Embed Size (px)
DESCRIPTION
Prof. Dr. Heikki Joensuu - How it began, how it continues
Citation preview
How it began, how it continues
Heikki Joensuu, MD, Dept. of Oncology, University of Helsinki
How it began?
Alexander LevitzkiSiverman Institute of Life Sciences, The Hebrew University of Jerusalem
Phase 1: ”It is not possible.”
Phase 2: ”It might be possible, but...”
Phase 3: ”We new it all along.”
Phases of ground-breaking research
Early investigators of tyrosine kinases inhibitors met disbelief1
1Levitzki A. Eur J Cancer 2002; 38 (Suppl 5):S11-18)
Discovery of mutations in the KIT gene in GIST
Prof. Seiichi Hirota
Found activating mutations in KIT in in 1998
Hirota et al. Science 1998
”Patient zero”
•
Metastatic aggressive GIST diagnosed in 1996 (KIT
exon 11 deletion)
•
In 1998: second surgery, chemo (MAID x 7)•
March 1999, third operation
•
April 1999 to Feb 2000, thalidomide + interferon
–
Cancer stabilization for 10 months
•
Imatinib started in March 2000
Apoptosis of GIST cells induced by imatinib
Prior to starting imatinib
4 weeks later
Apoptosis of GIST cells induced by imatinib
Prior to starting imatinib
4 weeks later
KIT
KI-67
H & E
Before STI571
4 weeks
8 months
Before STI571 4 weeksNEJM 2001;344:1052-6 (Apr 5)
Randomized Trial of STI571 in Randomized Trial of STI571 in Metastatic Metastatic GIST GIST
(STI(STI--B2222, the U.S.B2222, the U.S.--Finland study)Finland study)
SCREEN
REGISTER
400 mg/day
600 mg/day
Treat Dailyx 24 months
Progression
Demetri G et al. NEJM 2002
Fast clinical developmentFast clinical development
••
The first GIST patient started imatinib The first GIST patient started imatinib therapy in March in 2000therapy in March in 2000
••
The first multicenter study (B2222 trial) The first multicenter study (B2222 trial) was started in July 2000, all 147 patients was started in July 2000, all 147 patients entered to the study in April 2001entered to the study in April 2001
147 patients with advanced GIST treated with first-line imatinib (400 or 600 mg/day) in the B2222 trial
Demetri GD et al. N Engl J Med 2002;347:472-480.
Advanced GIST usually responds to imatinib
Study Responses No Not response evaluable
B22221 123 (84%) 17 (12%) 7 (5%)EORTC2 794 (84%) 103 (11%) 49 (5%)S00333 375 (69%) 79 (15%) 86 (16%)Total 1292 (79%) 199 (12%) 142 (9%)
1Demetri GD et al. New Engl J Med 2002;347:472-80; Blanke CD et al. J Clin Oncol 2008; 2Verwieij J et al. Lancet 2005; 3Blanke CD et al. J Clin Oncol 2008
0 5 10 15 20 25 300
5
10
15
20
25
30400 mg/d
700 mg/d
1000 mg/d
TUM
OR
VO
LUM
E
MONTHS ON IMATINIB
Patient zero: One liver metastasis started to grow
Copyright © American Society of Clinical Oncology
Blanke, C. D. et al. J Clin Oncol; 26:620‐625 2008
Time to GIST progression with first‐line imatinib in the B2222 trial
median, ~24 months
Several resistance mutations in a single patient
Copyright © American Society of Clinical Oncology
Blanke, C. D. et al. J Clin Oncol; 26:620-625 2008
B2222 Trial: Time to progression on imatinib and tumor bulk
9-year overall survival 35%
How to continue?
Adjuvant therapy
Recurrence‐free survival after surgery
~60% are likely cured by surgery
alone
Pooled data from 10 population-based series on GIST (n=2560), none received adjuvant imatinib1
Joensuu et al. Lancet Oncol 2012; 13:265-74
~40% could potentially benefit from adjuvant treatment
Years
SGXVIII/AIO trial: 1 versus 3 years of adjuvant imatinib in high-risk GIST
Number at risk36 months of imatinib 198 184 173 133 82 39 8 0 12 months of imatinib 199 177 137 88 49 27 10 0
Rec
urre
nce-
free
and
aliv
e (%
)
60.1%
47.9%
86.6%
65.6%
36 months of imatinib
12 months of imatinib
Hazard ratio 0.46 (95% CI 0.32-0.65)
p<0.0001
Years since randomisation0 1 2 3 4 5 6 7
0
20
40
60
80
100
Median follow-up time: 54 months Joensuu H et al. JAMA 2012;307:1265-72
Number at risk36 Months of imatinib 198 192 184 152 100 56 13 0 12 Months of imatinib 199 188 176 140 87 46 20 0
Years since randomisation
SSGXVIII/AIO trial: overall survival
Aliv
e (%
)
Hazard ratio 0.45 (95% CI 0.22-0.89)
p=0.019
96.3%92.0%
94.0%
81.7%
36 months of imatinib
12 months of imatinib
0 1 2 3 4 5 6 70
20
40
60
80
100
Copyright © American Society of Clinical Oncology
Blanke, C. D. et al. J Clin Oncol; 26:620-625 2008
B2222 Trial: Time to GIST progression on imatinib and tumor bulk
9-year overall survival 35%
SSG18: Time to GIST coming back (recurrence)
Rec
urre
nce-
free
and
aliv
e (%
)
36 months of imatinib
12 months of imatinib
Years since randomisation0 1 2 3 4 5 6 7
0
20
40
60
80
100
Intensive monitoring?
Intensive monitoring?
Joensuu et al. JAMA, March 28, 2012, 307(12):1265-1272.
High-Lowest risk (n=197, censored 165)High-Intermed. risk (n=104, censored 58)High-Highest risk (n=39, censored 9)
0
20
40
60
80
100
Aliv
e w
ithou
t rec
urre
nce
(%)
0 1 2 3 4 5 6 7
Time (years)
p<0.001
SSGXVIII: Time to GIST coming back: tumor mitotic count and site
Gastric, ≤
10 mit,Non-gastric, ≤5 mit
Gastric, 11-50 mitNon-gastric, 6-20 mit
Gastric, >50 mitNon-gastric, >20 mit
Imatinib 36 mo ± 3 mo
Stop imatinib
The SSGXXII Trial Design
RANDOMIZE
Screen
•High‐risk
GIST*•R0 or R1
resection
*Gastric GIST with >10
mitoses/50 HPFs; or
nongastric GIST with >5
mitoses/50 HPFs
Follow-up with CT or MRI at 6-month intervals during imatinib, at 4-month intervals for 2 years after stopping imatinib, then at 6-12 month intervals
Stratify for:•Tumour site•Mutation type•Imatinib dose at randomization (<400, 400, >400 mg/d)•Centre
Arm A
Arm B
Imatinib for 24 months
New drugs
Tested first in advanced disease
Demetri GD et al. The Lancet 2006; 368: 1329 -
1338
Efficacy of sunitinib in patients with advanced GIST after failure of imatinib: a randomised controlled trial
Demetri GD et al. The Lancet 2012
Efficacy of regorafenib for advanced GIST after failure of imatinib and sunitinib: a ranomised trial
Regorafenib inhibits KIT, PDGFR, VEGFR1–3, TEK, RET, RAF1, BRAF, BRAFV600E, and FGFR
Time to GISTprogression
Overall survival
Under testing•
New agents and drug combinations–
13 novel agents are being tested for advanced
GIST–
Multikinase inhibitors (dovitinib, dasatinib,
masitinib, nilotinib, pazopanib, sorafenib), immunomodulating agents (ipilimumab,
peginterferon), heat shock protein inhibitors (AT13387, AUY922), a PI3K inhibitor (BKM120)
–
Crenolanib probably efficient for D842‐mutated GISTs
Individually tailored dosing
Copyright © American Society of Clinical Oncology
Demetri, G. D. et al. J Clin Oncol; 27:3141-3147 2009
B2222 trial: Low plasma imatinib concentrations measured one month after starting IM are associated
with short time to progression in advanced GIST
<1110 ng/mL)
>1110ng/mL
Getting rid of GIST stem cells
Heinrich M et al. Lancet Oncol 2010; 11:910-11
month s
solu
ble
KIT
seru
m S
CF
month s
Soluble KIT (binds Soluble KIT (binds stem cell factor, SCF) stem cell factor, SCF) decreases in all GIST decreases in all GIST patients treated with IMpatients treated with IM
Serum growth factor Serum growth factor (SCF) levels increase in (SCF) levels increase in GIST patients treated GIST patients treated with IM with IM
13 patients treated in Helsinki
Bono P et al., Blood 2004
RImatinib, continuous
IMA IMAREGO REGO
weeks0 3 4 7 8 11 12 15
ALT-study in advanced GIST (first-line treatment)
1 week washout period –
might these revive GIST progenitor cells?
Entirely new molecular targets
BRAF
HIF1
HIF1
SDHB
SDHD
SDHA
SDHC
Fumarate
Succinate
ProlylHydroxyla
se
VEGF IGF2
ETV1 mediated
transcription
Joensuu H, Hohenberger P, Corless CL. Lancet, in press 2013
Future cancer biology
0
,2
,4
,6
,8
1
0
,2
,4
,6
,8
1
0 5 10 15 20 25 30 Years
KIT ex11 ins
KIT ex11 pm
KIT ex11 del
KIT ex11 complex
PDGFRA ex 18
wtKIT ex 11
KIT ex 9
From mutation classes to single mutations
Identification of more driver mutations with the ”next generation sequencing”
Individualized characterization of tumors
Mutation analyses from the blood
Early detection of GIST
•
Better and cheaper imaging tools•
Finding cancer from the blood
How to continue: Summary
•
New agents, combinations of targeted drugs•
More efficient adjuvant treatments
•
Early detection of GIST and disease recurrence•
Identification of novel biological targets
