Surviving GIST: Connecting the Dots

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Surviving GISTConnecting the Dots

• Life Fest 2006
• Norman Scherzer Jerry Call

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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.

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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

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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.

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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

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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.

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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)

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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)

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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?

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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.

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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).
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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.

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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

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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

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Higher Gleevec Dosage Level?
Higher than 400 mg?
Exon 11 Maybe
Wild-type No
Exon 9 Yes!
Wait until progression occurs?
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Wait for Progression to Cross-over?
Wait for progression to cross-over?
Exon 11 No???
Wild-type Yes??
Exon 9 No!
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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
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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?

Surgery Preferred treatment

• If it will make surgery easier
• Monitor closely for nonresponders

• Size
• Mitotic rate
• Other factors
• Clear margins at surgery
• Tumor rupture

Neoadjuvant Gleevec
Adjuvant Gleevec
Know your risk Of recurrence
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Adjuvant Treatment?
If risk of recurrence is high?
Consider Adjuvant Treatment
If anxiety level is high
Is mutational status known?
Pros Cons
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Pros Cons of Adjuvant Treatment

• Does It Produce Resistance?
• We Do Not Know
• More of a concern for Exon 9 patients treated
  with low-dose Gleevec?

• 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..

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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.
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Can we Predict Adjuvant Gleevec Benefit?
No, but we can generate some hypotheses

• 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?

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

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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?

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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

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The Case for Mutational Testing