gastrointestinal stromal tumours (gist) et al. ann surg oncol. 2007;14:134 -142. gist diagnosis...

What’s new in gastrointestinal stromal tumours (GIST) in the past

12 months

Professor John R Zalcberg

Alfred Health,Faculty of Medicine

Monash University, MelbourneAUSTRALIA

Disclosures

• Novartis• Pfizer• Bayer• BMS• MSD

• No stock ownership relevant to this topic

Research support/Travel Support/Advisory Board compensation relevant to this topic

;

Overview

• Treatment of advanced disease

• Adjuvant therapy

What’s new in gastrointestinal stromal tumours (GIST) in the past

12 months

but

… to know where you’re going, you need to know where you’ve come

from…. James Baldwin

GIST

Mesenchymal neoplasms: now recognized as a biologically and clinically distinct entity

Shared ancestry with Interstitial Cells of Cajal (coordinate peristalsis)

Clinical presentation is variable

Diagnosis is still challenging in some cases/based on c-kit expression

Nilsson et al. Cancer. 2005;103:821-829.Gold et al. Ann Surg Oncol. 2007;14:134-142.

GIST Diagnosis -Immunohistochemistry

KIT protein (CD117): positive in 95% of cases

DOG1: positive in >95% of KIT-positive GIST and 35% of KIT-negative GIST

Courtesy of J. Fletcher. Presented at: Global Interdisciplinary Specialists Training Around the World (GISTour) 2009. 22 November 2009, Taipei, Taiwan.* Parkkila S et al. Mod Pathol. 2010 Jan 15. [Epub ahead of print]

KIT and PDGFRα Tyrosine Kinases: Structure

KIT (78%) and PDGFRα (7.5%) are:

Highly homologous proteins of the type III receptor tyrosine kinase family

Involved in signal transduction in a range of cell functions, including proliferation, differentiation, apoptosis, survival, and adhesion

Corless CL, Heinrich MC. Annu Rev Pathol 2008;3:557–586.Annual Review of Pathology: Mechanisms of Disease by Corless. Copyright 2010 by Annual Reviews, Inc. Reproduced with permission of Annual Reviews, Inc.

SCF PDGF

Wild-Type (WT) GIST (15%)(No KIT or PDGFRA Mutation)

Alteration Estimated Frequency References

BRAF mutation < 7% Agaram et al. Genes Chromosomes Cancer. 2008;47(10):853-859

KRAS mutation <1% Heinrich and Corless, unpublished

Increased IGF1R expression 50% Tarn et al. PNAS. 2008;105(24):8387-8392

Germline SDHA, SDHB, SDHC or SDHD mutation* ~12% Janeway et al. PNAS. 2011;108(1):314-318

Pantaleo et al. J Natl Cancer Inst. 2011;103(12):983-7

Loss of SDHB expression High Janeway et al. PNAS. 2011;108(1):314-318

Germline NF1 mutation Rare Andersson et al. Am J Surg Pathol. 2005; 29:1170-1176

*Carney-Stratakis syndrome: association of GIST and paraganglioma

WT-GIST (qWT for KIT, PDGFRA, RAS, SDH

Presentation by J Sicklick; UCSD

qWT -GIST

Location

GIST may occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum:

– Oesophagus 2%

– Stomach 60%

– Small intestine 25%

– Colon / Rectum 5%

– Other (mesentery, retroperitoneum) 8%

Corless & Heinrich. Annu Rev Pathol Mech Dis. 2008;3:557-586.

Mutation Subtypes According to the Primary Location

Genotype Stomach (n=738)

Small bowel (n=261)

KIT mutationExon 9Exon 11Exon 13Exon 17

65.2%1.8%61.4%1.2%0.8%

79.7%23%54%2.3%0.4%

PDGFRA mutationExon 12Exon 14Exon 18

22.9%3.1%0.5%19.3%

1.2%0%0.4%0.8%

Wild type 11.9% 19.1%

Wardelmann et al. Pathologe 2010 epub ahead of print

Treatment of Advanced disease

MetaGIST; Analysis of High and Low Imatinib Doses: Design of Trials

Followfor PFS and OS

Imatinib(400

mg/day)

Imatinib(800

mg/day)

Progressivedisease

1. Verweij J, et al. Lancet 2004;364:1127–1134.2. Blanke CD, et al. J Clin Oncol 2008;26:626–632.

Metastatic or unresectable

GIST

EORTC/ISG/AGITG Study 620051

North American Intergroup Study S00332

Median OS (months) 49 / 49

3-year estimate (%) 60 / 61

Hazard ratio 1.00

P value (logrank test) 0.97

0 1 2 3 4 5 60

10

20

30

40

50

60

70

80

90

100

400 mg (818 patients)800 mg (822 patients)

Years

MetaGIST: Overall Survival

Van Glabbeke et al. ASCO 2007. Abstract 10004.

Median PFS (months) 6 / 19

3-year estimate (%) 5 / 17

P value (logrank test) 0.017

KIT exon 9 mutants: 400 mg / 800 mg

0 1 2 3 4 50

10

20

30

40

50

60

70

80

90

100

Years

KIT exon 9 mutants

MetaGIST: Progression Free Survival (KIT exon 9)

Van Glabbeke et al. ASCO 2007. Abstract 10004.

• 14% of GIST patients exhibit primary resistance:i.e. early tumor progression (within 6 months of beginning imatinib therapy)

• 50% of all GIST patients exhibit tumor progression within 2-5 years of starting imatinib therapy i.e.secondary resistance

Demetri et al. N Engl J Med. 2002;347:472-480.Verweij et al. Lancet. 2004;364:1127-1137.

Imatinib Resistance in GIST

• Primary imatinib resistance is more common in GISTs with the following genotypes

• KIT exon 9 mutations

• PDGFRA D842V mutations

• No detectable mutations (WT KIT/PDGFRAgenotype)

• Secondary imatinib resistance is commonly associated with the emergence of new kinase mutations

Antonescu et al. Clin Cancer Res. 2005;11:4182-4190.Heinrich et al. J Clin Oncol. 2003;21:4342-4349.Debiec-Rycher et al. Eur J Cancer. 2006;42:1093-1103.Heinrich et al. J Clin Oncol. 2006;29:4764-4774.

Mechanisms of Imatinib Resistance

Resistance to imatinib

Routine Practice

• Confirm progression (do not change a treatment that’s working)

• Check compliance• Test blood levels

(where appropriate)

• Surgery/ablation for localized or focal PD (continue TKI afterwards)

• Change TKI’s• Clinical trials of new agents

Change in TKI therapy

• Increase dose of imatinib• Replace imatinib with sunitinib• Replace sunitinib with

regorafenib• Other TKI’s

Management of Secondary Resistance

Dose Escalation of Imatinib in Case of Progression with 400 mg/day

133 patients crossover to 800 mg

response: 2% PR, 27% SDPFS: median 81 days

1Blanke et al. JCO, 20082Zalcberg et al. Eur J Cancer 41, 2005

EORTC 620052S00331

133 patients crossover to800 mg

response: 3% PR, 28% SDPFS: median 5 months

Progression free survival

(Sunitinib:placebo) Placebo (n=118)

Sunitinib (n=243)

50 mg/day, 4 weeks on, 2 weeks offImatinib-

refractory or -intolerant GISTpatients

Conducted at 56 sites in Europe, USA, Australia and Asia (Singapore).Final protocol dated August 2003

Randomization2:1

Placebo

4 weeks on, 2 weeks off

Cross over tosunitinib atprogression

Continue aslong as clinical benefit

Phase 3 trial of sunitinib in imatinib-resistant/-intolerant GIST

Sunitinib

Demetri et al. Lancet. 2006;3681329-1338.

Phase III Trial: Sunitinib in Advanced GIST After Imatinib Failure

17 / 214 16 / 187 22 / 142 19 / 86 7 / 47 5 / 23 2 / 522 / 96 9 / 84 10 / 66 7 / 37 2 / 25 3 / 6 0 / NA

Overall Survival with Crossover to Sunitinib

0 / 118Placebo0 / 243Sunitinib

No. events / no. at risk

Sunitinib (N=243)Placebo (N=118)Hazard ratio=0.7695% CI (0.54, 1.06)P=0.107

Current data

Time (weeks)

Ove

rall

surv

ival

pro

babi

lity

(%)

100

90

80

70

60

50

40

30

20

10

00 13 26 39 52 65 78 91 104

70% crossovers in placebo group

Heinrich M et al. J Clin Oncol 2008

Progression-Free Survival on Sunitinib in Imatinib-Resistant/Intolerant GIST

OF F

TREATMENT

Disease progression

blinded central review

GIST – Regorafenib In Progressive Disease (GRID): Study Design

– Global trial: – Stratification: treatment line (2 vs >2 prior lines),

geographical location (Asia vs “Rest of World”)– Primary endpoint = PFS

2 : 1

Regorafenib + best supportive

care (BSC)(n=133)

Placebo + BSC (n=66)

RANDOM I ZAT I ON

UnblindingCrossover offered for

placebo arm or continued regorafenib

for treatment arm

Regorafenib (unblinded)

until next progression

Metastatic/ unresectable

GIST pts progressing

despite at least prior imatinib and sunitinib

Demetri et al. ASCO 2012

GRID Study: PFS (primary endpoint per blinded central review)


GRID Study: Overall Survival (following 85% cross-over of patients on placebo arm)


ITT curves from Demetri GD et al. Lancet 2013; 381: 295–302

Days from randomization

1.00

0.75

0.50

0.25

00

PFS

pro

babi

lity

50 100 150 200 250 300

All patients (ITT population)Placebo (n=66) HR 0.27 (0.19–0.39)Regorafenib (n=133) p<0.0001

Secondary KIT mutation presentPlacebo (n=27) HR 0.22 (0.12–0.40)Regorafenib (n=50) p<0.001

Regorafenib shows benefit over placebo in patients with secondary KIT mutations

Other TKIs, when all 3 standard TKIs have failed for advanced GIST?

• Nilotinib• Masitinib • Vatalanib• Dasatinib• Dovitinib• Sorafenib• Pazopanib • Crenolanib • Ponatinib• BLU-285• DCC-2618

Clinical activity of BLU-285, a KIT/PDGFRα inhibitor in GIST


Abstract no: 2803523, CTOS 2017 Maui, Hawaii. Presented by Dr. Michael Heinrich

36

• High kinome selectivity*

• Binds active conformation

BLU-285

1. Evans EK et al. Sci Transl Med. 2017 Nov 1;9(414)*Kinome illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com)

BLU-285 IC50 Imatinib IC50

KIT Exon 11 deletion JM domain mutations

0.6 nM 12 nM

KIT Exon 11 V560G 1 nM 87 nM

KIT Exon 11/13 ATP binding site

mutations

11 nM 9160 nM

KIT Exon 11/14 28 nM 19650 nM

KIT Exon 17Activation

loop mutations

<2 nM 60–12750 nM

KIT Exon 17 D816V 0.27 nM 8150 nM

PDGFRα Exon 18 D842V 0.24 nM 759 nM

BLU-285: highly selective targeting and potent inhibition of mutant KIT and PDGFRα in GIST

http://www.cellsignal.com/

37

Advanced GIST(n=46) MTD

Part 2 Dose expansion

PDGFRα D842V-mutant GIST (n=50)

Unresectable GIST after imatinib and ≥1 other TKI (n=50)

Part 1 Dose escalation

Key objectives

• Part 1: MTD, safety, pharmacokinetics, ctDNA analyses, anti-tumor activity

• Part 2: response rate, duration of response, safety

• 3+3 design with enrichment• MTD determined to be 400 mg PO QD• RP2D determined to be 300 mg PO QD

BLU-285 Phase 1 study

Tumor reduction across multiple KIT genotypes (central radiology review)

38

N=30 patients 300 mg (RP2D) – 400 mg (MTD)

-7020 of 30 (67%) patients with tumor shrinkage

50

-10

-20

-40

-50Max

imum

redu

ctio

n: s

um o

f dia

met

er

chan

ge fr

om b

asel

ine

(%)

-60

-30

0

10

20

30

40

PD

SD

PR

1317

1113

1113

1117

913

11 13 111317

10 111317

1113

1117

1117

9 1117

9 1317

917

111318

1117

1117

9 9 11 KIT mutation by exon ^

111417

11 91318

1117

917

1117

* * * **

Activity in PDGFRα D842-mutant GIST (central radiology review)

31 of 31 (100%) patients with tumor shrinkage

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2-84

3VD

842V

D84

2VD

842-

H84

5VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

D84

2VD

842V

40

-40

-60

-100

Max

imum

redu

ctio

n: s

um o

f dia

met

erch

ange

from

bas

elin

e (%

)

-80

-20

0

20 PD

SD

PR

CR

80

60

100 N=31 patients across all dose levels

Mutation status*

* per archival tumor and ctDNA

400 400

400

30400

135 300

200

300 90 400

400200

300135

30

60400 90 609030040013560

2006040060030

90

Numbers under bars indicate dose level

High response rate and prolonged PFS in PDGFRαD842-mutant GIST (central radiology review)

Best response(N=31)*

Choi Criterian (%)

RECIST 1.1n (%)

CR 1 (3) 1 (3)^

PR 30 (97) 21 (68)†

CR+PR 31 (100) 22 (71)

SD 0 9 (29)

DCR (PR+SD) 31 (100) 31 (100)

PD 0 0

Median PFS not reachedPFS at 12 months 78%

0 8 16 24

1.0

0.8

0.6

0.4

0.2

0

Months from first dose

Pro

babi

lity

of p

rogr

essi

on-

free

surv

ival

(%)

6 14 224 12 202 10 18

37 35 32 30 20 18 15 12 5 3 2 1 0PDGFR

PDGFRαCensored

Approved agents are ineffective3,4

median PFS ~3 months

3. Cassier et al. Clin Cancer Res. 2012;18(16):4458–64 4. Yoo et al. Cancer Res Treat. 2016;48(2):546–52

Investigators conclusion; BLU-285 has potent, clinically important activity in GIST

41

• BLU-285 is well-tolerated

• High response rates and prolonged PFS in PDGFRα-driven GIST

• Prolonged PFS in heavily pretreated KIT-driven GIST

• Based on these encouraging data:

– Phase 3 randomized study comparing BLU-285 to regorafenib in third-line GIST is planned to begin 2018

Switch pocket inhibitors – DCC2618

1Janku et al. JCO 2017; 55 (suppl. abstr. 2515)

• Bind to the ”switch pocket” of the kinase stabilizing it in an inactive confirmation

• Also inhibits the most aggressive exon 17 and 18 gain-of-function mutations in the activation switch.

On dose escalation Responses1

FDG-PET response 14/18 (78%)RECIST response 2/18 (11%)

Tumor Control in GIST Patients – DCC2618

Best Response per RECIST KIT & PDGFRα All Doses (n=37)

91% Disease Control (PR & SD) at Best Responseby RECIST at ≥100 mg Daily

##

*

# ##### #

Early Progression Free Survival Data

Notes: (a) Circles are patients (potentially >1 at any time point) who had not progressed as of end of treatment/study or last visit date if still on treatment; (b) Data is based on tumor response data investigator assessment.

Progression-Free Survival Rate KIT- and PDGFRα-driven GISTPatients; ≥ 100 mg daily (n=49) vs. < 100 mg daily (n=4)

Median PFS with placebo in 3rd/4th line (<1 month)

All patients treated at <100mg daily (n=4)

mPFS cannot be determined

mPFS is 15.2 weeks (CI 4.4 to 24)P

rogr

essi

on-fr

ee s

urvi

val

All patients treated at ≥100mg daily (n=49)

DCC-2618: Overview

• Phase 3 Registration Study for the treatment of patients with GIST who have received 3 prior therapies

• Phase 3 study for patients who have progressed on or are intolerant of imatinib

• 91% Disease Control by Best Response (PR & SD) by RECIST ≥100 mg daily

• Disease Control Rate ≥ 100 mg daily: • 76% (12 weeks)• 57% (24 weeks)

• Encouraging early PFS data• Clinical validation of broad

spectrum KIT profile

Current &Future Plans

Clinical Proof-of-Concept

in Heavily-Pretreated GIST Patients

Pivotal Phase 3 Study in 4th Line+ GIST Initiated Jan 2018(1)

Global Trial(n=120)

Placebo

150 mg QDDCC-2618

GIST Patients

3 prior lines of therapy(1)

80 Patients

40 Patients

Randomized2:1

Primary Endpoint for Approval = Median Progression Free Survival

Following progression: (a) placebo patients can crossover to DCC-2618 and (b) DCC-2618 patients can continue on treatment.

Abstract no: 2803523, CTOS 2017 Maui, Hawaii. Presented by Dr. Michael Heinrich

GIST the new generation*

*Robert Maki – ASCO CSS 2017

• Inhibition of ETV1 ( a survival factor for GIST); KIT and MEK inhibitors resulted in a DCR of 65% @8 weeks – no PR

• Immmune modification; Dasatanib + ipilimumab; Phase 1 reported. RR seen using Choi criteria

• RCT of Nivolumab vs Nivolumab + Ipilimumab underway Responses seen

• Dysregulation of hedgehog pathway (in 10% of mGIST) leads to increased expression of KIT

RImatinib, continuous

IMA IMAREGO REGO

weeks0 3 4 7 8 11 12 15

ALT-GIST study

1 week washout period – might these revive GIST progenitor cells?

Adjuvant Therapy: Imatinib

Recurrence-Free Survival

Presented By Chandrajit Raut at 2017 ASCO Annual Meeting

PERSIST-5: Five years of adjuvant imatinib

• 67 (74%) patients had high risk and 24 (26%) intermediate risk GIST

• 45 (49%) out of the 91 patients discontinued adjuvantimatinib

Ongoing randomised Phase III adjuvant trials

Trial Design Key eligibility criteria Primaryend point

SSG XXIINCT02413736

Imatinib 400mg/d 3 vs. 5 yrs

Very high risk of recurrence• gastric GIST, >10

mitoses/50 HPFs;• non-gastric GIST, >5

mitoses/50 HPFs, or• rupture

RFS

ImadGISTNCT02260505

Imatinib 3 yrs vs. imatinibmaintenance

Estimated risk of recurrence≥ 35%

DFS

Joensuu H et al. JAMA Oncol 2017;3:602-9

Acknowledgements

• The many patients and their families who contributed to these studies

• LifeRaft and other patient advocacy groups

• The many investigators that have designed and conducted these studies and were happy to share their data for this presentation

• The many companies involved in this international effort to improve outcomes for patients with GIST

gastrointestinal stromal tumours (gist) et al. ann surg oncol. 2007;14:134 -142. gist diagnosis...

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