Surviving GIST: Connecting the Dots

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

2. 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.

3. Connecting the DotsSurvival 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

4. 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.

5. 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

6. 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.

7. 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%)

8. 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%)

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

11. EORTC phase III trial • Strong points • Randomized trial • Mutational data • Large trial • Weak points • 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. • The effect is a dilution of the data to show the minimum likely benefit of the high dose arm.

12. LRG Data-Progression rates over 6 month time periods-analysis by actual dose 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%).

13. LRG Data • Strong points • Looked at actual dose as well as intent-to-treat dose • Weak points • Non-randomized; may introduce bias • 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.

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

15. 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 • Requires expertise to evaluate a single test result

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

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

18. 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

19. Primary Disease • 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 • If it will make surgery easier • Monitor closely for nonresponders Surgery Preferred treatment Neoadjuvant Gleevec Adjuvant Gleevec Know your risk Of recurrence

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

21. 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?

22. Know your Risk of Recurrence • Other Factors • Clear margins • Tumor rupture • Small bowel may be more aggressive Recent papers by Miettinen provide better risk assessment, especially for gastric GISTs Caution: See the LRG website for additional explanatory material that goes with this table.

24. Most likely to benefit High-risk patients with Exon 11 mutations Exon 9 patients On high-dose Gleevec OR 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? Can we Predict Adjuvant Gleevec Benefit? No, but we can generate some hypotheses:

25. Metastatic Disease

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

27. Wider therapeutic range Side effects PFS 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

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

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

30. The Case for Mutational Testing