Transcript Connecting the Dots - The Life Raft Group

Surviving GIST:
Connecting the Dots
Life Fest 2006
Norman Scherzer & Jerry Call
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.
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
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.
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
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.
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%)
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%)
PDGFRA
 Exon



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


18, D842V mutation
12
Sensitive to Gleevec; little other data
Similar to exon 11 KIT mutations?
PFS Differs by Genotype and Dose
400 mg
800 mg
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
All phase III patients
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.
EORTC phase III trial

Strong points




Weak points



Randomized trial
Mutational data
Large trial
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.
Percent progressing in each 6 month period
LRG Data-Progression rates over 6 month time
periods-analysis by actual dose
25%
Lower Dosage
< 600
20%
15%
10%
Higher Dosage
≥ 600
5%
0%
12--18
18--24
24--30
30--36
36--42
Time periods
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
 Strong

Looked at actual dose as well as intent-totreat dose
 Weak


points
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.
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
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
Higher Gleevec Dosage Level?
Higher than
400 mg?
Exon 11
Maybe
Exon 9
Yes!
Wild-type
No
Wait until progression occurs?
Wait for Progression to Cross-over?
Wait for
progression to
cross-over?
Exon 11
No???
Exon 9
No!
Wild-type
Yes??
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
Primary Disease
Surgery
•Size
Preferred treatment
•Mitotic rate
•Unknown
benefit
•Otherhypotheses
factors
•Some
can be generated
•Clear margins
at surgery
•Questionable
for low-risk
tumors
Neoadjuvant
Gleevec
Adjuvant Gleevec
•Tumor
rupture
•Know
your genotype
•If it will make surgery easier
•Low-dose Gleevec unlikely•Monitor
to benefit
closely for nonresponders
exon 9 patients; could it promote
resistance?
Know your risk
Of recurrence
Adjuvant Treatment?
If risk of recurrence
is high?
Consider Adjuvant Treatment
If anxiety
level is
high
Is mutational
status known?
Pros & Cons
Pros & Cons of Adjuvant Treatment
Does It Produce
Resistance?
Does It Prevent
Recurrence?
 We

Do Not Know

We Do Not Know
 More of a concern for
Exon 9 patients
treated with low-dose
Gleevec?
Outstanding Clinical Trials: Limited to
evaluating 400mg of Gleevec for one year and
three years but not higher dosage..
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
Defining Risk
Risk
Size
Mitotic Count
Very low
<2cm
<5/50 HPF
Low
2-5cm
>5/50 HPF
Intermediate
>5cm
6-10/50 HPF
5-10cm
<5/50 HPF
>5cm
>5/50 HPF
High
>10cm
Any size
Any rate
>10/50 HPF
Caution: See the LRG website for additional explanatory material that goes with this table.
Suggested Guidelines for Assessing the Malignant Potential
of Gastric GISTs of Different Sizes and Mitotic Activity*
Benign
(no tumor-related mortality detected)
Probably benign
(very low malignant potential, <3% PD)
Uncertain or low malignant potential
Group 1 (no larger than 2 cm, no more than 5
mitoses/50 HPF)
Group 2 (>2 ≤5 cm, no more than 5 mitoses/50 HPF)
Group 3a (>5 ≤10 cm, no more than 5 mitoses/50
HPF)
Group 4 (no larger than 2 cm, >5 mitoses/50 HPF)
(no PDs but too few cases to reliably
determine prognosis)
Low to moderate malignant potential
(12–15% tumor-related mortality)
High malignant potential
(49%–86% tumor-related mortality)
Group 3b (>10 cm, no more than 5 mitoses/50 HPF)
Group 5 (>2 ≤5 cm, >5 mitoses/50 HPF)
Group 6a (>5 cm ≤10 cm, >5 mitoses/50 HPF)
Group 6b (>10 cm, >5 mitoses/50 HPF)
*Miettinen et al, Gastrointestinal Stromal Tumors of the Stomach. A Clinicopathologic, Immunohistochemical, and
Molecular Genetic Study of 1765 Cases With Long-term Follow-up
Can we Predict Adjuvant Gleevec
Benefit?
No, but we can generate some hypotheses:
Most likely to benefit
Least likely to benefit

High-risk patients with

Exon 11 mutations
Exon 9 patients



• On high-dose Gleevec
OR
• On Sutent ?
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?
Metastatic Disease
Surgery for mets?
Responding patients
(Stable)
Maybe
Local progression
Yes! Perhaps followed
by
a dose increase
Widespread progression
Probably Not
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
Wider
therapeutic
range
High-dose
Side effects
PFS
Pts w/
•Less side effects
•Accept less risk
Exon 9-Metastatic
Should exon 9 patients
take low-dose Gleevec?
Intermediate initial
Response to Gleevec
Large benefit from
High-dose Gleevec
Low-dose
High-dose
•Low response rate
•4 months median PFS
•8 times more likely to
have a response
•20 months median PFS
•Quick dose escalation?
Sutent
63% to 80%
Benefit after
IM progression
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
The Case for Mutational Testing
Dose selection
Initial drug
selection
Predicting
drug response
Mutational
testing
Adjuvant
treatment
Trial
selection
Drug selection
at resistance