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GIST DISEMINADO:
NUEVOS ENSAYOS DEL GEIS
Madrid, November 20th, 2017
César Serrano García, M.D., Ph.D. Sarcoma Translational Research Lab, VHIO
Sarcoma Unit, Oncology Department Vall d’Hebron University Hospital
Barcelona, Spain
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
Primary GIST – KIT Exon 11 Major response after 7 months of Imatinib
Blanke et al. J Clin Oncol. 2008
mPFS
Long-term benefit with first-line imatinib
Blanke et al. J Clin Oncol. 2008
mPFS
Long-term benefit with first-line imatinib
80%
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
Debiec-Rychter M, 2005 Antonescu CR, 2005 Wardelmann E, 2006 Desai J, 2008 Heinrich MC, 2008 Liegl B, 2008
ATP-
binding pocket
39.6%
11.1%
90%
Specimen KIT 2nd Mutation Specimen KIT 2nd Mutation Specimen KIT 2nd Mutation1 QLP575-577H del 17 N822K 32 N822K2 S840N 18A N822K 33 F681L3 S840N 18B 344 18C S840N 35A5 19 N822K 35B6 S840N 20 S840N 35C7 ID571-572T 21 N822K 36A N680K
8A S840N 22 S840N 36B N680K8B S840N 23 S840N 379 S840N 24 N822K 3810 S840N 25 N822K 3911 ID571-572T 26 S840N 4012 N822K 27 N822K 41 S840N13 28 N822K 42 ID571-572T14 N822K 29 N655S 4315 S840N 30 N822K 44 N822K16 31 N822K 45
46 N822K
Tumor heterogeneity: KIT TKI-resistance mutations in 46 progressing metastases (52 samples)
Yuexiang Wang, PhD
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
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
DRUG CLINICAL TRIAL SETTING ORR (%) mPFS (mo) PHASE
Dovitinib
Kang, 2013 Joensuu, 2014
≥ 3rd line ≥ 3rd line
3 5
3.6 4.6
II II
Masitinib Adenis, 2014 2nd line N.A. 3.7 II
Nilotinib
Montemurro, 2009 Sawaki, 2011 Cauchi, 2012
Reichardt, 2012
≥ 3rd line 3rd line
≥ 3rd line 3rd line
10 3 0
<1
2.8 3.7 2.0 3.6
II II II
III-R
Pazopanib
Ganjoo, 2014 Mir, 2016
≥ 2nd line ≥ 2nd line
0 0
1.9 3.4
II II-R
Ponatinib Heinrich, 2015 ≥ 2nd line 8 4.3 II
Sorafenib Kindler, 2011 Park, 2012
≥ 2nd line ≥ 3rd line
13 13
5.2 4.9
II II
Other broad-spectrum TKIs after IM failure
Serrano et al, Target Oncol 2017
Cross-resistance heterogeneous populations in IM-resistant GISTs leads to clinical progression, typically in six months,
irrespective of the second or third-line TKI used
TRIAL PHASE PROMOTOR 1st line Imatinib v. Masitinib Imatinib - Regorafenib
Phase III Phase III
ABScience Australasian GIST group
2nd line DCC-2618 vs sunitinib
Phase III
Deciphera
3rd line BLU-285 v. Regorafenib
Phase III
Blueprint
Multiple Lines BLU-285 TNO-155 DCC-2618 v. Placebo Selinexor (GEIS-41)
Phase I Phase I Phase III Phase I/II
Blueprint Novartis Deciphera GEIS
GIST WT Regorafenib (GEIS-40)
Phase II
GEIS
PDGFRA D842V CrenoGIST (GEIS-50) BLU-285
Phase III Phase I
Arog Blueprint
1st line treatment
TRIAL PHASE PROMOTOR 1st line Imatinib v. Masitinib Imatinib - Regorafenib
Phase III Phase III
ABScience Australasian GIST group
1st line treatment
A Phase 3 Study to Evaluate Efficacy and Safety of Masitinib in Comparison to Imatinib in Patients With Gastro-Intestinal
Stromal Tumour in First Line Medical Treatment
Spain: participating centers Hospital Univ. Vall d’Hebron (Barcelona – C Valverde) Hospital Univ. de Canarias (Tenerife– J Cruz) Hospital Univ. Son Espases (Mallorca– P Luna) Clinica Universitaria Navarra (S. Martin Algarra) H Ramón y Cajal (Madrid) H Gregorio Marañón (Madrid) Hospital Universitario Miguel Servet, Zaragoza (J. Martínez Trufero)
RECRUITMENT STOPPED
1st line treatment
A Randomised Trial of Imatinib Alternating With Regorafenib Compared to Imatinib Alone for the First Line Treatment of Advanced Gastrointestinal Stromal Tumour (GIST)
(ALT GIST)
Spain: participating centers ICO Hospitalet (Barcelona, X. García del Muro)
SLOW RECRUITMENT
2nd line treatment
TRIAL PHASE PROMOTOR 2nd line DCC-2618 vs sunitinib
Phase III
Deciphera
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.
DCC-2618 activity against KIT mutants in vitro
Cell line KIT genotype DCC-2618 IMATINIB SUNITINIB REGORAFENIB
GIST-T1 Ex 11 1.4 10.7 8.4 36.0
GIST882 Ex 13 4.6 42.7 14.8 121.5
GIST-T1/670 Ex 11 + Ex 13 173.5 >1,000 59.4 287.5
GIST430/654 Ex 11 + Ex 14 217.3 >1,000 13.5 905.0
GIST48/820 Ex 11 + Ex 17 293.6 >1,000 >1,000 567.3
GIST48B KIT negative >1,000 >1,000 >1,000 >1,000
Cell viability studies show that the pan-KIT inhibitor DCC-2618 is active against all types of KIT mutants in a GIST-cell line context
Serrano C & Flynn D, unpublIshed data
$One subject has a "Decreased appetite" AE with no severity grade. This is included in the total events column but nowhere else #One subject has a "Dyspnoea" AE that resulted in death (G 5). This is included in the G3/4 column for the ≥ 100 mg/d group *Unconjugated bilirubin, both patients are homozygous for 28 *(TA)7/(TA)7 UGT1A1 polymorphism
All DLT events were not clinically significant: 2 G3 lipase ↑ at 100 mg & 200 mg BID and a G4 CPK ↑ at 150 mg QD
Event Term Total Events
<100 mg/d (N = 8) ≥ 100 mg/d (N = 62)
G1/2 G3/4 G1/2 G3/4 Lipase increased 33 5 1 15 12 Fatigue 32 6 0 25 1 Anaemia 29 1 1 9 18 Decreased appetite$ 20 1 0 17 1 Diarrhoea 16 1 0 15 0 Alopecia 15 1 0 14 0 Hypertension 15 0 1 9 5 Amylase increased 14 3 0 10 1 Myalgia 14 2 0 12 0 Weight decreased 14 1 0 13 0 Dyspnoea# 13 4 0 8 1 Abdominal pain 11 3 0 7 1 Constipation 11 4 0 7 0 Nausea 11 2 0 9 0 Palmar-plantar erythrodysaesthesia syndr. 11 0 0 11 0
Arthralgia 10 2 0 8 0 Blood bilirubin increased 10 1 0 7 2* Rash 8 2 0 6 0
150mg QD (N = 21)
G1/2 G3/4 3 2 5 0 0 1 3 0 0 0 4 0 0 0 1 0 2 0 1 0 1 0 0 0 2 0 1 0
2 0
0 0 0 1* 1 0
DCC-2618 Safety Population - Summary of TEAEs (Treatment-Emergent AE / Regardless of Causality) ≥10% (N=70)
ESMO 2017
Waterfall Plot of KIT/PDGFRα GIST Patients (Best Response Per RECIST, N=37)
PD = Progressive disease, SD = Stable disease, PR = Partial response *66% increase in tumor size; #PR at RP2D
# #
*
ESMO 2017
Use of cfDNA as Pharmacodynamic Biomarker Demonstrates pan−KIT Activity of DCC-2618 in KIT mutant, advanced GIST Patients
(Best Response, N=19)
Enrolled patient population reveals broad range of KIT mutations DCC-2618 leads to reductions in MAF in cfDNA across all exons associated with resistance Treatment decisions were made based on disease control and not on changes in MAF
#Patient in first dose cohort, *Patient represented with mixed histology
Best
Fol
d Ch
ange
in M
utat
ion
Alle
le F
requ
ency
(L
og S
cale
)
-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 *
*
*
*
* *
MAF reductions from baseline for Exons 9, 11, 13, 14, 17, and 18. Patients with detectable plasma cfDNA at baseline and at least one follow up are included
ESMO 2017
DCC-2618: Progression-Free Survival Patients treated at ≥100 mg/d compared to <100 mg/d
Despite small sample size results suggest that doses of 40 or 60 mg/d are insufficient The fact that 30 mg BID is an insufficient dose is supported by improvement in disease control in a patient with
PD after 24 weeks following dose escalation (not shown)
mPFS not reached
mPFS is 15.2 weeks (CI 4.4 to 24)
ESMO 2017
3rd line treatment
TRIAL PHASE PROMOTOR 3rd line BLU-285 v. Regorafenib
Phase III
Blueprint
BLU-285 is active against activation loop mutants
BLU-285 activity in vivo: GIST
GIST PDX model KIT ex11+ex17
(del556-558+Y823D)
CTOS 2017
CTOS 2017
CTOS 2017
Multiple lines
TRIAL PHASE PROMOTOR Multiple Lines BLU-285 TNO-155 DCC-2618 v. Placebo Selinexor (GEIS-41)
Phase I Phase I Phase III Phase I/II
Blueprint Novartis Deciphera GEIS
CTOS 2017
Spain: participating centers Hospital Vall d’Hebron (Barcelona, C. Serrano)
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 µM; VMAT 6.9 µM SST3 11 µM; all others > 30 µM
Oral bioavailability: Mouse 78%, Rat 86 %, Monkey 60%
In vivo efficacy demonstrated.
TNO155: study design
Spain: participating centers Hospital Vall d’Hebron (Barcelona, I. Braña & C. Serrano)
DCC-2618 in TKI-multiresistant GIST
A non-randomized, multicenter, Phase Ib/II study of
the selective inhibitor of nuclear export Selinexor (KPT-330)
in combination with imatinib in patients with metastatic and/or
unresectable gastrointestinal stromal tumors (GISTs)
refractory to imatinib, sunitinib and regorafenib.
GEIS-41
GEIS-41: Phase I/II Trial of Selinexor in GIST
Nakayama R, et al. Oncotarget 2015
Selinexor: XPO1 inhibitor
GEIS-41: Phase I/II Trial of Selinexor in GIST
Primary Objective To determine the maximum tolerated dose (MTD) and recommended phase II doses (RP2D) of selinexor in combination with imatinib Secondary Objectives • To determine clinical benefit rate (CBR). • To assess progression free survival (PFS) and overall survival (OS). • To determine overall response rate (ORR). • To assess long-term toxicity in participants receiving selinexor in combination with imatinib. Experimental Design A) Dose-finding cohort: IM 400 + increasing doses of Selinexor
(3 dose levels, 3+3) B) Dose expansion cohort: 20 pts.
GIST WT
TRIAL PHASE PROMOTOR GIST WT Regorafenib (GEIS-40)
Phase II
GEIS
KIT/PDGFRA mutantKIT/PDGFRA wild-type
~85%
~15%
KIT/PDGFRA genotyping and GIST subtypes
KIT/PDGFRA WT GIST
KIT/PDGFRA mutantKIT/PDGFRA wild-type
~85%
~15%
KIT/PDGFRA mutantKIT/PDGFRA wild-type
~85%
~15%
SDH-deficient GIST
• Female ≤ 40 years
• Gastric
• Epitheiolid
• Multifocal nodular
KIT dependence?
KIT/PDGFRA WT GIST
KIT/PDGFRA mutantKIT/PDGFRA wild-type
~85%
~15%
SDH-intact GIST
• BRAF V600E
• HRAS/NRAS/KRAS
• NF1
• Unknown
KIT independent
KIT/PDGFRA WT GIST
Ensayo Clínico Fase II de un solo brazo, no randomizado y multicéntrico de regorafenib como agente único para el tratamiento de primera línea de pacientes con GIST
KIT/PDGFR Wild Type metastásico y/o irresecable.
REGISTRI (GEIS-40)
F
Cl
F
F F
O O
O
N H
N H
N H
N
Regorafenib in KIT/PDGFRA WT GIST
Regorafenib
Inhibits: KIT
PDGFR VEGFR
RAF RET TIE-2
FGFR1 BRAF
Size of bubble reflects binding affinity for target. Wilhem et al 2011
-70,0%
-60,0%
-50,0%
-40,0%
-30,0%
-20,0%
-10,0%
0,0%
10,0%
20,0%
7 3 1 27 18 10
Cha
nge
from
bas
elin
e (%
)
Patient number
Waterfall plat of best response of target lesions in SDH deficient GIST
Phase II regorafenib trial in GIST identifies activity in KIT/PDGFRA WT GIST
Courtesy of Suzanne George, MD
Phase II regorafenib trial in GIST identifies activity in KIT/PDGFRA WT GIST
Courtesy of Suzanne George, MD
Primary Mutation
PR*
Overall Clinical Benefit (%) CB 95% CI
Exon 11 ( n=19) 2 16 (84) 60 – 96 Exon 9 (n=3) 1 2 (66) 9 – 99 SDH deficient (n=6) 2 6 (100) 54- 100
Clinical Benefit by Primary Genotype: median follow-up 20 months
*An additional patient achieved, PR, however tumor was unable to be amplified for mutational testing on three attempts
H Canarias J Cruz H Virgen del Rocío J Martín Broto H Sant Pau A López Pousa H Miguel Servet J Martínez Trufero IVO A Poveda H Vall d'Hebron C Valverde H Gregorio Marañón R Alvarez H Cruces N Fuente H Virgen de la Macarena D Vicente H La Paz V Martinez
PAÍSES PARTICIPANTES CENTROS N ESTIMADO
ESPAÑA 10 20 ( estimado 2/centro)
ITALIA 8 19
Participating centers
General Overview
OBJETIVO PRINCIPAL o Tasa de control de la enfermedad
INCLUSIÓN DE PACIENTES: o Antes de administrar Imatinib, realizar Análisis Mutacional local si
GIST Wild Type firma CI envío al IVO (NGS). o Si un centro no tiene posibilidad de realizar Análisis Mutacional para GIST Envío de muestra al IVO para análisis
o Si tras secuenciación (SANGER) es KIT/PDGFRA WT El estudio cubre realizar secuenciación por NGS (IVO).
GIST PDGFRA D842V
TRIAL PHASE PROMOTOR PDGFRA D842V CrenoGIST (GEIS-50) BLU-285
Phase III Phase I
Arog Blueprint
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
KIT/PDGFRA as primary drivers of oncogenic signal in GIST
Lasota et al, Lab Invest 2004
Exon 18
Exon 12
D842V
PDGFRA genotype predict sensitivity to IM
Cassier et al, Clin Can Res 2012
Response Rate
mPFS mOS
Crenolanib: Type I, mutation specific class III, TKI
Heinrich et al, Clin Can Res 2012
Crenolanib data from 20 GIST patients: activity
ARO-002 study
von Mehren et al, ASCO 2016
Crenolanib data from 20 GIST patients: safety
von Mehren et al, ASCO 2016
ARO-002 study: toxicity (G3 and G4)
CrenoGIST: Study design and treatment schema
Multicenter
Randomized 2:1
Double-blind
Placebo-controlled
120 patients
60 sites (4 in Spain)
Stratific.: TKI and PS
1º endpoing: OS
CrenoGIST: Study design and treatment schema
Spain: participating centers Hospital Univ. Vall d’Hebron (Barcelona – C. Serrano) Hospital Virgen del Rocío (Sevilla – J. Martín) Hospital Puerta de Hierro (Madrid – R. Cubedo) Fundación IVO (Valencia – A. Poveda) Hospital 12 de Octubre (Madrid)
CTOS 2017
Spain: participating centers Hospital Vall d’Hebron (Barcelona, C. Serrano)
CTOS 2017
CTOS 2017
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.