STEVEN M KORNBLAU, MDHouston, USA

• Professor of Medicine, UT MD Anderson Cancer Center• He was a fellow in Hematology and Oncology at the MD

Anderson Cancer Center from 1988 through 1991 and also completed six months of training at the Royal Free Hospital in London, after which he joined the faculty at MD Anderson in 1991 and became a full professor in 2007. He holds a dual position in the department of leukemia and the department of stem cell transplantation and cellular therapy. Dr. Kornblau’s laboratory research focuses on protein expression patterns in hematological malignancies. Additionally, he runs the Leukemia Sample Bank at MDACC, one of the largest leukemia and myeloma tissue repositories in the world..

Is it time to consider targeted therapy in combination for

newly diagnosed AML?

Steven M. Kornblau, M.D.Department of Leukemia

Department of Stem Cell Transplantation and Cellular Therapy

When you say targeted, which type of target?

• Clinical features– Age– PS – Gender

• Molecular features ?

Covered by other

lectures

Covered in this lecture

Many Molecular Targets, Which do you Mean?

• Mutation

• Methylation: Epigenetics

• MicroRNA

• mRNA

• Microenvironment

• Modus Operandi/Mechanistic: Proteins

• IMmunity

When Might Targeted Therapy be Indicated?

You have identified a target that:• Divides the population into discrete groups

– Haves & Have nots• A reproducible standardized assay exists

– so grouping patients is possible• An agent that targets the target exists• Responses in vitro are better (restricted to?)

the population with the target

When Is Combined Targeted Therapy Indicated?• Targets with available agents exist• Targets occur together simultaneously

– Not mutually exclusive like IDH1 & Tet2• There is a rationale for combining therapy against both

targets simultaneously– Non overlapping pathways targeting 2 key functions– Within the same pathway or function

• Like Bactrim for bacteria

– Combination additive or synergistic & preliminary data supports use

• Both agents are available to combine– Licensed so can have investigator initiated trial– Companies agree to work together

What about combining targeted therapy with non targeted therapy?

• Many targeted therapies in development• Individual use often disappointing• Decades of experience with “non-targeted”

traditional chemotherapy• Maybe “targeted” agents would be more

effective if combined with “traditional” chemotherapy ?

The BIG Caveat• In 2015, almost none of these agents

are FDA approved• Can only use them in a clinical trial • Therefore cannot combine them

with existing chemotherapy, or each other.

Genetic Events: Translocations

These establish the paradigm for getting better results in AML when selected therapies are applied to selected patients based on molecular features

Core Binding Factor AML. Survival with Chemo + GO

MDACC SWOG (RFS))

Borthakur. Cancer. 113:3181; 2008. Petersdorf. Blood. 114:abst 790; 2009

FLAG-Ida

APL. Survival with ATRA+As2O3±GO

Ravandi. JCO 27:504; 2009

ATRA + Arsenic Trioxide in APL• 276 pts (254 evaluable) aged 18-71 yrs with APL

(WBC ≤ 10,000) randomized to ATRA-ATO vs AIDAParameter ATRA-ATO

(n=122)AIDA

(n=132)P-Value

% CR 100 97 .12

% 2-yr EFS 98 85 .0002

% Relapse 1.1 9.4 .005

% OS 99 94 .01

Platzbecker. Blood 124: abst 12; 2014

No longer a role for conventional chemotherapy in APLMolecularly targeted therapy cures more

Genetic EventsCommon Mutations

Common Mutations & Available AgentsMutation Incidence Prognostic Drugs in

Development ?All Diploid

NPM1 25-35% 45-60% Favorable (FLT3 WT)

No

FLT3 ~20% 28-34% ITD: AdverseD835 ?

Multiple in trial

DNMT3a 18-22% 30-37% Unclear No, but…IDH1 & IDH2 15-20% 25-30% Adverse ? 2 in trial, others

in developmentASXL1 5-11% 5-12% Adverse NoTET2 ~13 % 9-23% Adverse ? NoRUNX1 5-15% 8-16% Adverse No

FLT3 Inhibitors

FLT3 Inhibitors Under DevelopmentPreclinical Phase I Phase II Phase III

VX-322 IMC-EB10 Sorafenib Lestaurtinib

VX-398 KW-2449 MLN-518 Midostaurin

MC-2002 Ponatinib Crenolanib Quizartinib

MC-2006 CHIR-258 PLX3397

ASP2215

None are mutation specific – So really targeted?

The only FDA approved FLT3 inhibitor….….but not approved for this indication

FLT3 inhibitors• As single agents very few CRs

– Better at reducing PB than BM blasts• Will addition to Chemotherapy improve results ?

ALL FLT3 mut Chemo Chemo + L

N 112 112

Age 54 (21-79) 59 (20-81)

CR 12% 17%

CRp 9% 9%

CR1 <6 11% 19%

CR1 >6 29% 32%

Survival 160D 160D

CR1 <6mo MEC + Lestaurtinib 80mgCR1 >6 mo HiDAC + Lestaurtinib 80mg

Response correlates with target level inhibitionOnly 58% got inhibited at D 15

Levis Blood 2011:117;3294-3301

FLT3 Mut FLT3 WT

Dose 50 100 50 100

N 18 17 31 29

Age>64 39% 53% 77% 72%

CR 0 0 0 0

PR 0 1 0 0

Heme improvement

50% 41% 43% 26%

Midostaurin 50 or 100 mg twice daily

Fischer JCO 2010:28;4239-45

No evidence of FLT3 –ITD targeting Barely better than chemo alone

AC220-002 (Quizartinib) Phase II in AML salvage

Cohort >60, CR1 < 1 yr or 1oRef >18 Rel/Ref to 2nd line or HSCT

Mutation Status ITD+ FLT3-WT ITD+ FLT3-WTN 92 41 99 38Age 70 (54-85) 69 (60-78) 50 (19-77) 55 (30-73)

CR composite 54% 32% 44% (4% CR) 34% (3% CR)

PR 18% 9% 24% 13%

Median CRc duration

12.7 wks 22.1 wks 11.3 5

Median Survival 25 19 23.1 25.6

Cortes ASH 2012 Abstract # 48

Dose: Females 90 mg Males 135 mg continuously

QTc 25 % Grade 3-4 13% 26% Gr 3-4 10%

Levis ASH 2012 Abstract # 673

Quizartinib+AZA or LDAC in FLT3-positive AML

• 33 pts – 12 in phase 1; 21 in phase

2– Rx with quizartinib 60-90

mg orally daily and AZA or LDAC

• 63% responded: – CR 9%, CRp 15%, CRi 36%, – PR 3%

• 22 with FLT3-ITD: ORR 82%

Borthakur. Blood 124: abst 388; 2014

Survival

0 2 4 6 8 1 0 1 2 1 4

Mo n th s

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

Su

rviv

al P

rob

ab

ility

Quizartinib+ Total Died Median Azacitidine 24 6 NR LD Ara-C 9 5 8 .2 m o

p = 0 .24

• Median Overall Survival = not reached• Alive at 6 months= 22 (66%)

Improved Outcome (?) of FLT3-mutated AML

Badar. Blood 124: abst 949; 2014

Pre FLT3 Agents

FLT3 Agents

20%

8 %

So maybe FLT3 patients are doing a bit better with targeted therapy

So What about FLT3 combinations?• FLT3i + chemotherapy ?

– 1st Generation +High Does MEC/HiD ara-C • no definite improvement

– 2nd Generation +Low dose LDAC • hints at improvement

• FLT3i + other targets– Not tested yet

• FLT3i + Demethylators/HDACi– Mutations often co-occur– Not tested yet– In vitro MS-275(entinostat) induces growth arrest Patel NEJM 2012;366:1079-89.

FLT3 Inhibition- Ready to be a “dynamic duo”?

• Target Identified ?• Standardized Tests ?• Drugs available ?• Drugs show single

agent efficacy?• Response better in

target population?• Synergy with other

agents in vitro or trials?

YesYes

Yes – SorafenibSort of

Not really

Yes for synergy

Jury out on efficacy

IDH 1 & 2 Inhibitors

IDH in Leukemia• IDH mutations occur in ~ 20% of AML

– frequency: 6-16% IDH1 & 8-18% IDH2– Majority (85%) with diploid or +8

cytogenetics– ↑ prevalence with ↑ patient age – Strongly associate with NPM1+ and

MPN-derived AML (21-31%)– Mutated residues occur in

conserved active site• IDH1-R132, IDH2-R172 or -R140• GAIN of Function

– Founder mutations, not progression• 0/225 pts WT IDH at dx develop

IDH mutation during f/u

Dang L. Trends in Mol Med, 2010 Chou et al, Leukemia 2011Patel NEJM 2012;366:1079-89.

Drugs Targeting IDH• IDH1 = AG 120 IDH2 = AG 221

73 pts R140 =54 R172= 13Rel Ref 55 MDS 6 New 5 CMML 5Prior BMT 18%Daily or BID. 30mg to 150 BID, 200mg/D

Responses in 25 / 45 = 56%: 8CR =6 CRp =5 mCR=1 Cri=5 PR = 10No clear dose responseDuration: 90% > 3 months

Toxicities: LFTs

Stein. ASH 2014 # 115

14 pts

100 mg BID, 3,5,800/D

Responses in 7/ 14 = 50%: 8CR =4 mCR=2 PR = 1 SD = 6No clear dose responseDuration: ?

Toxicities: ?

Patient 2 Patient 3 Patient 4 Patient 80

102030405060708090

100110

2-H

G r

ela

tive to u

ntr

eate

d (

%)

UntreatedDMSO

0.5 M AG-1201 M AG-1205 M AG-120

EORTC-NCI-AACR 2014 & Hansen ASH 2014 #3734

IDH Inhibition- Will they pair famously with other targeted therapies?

• Target Identified ?• Standardized Tests ?• Drugs available ?• Drugs show single

agent efficacy?• Response better in

target population?• Synergy with other

agents in vitro or trials?

YesYesYES & NO – Phase 1-II trials

YES!

Unknown, no WT treated in vitro data says yes

Not tested yet.

Reason to be excited- Yes!

Mutations in Other Epigenetic

Modifiers

5’…CpG….…GpC….5’

5’…MECpG….…GpCME….5’

DNMT3a

DNMT1

HDACAC essible

Tet2IDH1/2 2-HG

Jumongi (Histone Lysine)

Bromodomain

miRNA29-b

SP1

De niedAC cess

K4-MEK79

MLL

K27-MEK79

Set

EZH2

LSD1

JMJD3

HAT AC

Mutations in Genes affecting Epigenetics in AML

Asxl1

Tet2Mut

Asxl1 mut

Epigenetic Regulation Single Agent Trials DNA Methylation Histone Acetylation

• Two clinically available agents• Azacitadine• Decitabine

• Trials mostly AML

• Activity seen• Demethylation seen

• In general single agent responses have been modest

• Trials a mix of MDS & AML• Valproic Acid ( usually + ATRA)

• Response rate 5-30% “Heme improvement”

• Responses in low risk MDS, normal blast %

• Vorinostat • 2 trials as a single agent 78 patients• Response 4.5 (1 CR) & 17% (2 Cr 2

Cri 3 HI)• MGCD0103 29 patients, 10% 3 mCRs• Entinostat N= 39 RR= 0%• All induce histone deacetylation• Correlation of response with baseline

histone acetylation ?

Dec Aza

CR 17%1 24%2 26%3

40%4

17%6 33% + CRp 23%7

Survival Advantage

Yes5 Yes6

1. Kantarjian JCO 2012:30;26702. Lubbert, Hematologica 2012:973. Cashen JCO 2010:28:556

4. Ritchie LeuLym 2013:54;20035. Eisai FDA submission 5-10-14

6. Feneaux JCO 2010:28;5627. Thepot AmJH 2014:89;410

• Unfortunately nearly no data in AML• 7 Gene Epigenetic profile predict overall response to “therapy”,

but to demethylating ? Marcucci JCO 2014:32:548-556• No association baseline methylation or demethylation & response

• To Aza Valproic Soriano Blood 2007:110;2302-8• To 5-aza+entinostat Fandy Blood 2009:114;2764-73

• DNMT3a correlate with response to Decitabine- Metzler leukemia 2012:26,1106

• Data from MDS suggests maybe so, or maybe not….• TET2 mutant 82% response vs 45% (p=0.007) to AZA in MDS, low blast %

AML Izakson Leukemia (2011) 25, 1147–1152• TET2 (ASXL1-WT) Highest response rate in MDS treated with

hypomethylating Bejar Blood. Oct 23, 2014; 124(17): 2705–2712• Higher levels of miR-29b were associated with clinical response (P = 0.02) to

decitabine x 10D in AML Blum PNAS 2010 107:7473-78• Baseline methylation not predictive of response to decitabine. Shen JCO

2010:28;605-13

Does Baseline Methylation or Having a Epigenetic Regulator Mutation Confer Sensitivity to Demethylating agents in AML?

Bejar Blood. Oct 23, 2014; 124(17): 2705–2712

Absolutely no details on whether these patient were treated, or what they were treated with was mentioned in the manuscript or supplemental materialsA mixture of Epigenetic modifiers and standard per Dr. G-GM

Some (% ??) gotdemethylating agents?

Traina et al. Leukemia 2014:28;78-87 & ASH 2011 Abstract #461

Methylation and Histone Modifying Gene Mutations and response to Demethylating agents in MDS

Individual Mutations Combined Mutations

5’…CpG….…GpC….5’

5’…MECpG….…GpCME….5’

DNMT3a

DNMT1

HDAC

AC essible

De niedAC cess

IDH1/2 2-HG

Jumongi

Bromodomain

K4-MEK79

MLL

K27-MEK79

Set

EZH2

LSD1

JMJD3

HAT AC

miRNA29-b

SP1

AG120AG221

Bromo IGSK525762

DOT1L (h3k29)

HDACiValproicVorinostatPanobinostat

DemethylatingVidazaDac

Tet2

Asxl1

Drugs Affecting Genes Mutated in AML

Would combined therapy against different points work?

Epigenetic Regulators + Standard Chemotherapy?

Regimen Phase Dose & Schedule New or Relapsed refractory

A = AzacitidineB = BortezemibBR = BrentuximabC = cyatarabineCL = ClorarabineD = DecitabineDA = DaunorubicineE = EtoposideEN= EntinostatER = ErismodegibGO = Gemtuzumab ozogamicinHI = Hedgehog inhibitorI = IdarubicinL = LenalidomideM = MitoxantroneMD = MidostaurinP = PanobinostatPR = PracinostatR = RigosertibRA = RapamycinRBV = RibavirinS = SelinexorSI = SirolimusSO = SorafenibT = TemozolomideV = VosaroxinVA = Valproic AcidVO = VolasertibVOR = Vorinostat

No shortage of combinations in trial…

Demethylating agent + ?Roboz ASH 2014 Educational book , P44

Histone Methyltransferase +

Demethylator + HDAC

Vorinostat + IA• Does adding Histone deacetylase inhibitor improve response?

– Vorinostat 600 mg t.i.d. Days 1 2 3– Ida 12mg/m2 /d x 3 Days 4 5 6– ara-C 1.5 g/m2 /d x 3 or 4 Days 4 5 6 (7)

• N= 75 newly diagnosed • median age 52 (19-65)• Cytogenetics

– 29 diploid– FLT3-ITD =11

• Mortality 4%• CR = 76% (n=56) including 100% in FLT3 53% in -5 -7• Relapse in 27 • OS median all patients =82 weeks FLT3-ITD 91 weeks• Toxicity “ no excess” w.r.t. standard IA, Skin 38%

Garcia-Manero JCO 2012;30:2204-10

Alas….No data on whether methylation status correlates with response

Epigenetic Regulators + Targeted? An Irresistible Combination?

• Target Identified ?• Standardized Tests ?• Drugs available ?• Drugs show single

agent efficacy?• Response better in

target population?• Synergy with other

agents in vitro or trials?

YesNo, which target matters?Yes

Yes

Data equivocal

Many trials underwayEfficacy?Targeting?Prognosticators?

If you can’t target the mutation can you target

something else?

A Finite Number of Mutations in AMLA Near Infinite # of Combinations

TCGA NEJM 2013

TCGA Identified ~ 23 common mutations

How do you figure out which to target?

Patients N= 511Patient Signature1 2 3 4 5 6 7 8 9

But a Finite Number of Protein Signatures

Kornblau Unpublished

Could we use this to triage patients to targeted therapy against pathways ?

Apoptosis Regulation

Pathway map from Cell Signaling

Agent/Co Mechanism Ph

OblimersonGenasenseGenta

BCL2 AS

III

AT-101GossypolAscenta

BH3 mimetic II

ObatoclaxTeva

BH3 mimetic II

NavitoclaxABT-263Abbvie

BH3 mimetic II

ABT-199Abbvie

BH3 mimetic I/II

LY2181308ISIS

Survivin AS II

LCL-161 Smac mimetic I

Birinapent Smac mimetic

Venetoclax (ABT199) in AML• Venetoclax 20-800 mg orally daily• 32 pt with refractory AML Rx; 11 with

IDH mutations• ORR 6/32 = 19% (2CR, 4 marrow CR)• IDH mutations may be more sensitive:

4 responses/11 = 36%

Konopleva. Blood 124: abst 118; 2014

LCL161-regulated signalling pathways are shown.

Fulda S JCO 2014;32:3190-3191

©2014 by American Society of Clinical Oncology

Small molecule inhibitor that mimics the N-terminal portion of second mitochondrial-derived activator of caspases (Smac)

Endogenous IAP antagonist released from mitochondria into the cytoplasm during apoptosis

Phase 1-2 data from Advanced solid tumors, multiple myeloma, pancreatic & breast cancer

Smac mimetics in hematologic malignancies (Bing Carter)Birinipant + AZA in MDS clinical trial (PI: G. Borthakur)

Clinical trial underway at MDACC

Signal Transduction

If it is on here, then it is a “target” and someone is developing a drug against it.

Pathway maps from Cell Signaling

PI3K-AKT Ras-Raf-Mek-Erk

RG7388 (MDM2 antagonist) in AML

• RG7388 single-agent 400-1600 mg /D x 5 Q mo (n=20), then extension in unRx (n=9), then in combo with ara-C (n=23+34)

Regimen No. Rx No. Response (%)

RG single 20 2 CR, 3 CRi/MLFS (25)

RG single unRx 9 1 CRi (11)

RG+ara-C 23 6 CR + 2 PR (35)

RG+ara-C 34 4 CR+1 CRi/MLFS+1 PR (18)

Yee. Blood 124: abst 116; 2014

MDM2 inhibition: RG7112 + ara-C

Yee ASH 2013 Abstract # 498

Arm A N=16 Median age 70 Arm B N=27 Median age 50

Who Unsuitable for standard (re) induction Relapsed refractory

Regimen RG7112 + Ara-C 20 mg/M2 sc x 10D RG7112 x 5 D + ara-C 1g/M2 iv x 6 D

Response

CR 3 all P53 WT 2Cr 1 Cri 1 CRp all P53 WT

PR 0 1

SD 3 7 P53 mutated in 1

PD 8 P53 mutated in 3 11 P53 mutated in 1

Deaths 2 ARDS, Sepsis 2 sepsis

MTD 1000 mg bid x 10 D 1500 mg bid x 5 D

Functional P53 likely required CR1 duration?Cytogenetics?

Surface Targets

CD33

CD123

Car T Cell

KILL

CD123

Calachiamicin

NK CellCD16

KiLL

CSL3662

NO• But not because we don’t want to.

• Availability of agents outside of Phase I-II trials is the limiting factor

• In the not too distant future there may be a lot of targeted agents worth combining

Is it time to consider targeted therapy in combination for

newly diagnosed AML?

Conclusions• Tons of Targets• Many agents in development

– Not licensed yet

• Selectivity for population bearing target not always clear

• Improved responses in target population generally not demonstrated

• Need a rational way to test combinations (when targeted agents become available)

• Need reliable means to match patients & targets• We are not there yet….

Other Great Combos