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.

THANK YOU!

cserrano@vhio.net