#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.

#SEOM2018

¡MUCHAS GRACIAS!

cserrano@vhio.net

@DrCeSarcoma