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#SEOM2018
GIST refractario:
MUTACIONES Y ACTUALIZACIÓN DEL TRATAMIENTO
Madrid, September 28th, 2018
César Serrano García, M.D., Ph.D.
Sarcoma Translational Research Lab, VHIO
Sarcoma Unit, Oncology Department
Vall d’Hebron University Hospital
Barcelona, Spain
#SEOM2018
Disclosure Information
Employment: none.
Consultant or Advisory Role: Deciphera.
Stock Ownership: none.
Research Funding: Bayer, Deciphera, Pfizer.
Speaking: Bayer.
Grant support: travel grants (Novartis, Lilly, Pharmamar, Pfizer).
Other: none.
#SEOM2018
Disclosure Information
#SEOM2018
Exon 11 (67%)
Exon 9 (9%)
Exon 13 (1%)
Exon 17 (1%)
KIT (78.5%)
Exon 14 (rare)
PDGFRA (7.5% total)
Exon 12 (2%)
Exon 18 (5.5%)
Overall Mutation Frequency (950 GISTs): 86%
Courtesy of Jonathan A. Fletcher
KIT/PDGFRA as primary drivers of oncogenic signal in GIST
#SEOM2018Blanke et al. J Clin Oncol. 2008
mPFS
Long-term benefit with first-line imatinib
#SEOM2018
Response and primary KIT genotype
Heinrich et al J Clin Oncol. 2003
KIT Exon 11
KIT Exon 9
KIT WT
#SEOM2018Blanke et al. J Clin Oncol. 2008
mPFS
Long-term benefit with first-line imatinib
80%
#SEOM2018
Ex 13
Ex 14
Ex 17
Membrane
Ex 11
Ex 9
SECONDARYMUTATIONS
V654
T670
D816
D820
N822
Y823
8.3%
11.8%
12.5%
9.0%
FREQUENCY
Other KIT mut
7.7%
KIT secondary resistant mutations
Activation Loop
ATP-binding pocket
39.6%
11.1%
90%
Serrano et al. Br J Cancer, in press
#SEOM2018
Specimen KIT 2nd Mutation Specimen KIT 2nd Mutation Specimen KIT 2nd Mutation
1 QLP575-577H del 17 N822K 32 N822K
2 S840N 18A N822K 33 F681L
3 S840N 18B 34
4 18C S840N 35A
5 19 N822K 35B
6 S840N 20 S840N 35C
7 ID571-572T 21 N822K 36A N680K
8A S840N 22 S840N 36B N680K
8B S840N 23 S840N 37
9 S840N 24 N822K 38
10 S840N 25 N822K 39
11 ID571-572T 26 S840N 40
12 N822K 27 N822K 41 S840N
13 28 N822K 42 ID571-572T
14 N822K 29 N655S 43
15 S840N 30 N822K 44 N822K
16 31 N822K 45
46 N822K
Tumor heterogeneity: KIT TKI-resistance mutations in
46 progressing metastases (52 samples)
Courtesy of Yuexiang Wang
#SEOM2018
GIST emerges as a paradigmatic model to
study for oncogene addiction
IM-resistant GISTs are still dependent upon KIT
signaling for survival and proliferation
KIT inhibitory strategies after failure of IM
remain useful
#SEOM2018
Approved broad-spectrum TKIs
after IM failure
Imatinib(n=147)
Sunitinib(n=207)
Regorafenib(n=133)
Imatinib rechallenge
(n=41)
ORR 68.1% 7% 4.5% 0%
SD12 weeks 15.6% 53% 48.1% 32%
TTP/PFS 24 mo 6.1 mo 4.8 mo 1.8 mo
Serrano C & George S, TAMO 2014
#SEOM2018Serrano et al, Targ Oncol 2017
Other broad-spectrum TKIs
after IM failure
#SEOM2018
KIT inhibitors are active against only
a subset of IM-resistant mutations
KIT MUTATION IMATINIB SUNITINIB REGORAFENIB SORAFENIB NILOTINIB PONATINIB MASITINIB DASATINIB DOVITINIB
Ex 11 4.5 5 35 30 15 4 15 4 4
Ex 11 35 10 150 40 50 5 30 10 50
Ex 13 300 70 800 300 350 50 350 150 500
Ex 11 + Ex 13 (V654A) 2500 45 2000 800 850 100 3500 1000 250
Ex 11 + Ex 14 (T670I) n.r. 30 60 150 5000 5 10000 n.r. 200
Ex 11 + Ex 17 (D816E) 1500 n.r. 550 650 500 40 6500 300 6000
Ex 11 + Ex 17 (D820A) 1500 n.r. 600 600 400 25 3000 90 1200
Ex 11 + Ex 18 (A829P) 3000 10000 2500 1500 650 25 n.r. 70 1500
KIT-independent n.r. n.r. n.r. n.r. n.r. 1500 n.r. n.r. 750
KIT-independent n.r. n.r. n.r. n.r. 8000 6000 n.r. n.r. n.r.
Sensitive Intermediate Resistant
Serrano et al. Br J Cancer, in press
#SEOM2018Serrano et al, manuscript in preparation
ctDNA secondary KIT mutations in heavily
pretreated GIST population are predominantly in
the exon 17-18 activation loop (91%)
9%0%
80%
11%
KIT Ex 13 (V654A) KIT Ex 14 (T670I)
KIT Ex 17 KIT Ex 18 (A829P)
Distribution by exon of all
the KIT secondary mutations
found by TEC-seq and
ddPCR
#SEOM2018
New strategies to:
Overcome disease heterogeneity
Better inhibition of KIT
#SEOM2018
TRIAL PHASE PROMOTOR
2nd line
DCC-2618 vs sunitinib Phase III Deciphera
3rd line
BLU-285 v. Regorafenib Phase III Blueprint
Multiple Lines
DCC-2618 v. Placebo
Selinexor (GEIS-41)
TNO-155
Phase III
Phase I/II
Phase I
Deciphera
GEIS
Novartis
PDGFRA D842V
CrenoGIST (GEIS-50)
BLU-285
Phase III
Phase I
Arog
Blueprint
#SEOM2018
2nd line treatment
TRIAL PHASE PROMOTOR
2nd line
DCC-2618 vs sunitinib Phase III Deciphera
#SEOM2018
Novel approaches to target KIT/PDGRA kinase:
KIT switch pocket inhibitor DCC-2618
Compared to Type I or classical Type II kinase inhibitors,
DCC-2618 switch pocket inhibitor:
- Binds potently and durably to KIT and PDGFRA.
- Inhibits wild-type and virtually all mutant isoforms of KIT.
- Is resilient to development of gain of function mutations
leading to drug resistance.
Janku et al, ENA 2016
#SEOM2018
Waterfall Plot of KIT/PDGFRa GIST Patients (Best Response Per RECIST, N=37)
##
*
Janku et al, ESMO 2017
#SEOM2018
Use of cfDNA as Pharmacodynamic Biomarker Demonstrates pan−KIT
Activity of DCC-2618 in KIT mutant, advanced GIST Patients
(Best Response, N=19)
Bes
t Fo
ld C
han
ge in
Mu
tati
on
Alle
le F
req
uen
cy(L
og
Scal
e)
-3
-2
-1
0
1
2
E x 9 E x 1 1 E x 1 3 E x 1 4 E x 1 7 E x 1 8
+ 100 fold
+ 10 fold
- 10 fold
- 100 fold
##
1*
*
*
*
**
Janku et al, ESMO 2017
#SEOM2018
DCC-2618: Progression-Free Survival Patients treated at ≥100 mg/d compared to <100 mg/d
mPFS not reached
mPFS is 15.2 weeks (CI 4.4 to 24)
Janku et al, ESMO 2017
#SEOM2018
3rd line treatment
TRIAL PHASE PROMOTOR
3rd line
BLU-285 v. Regorafenib Phase III Blueprint
#SEOM2018
BLU-285 is active against activation loop mutants
Heinrich et al, ENA 2016
#SEOM2018
BLU-285 activity in vivo: GIST
GIST PDX model
KIT ex11+ex17
(del556-558+Y823D)
Heinrich et al, ENA 2016
#SEOM2018Heinrich et al, CTOS 2017
#SEOM2018
Multiple lines
TRIAL PHASE PROMOTOR
Multiple Lines
DCC-2618 v. Placebo
Selinexor (GEIS-41)
TNO-155
Phase III
Phase I/II
Phase I
Deciphera
GEIS
Novartis
#SEOM201827
DCC-2618 in TKI-multiresistant GIST
#SEOM2018
GEIS-41: Phase I/II Trial of Selinexor in GIST
Nakayama R, et al. Oncotarget 2015
Selinexor: XPO1 inhibitor
#SEOM201829
TNO155: SHP2 inhibitor
• Aberrant activation of receptor tyrosine kinases (RTKs) is frequent across many cancers, and is often associated with dependence on RTK signaling; SHP2 is a transducer of RTK signaling.
• TNO155 is a potent and selective first-in-class inhibitor of wild-type SHP2, with high oral bioavailability and BCS class I properties
• First-in-human study proposes to examine the safety, tolerability, and preliminary efficacy of TNO155 in RTK-dependent malignancies
• Target population includes patients with metastatic, RTK-dependent solid tumors
TNO155
SHP2 biochemical IC50 : 0.011µM
KYSE520 pERK IC50 : 0.008 µM
KYSE520 5-day cell prolif IC50 : 0.100 µM
P5, EPK and phosphatase panels: > 10 µM
Off-target IC50: Cav1.2 18 mM; VMAT 6.9 mM SST3 11 mM; all
others > 30 mM
Oral bioavailability: Mouse 78%, Rat 86 %, Monkey 60%
In vivo efficacy demonstrated.
#SEOM2018
GIST PDGFRA D842V
TRIAL PHASE PROMOTOR
PDGFRA D842V
CrenoGIST (GEIS-50)
BLU-285
Phase III
Phase I
Arog
Blueprint
#SEOM2018Cassier et al, Clin Can Res 2012
Response Rate
mPFS
PDGFRA D842V: Multi-resistance to all treatments
#SEOM2018
Crenolanib
Heinrich et al, Clin Can Res 2012
#SEOM2018
ARO-002 study
#SEOM2018 CTOS 2017Heinrich et al, CTOS 2017
BLU-285 (Avapritinib) activity in PDGFRA D842V-mutant GIST
#SEOM2018
Conclusions / Remarks
Imatinib-resistant GIST is an unmet clinical need.
We are currently assisting to a golden-age with
paradigm-shifting drugs coming into clinical trials.
GIST genotyping is critical for personalized medicine.
BLU-285 and Crenolanib are two drugs targeting for the
first-time ever PDGFRA D842V mutation.
Future efforts will focus on agents alternative resistance
mechanisms involved in KIT/PDGFRA signaling.