Jerry Call

3. Disclaimer!  Jerry Call and Norman Scherzer are not physicians  This presentation, and the opinions given, are intended to help patients discuss their care with their physicians.  Nothing we present is intended to be a substitute for discussion with your physician.

4. Connecting the Dots Survival Decision Making  Consensus Medicine: What do the experts agree upon? Consensus vs. Excellence  Waiting for the data: We are still waiting for the U.S. and European Phase lll GIST data to be combined.  Survival Decision Making: Connecting the Dots To Survive In the Interim

5. Genotype  The genotype is the specific genetic makeup of an individual, in the form of DNA. Typically, one refers to an individual's genotype with regard to a particular gene of interest.  In GIST, it is typically used to describe the common mutations that occur in the KIT and PDGFRA genes-usually to the level of the affected exon, e.g., KIT exon 11.

6. Know your Mutation Mutational data can be used to:  Determine Gleevec dose levels  Predict response to Gleevec  Predict response to Sutent  Generate hypotheses about adjuvant treatment with Gleevec  Help evaluate new drugs

7. PFS = Progression Free Survival  We will be using the term PFS to help understand the effectiveness of treatments. PFS means Progression Free Survival, the length of time a patient remains alive and free of disease or stable-i.e...., minimal growth of existent tumors and no new tumors.  When comparing groups, the term median PFS is often used. Example: A median PFS of 12 months means that half of the patients had a PFS of over 12 months and half had less than 12 months PFS. Example: A median PFS of 12 months means that half of the patients had a PFS of over 12 months and half had less than 12 months PFS.

8. Exon 11  Best response to Gleevec  Appears to be a 4 to 5 month PFS advantage at high doses of Gleevec  The PFS advantage of high-dose Gleevec may equal that of Sutent (about 5 months)  About 1/3 of exon 11 patients respond to Sutent (with at least 6 months stability)  High rate of secondary mutations upon resistance (62%)

9. Exon 9  Low-dose Gleevec = 4 months median PFS  High-dose Gleevec = 19.5 months PFS  Should any exon 9 patient be on low-dose Gleevec? Avoid low-dose for adjuvant?  Excellent response to Sutent = 19.5 months PFS after progression on Gleevec; 63% to 80% benefit rate  Lower rate of secondary mutations upon resistance (16%)

10. PDGFRA  Exon 18, D842V mutation Insensitive to Gleevec and Sutent Insensitive to Gleevec and Sutent Poor candidate for adjuvant therapy? Poor candidate for adjuvant therapy? Other exon 18 mutations are less frequent and their response to drugs is unknown Other exon 18 mutations are less frequent and their response to drugs is unknown  Exon 12 Sensitive to Gleevec; little other data Sensitive to Gleevec; little other data Similar to exon 11 KIT mutations? Similar to exon 11 KIT mutations?

11. PFS Differs by Genotype and Dose 400 mg 800 mg All phase III patients 21 months 25 months All types (377 pts) 21.5 months 24 months Exon 11 (248 pts) 25 months 29 months Exon 9 (58 pts) 4 months 19.5 months Wild-type (52 pts) 19 months 15.5 months Median PFS times were estimated by J. Call from Kaplan-Meier curves (EORTC data). Estimates are rounded to 1/2 month. NOTE: This type of analysis is not as accurate as examining the numbers.

12. EORTC phase III trial  Strong points Randomized trial Randomized trial Mutational data Mutational data Large trial Large trial  Weak points Fails to account for improvement in side effects over time. Fails to account for improvement in side effects over time. 60% of high-dose pts had a dose reduction, but are counted in the high-dose arm. 60% of high-dose pts had a dose reduction, but are counted in the high-dose arm.  The effect is a dilution of the data to show the minimum likely benefit of the high dose arm.

13. Progression rates were relatively consistent in five six month time periods starting with month 12, although the fifth period (36 – 42 months) numbers are small. This brings us 42 months out from day one. On average, the progression rate in 6 month periods was almost twice as high in the lower dose group (19%), compared to the higher dose group (10%). LRG Data-Progression rates over 6 month time periods-analysis by actual dose

14. LRG Data  Strong points Looked at actual dose as well as intent-to- treat dose Looked at actual dose as well as intent-to- treat dose  Weak points Non-randomized; may introduce bias Non-randomized; may introduce bias Subjective progression criteria with no independent review (patient reported data) Subjective progression criteria with no independent review (patient reported data)  The effect is that this study may show the maximum possible benefit for high doses.

15. Drug Levels Fall over Time  Gleevec levels may drop 30% to 40% within one year  At least 3 different explanations Increased drug clearance Increased drug clearance Decreased drug transport across the intestinal barrier Decreased drug transport across the intestinal barrier Decreased patient adherence Decreased patient adherence Side effects management Side effects management Dose escalation strategies Dose escalation strategies

16. Implications of Falling Drug Levels  Patients on lower doses may be more at risk for progression  Starting at a lower dose and increasing the dose over time may restore drug levels  If we had routine drug-level testing dosage could be adjusted (whatever the cause) Better at following a patient over time Better at following a patient over time Requires expertise to evaluate a single test result Requires expertise to evaluate a single test result

17. Higher Gleevec Dosage Level? Exon 11 Maybe Higher than 400 mg? Wild-type No Exon 9 Yes! Wait until progression occurs?

18. Wait for Progression to Cross-over? Exon 11 No??? Wait for progression to cross-over? Wild-type Yes?? Exon 9 No!

19. Managing Higher Gleevec Dosage Side effects are worse at higher dosage Side effects get better over time Start at 400 mg and phase up to higher dose

20. Primary Disease Know your risk Of recurrence Surgery Preferred treatment Neoadjuvant GleevecAdjuvant Gleevec If it will make surgery easier Monitor closely for nonresponders Unknown benefit Some hypotheses can be generated Questionable for low-risk tumors Know your genotype Low-dose Gleevec unlikely to benefit exon 9 patients; could it promote resistance? Size Mitotic rate Other factors Clear margins at surgery Tumor rupture

21. Adjuvant Treatment? Pros & Cons Consider Adjuvant Treatment If anxiety level is high Is mutational status known? If risk of recurrence is high?

22. Pros & Cons of Adjuvant Treatment Does It Prevent Recurrence?  We Do Not Know  Outstanding Clinical Trials: Limited to evaluating 400mg of Gleevec for one year and three years but not higher dosage.. Does It Produce Resistance?  We Do Not Know  More of a concern for Exon 9 patients treated with low-dose Gleevec?

23. Know your Risk of Recurrence  Other Factors Clear margins Clear margins Tumor rupture Tumor rupture Small bowel may be more aggressive Small bowel may be more aggressive Defining Risk RiskSize Mitotic Count Very low <2cm <5/50 HPF Low2-5cm >5/50 HPF Intermediate>5cm 6-10/50 HPF 5-10cm <5/50 HPF High>5cm >5/50 HPF >10cm Any rate Any size >10/50 HPF Caution: See the LRG website for additional explanatory material that goes with this table. Recent papers by Miettinen provide better risk assessment, especially for gastric GISTs

24. Suggested Guidelines for Assessing the Malignant Potential of Gastric GISTs of Different Sizes and Mitotic Activity* Benign (no tumor-related mortality detected) Group 1 (no larger than 2 cm, no more than 5 mitoses/50 HPF) Probably benign (very low malignant potential, <3% PD) Group 2 (>2 ≤5 cm, no more than 5 mitoses/50 HPF) Group 3a (>5 ≤10 cm, no more than 5 mitoses/50 HPF) Uncertain or low malignant potential (no PDs but too few cases to reliably determine prognosis) Group 4 (no larger than 2 cm, >5 mitoses/50 HPF) Low to moderate malignant potential (12–15% tumor-related mortality) Group 3b (>10 cm, no more than 5 mitoses/50 HPF) Group 5 (>2 ≤5 cm, >5 mitoses/50 HPF) High malignant potential (49%–86% tumor-related mortality) Group 6a (>5 cm ≤10 cm, >5 mitoses/50 HPF) Group 6b (>10 cm, >5 mitoses/50 HPF) *Miettinen et al, *Miettinen et al, Gastrointestinal Stromal Tumors of the Stomach. A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 1765 Cases With Long-term Follow-up

25. Can we Predict Adjuvant Gleevec Benefit? Most likely to benefit  High-risk patients with Exon 11 mutations Exon 11 mutations Exon 9 patients Exon 9 patients On high-dose GleevecOn high-dose GleevecOR On Sutent ?On Sutent ? Least likely to benefit  Low-risk patients  High-risk patients with Exon 9 mutations while taking low-dose Gleevec Non-responsive mutations PDGFRA D842A Distal exon 11? Wild-type GIST? No, but we can generate some hypotheses:

26. Metastatic Disease

27. Surgery for mets? Responding patients (Stable) Widespread progression Local progression Maybe Yes! Perhaps followed by a dose increase Probably Not

28. Exon 11-Metastatic Best response to Gleevec Dose-benefit From high-dose controversial Low-dose Pts w/ Side-effect issues Good adherence Accept more risk High-dose Pts w/ Less side effects Accept less risk Side effects Wider therapeutic range PFS

29. Exon 9-Metastatic Intermediate initial Response to Gleevec Large benefit from High-dose Gleevec Low-dose Low response rate 4 months median PFS High-dose 8 times more likely to have a response 20 months median PFS Quick dose escalation? Sutent 63% to 80% Benefit after IM progression Should exon 9 patients take low-dose Gleevec?

30. Choosing a Clinical Trial  What Is Available? At this institution At this institution Locally Locally Nationally Nationally Internationally Internationally  What Do We Know Now About Each Drug?  Navigating a Phase l Clinical Trial-Timing Can Be Everything

31. Mutational testing Dose selection Initial drug selection Trial selection Drug selection at resistance Adjuvant treatment Predicting drug response The Case for Mutational Testing