Selection of 2nd Generation TKI treatment of patients with

Ph+ CML

Francis J. Giles

National University of Ireland, Galway & Trinity College Dublin

CML: Typical topics after 1 year of therapy

• 1980 – How long will I live? Pre-imatinib

• 2006 – When can I have a child? Imatinib

• 2011 – When can I stop therapy? Nilotinib

Imatinib discontinuation following CMR for ≥ 2 years: STIM

Mahon et al. Lancet Onc 11:1029,2010

Time

CML: Correlation between response and disease burden: Hematologic response

Time

CML: Correlation between response and disease burden: Cytogenetic response

Time

CML: Correlation between response and disease burden: Molecular response

CML: Optimal therapy

• No disease progression

• No disease or therapy-related reduction in QoL,

time-related demand

• Acceptable level of detectable disease

• Defined period of therapy with cessation

endpoint

• No “trade” of CML for 2nd malignancy, serious

comorbidities

Overall survival after progression to AP/BP on IRIS study

Months Since AP/BP Treatment

100

80

60

40

20

0 36 96

Aliv

e fo

llow

ing

prog

ress

ion,

%

0 12 24 48 60 84

90

70

50

30

10

72

Novartis IRIS data on file

Estimated % alive at: 12 months

43%

24 months 30%

Dasatinib (N=367) or Nilotinib (N=136) in BP - Overall survival

Prop

ortio

n al

ive

(%)

Months since start of treatment

Giles et al. Abs 117 EHA 2010 Saglio et al. Cancer 116, 3852, 2010 Martinelli et al. Abs 745 ASH 2006 Cortes et al. Leukemia 22, 2176, 2008

Nilotinib Dasatinib Lymphoid

0

10

20

30

40

50

60

70

80

100

Prop

ortio

n al

ive

(%)

90

22 19

Dasatinib Myeloid

Months since start of treatment 20 18 17 16 15 14 13 12 10 8 7 6 5 4 3 2 1 0 11 9 21

Imatinib, Nilotinib, Dasatinib:Kinase selectivity Imatinib Cell IC50 (nM): PDGFRα/β (39), KIT (106), BCR-ABL (669), DDR1/2 (43 / 141), CSF-1R (450)

Cellular IC50

< 10 nM 10-50 nM 50-250 nM 250-1000 nM

ABL

Nilotinib Cell IC50 (nM): BCR-ABL (25), PDGFRα/β (52), KIT (160), DDR1/2 (4/5), EphB4 (250), CSF-1R (300)

Dasatinib Cell IC50 (nM): c-Src (<5), Blk (<5), Fgr (<5), Fyn (<5), Hck (<5), Lck (<5), Lyn (<5), Yes (<5), BCR-ABL (1), DDR1/2 (1/5), PDGFR (3), KIT (18), EphA (17), p38 (100), HER1 (180), Jak2 (450), HER2 (710), FGFR (880), Raf (50), Zap70 (50)

ABL

After Fabian et al. Nature Biotech. 23,329:2005

Nilotinib / Imatinib / Dasatinib Potency and selectivity

Mestan. Blood 104 546a: Abs 1978, 2004 Weisberg. Cancer Cell 7:129, 2005

Nilotinib BcrAbl > PDGFR > Kit > Src

(Phos. IC50) 19 nM 75 nM 209 nM >1000 nM

Imatinib PDGFR > Kit > BcrAbl > Src

(Phos. IC50) 72 nM 99 nM 192 nM >1000 nM

Dasatinib Src > BcrAbl > PDGFR > Kit

(Phos. IC50) 0.1 nM 1.8 nM 2.9 nM 18 nM

ENESTnd: Progression to AP/BP (on study treatment)*†

Larson et al., ASCO 2011

2 235

12

17

0

5

10

15

20

25

Num

ber o

f Pat

ient

s

0.7% 1.1% 4.2% 0.7% 1.8% 6.0%

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

P = .0059

P = .0196

P = .0003

P = .0089

Without Clonal Evolution With Clonal Evolution

*ITT population † Progression to AP/BC or death due to CML while on study drug

GIMEMA Nilotinib First Line: 3 year FU

(n=73)

• Responses are stable • 1 patient progressed to AP/BP (T315I LBP)

• 92% of the patients are on nilotinib, 63% on 400 mg BID • 97% obtained an MMR

• 25% of CMRs are stable (longer follow-up needed)

• Imatinib 800mg daily in intermediate Sokal 1– median FU of 24 months – 3/78 progressed

Castagnetti et al. Blood 113; 3428, 2009 Rosti et al. Abs 359. ASH 2010

Dasatinib or Nilotinib versus Imatinib in newly diagnosed CML CP minimum 24 month follow up

Study

ENESTnd Nilotinib 300 BID (n = 282)

ENESTnd Nilotinib 400 BID (n = 281)

ENESTnd Imatinib 400 QD

(n = 283)

DASISION Dasatinib 100 QD

(n = 259)

DASISION Imatinib 400 QD

(n = 260) MMR by 24 months (%)

71

67

44 64 46

MR4.5 by 24 months (%) 26 21 10 17 8

CCyR by 24 months (%) Confirmed

85 -

85 -

77 -

86 80

82 74

Progression (%) P-value vs imatinib

0.7

0.0059

1.1

0.0196

4.2 -

2.3

5 -

Hochhaus et al. Abs 484. EHA 2011

Hochhaus et al. Abs 1011. ASH 2011 Statistically significant versus imatinib

Manley. Biochem Bio Acta 1754:3, 2005

Nilotinib

Lipophilic interactions improve fit to auxiliary pocket

Two hydrogen-bonds less required

Imatinib

Hydrogen bonds formed with specific amino acids lining the binding site

Hydrogen bonds with Ile360 & His361

Abl kinase inhibition: Imatinib or Nilotinib

Extra medullary cross-intolerance between imatinib and nilotinib

CP (N=94) / AP (N=23)

31

23

17

13 10

0 0 1 1 0

Patients enrolled in nilotinib study 2101 with grade 3/4 imatinib intolerance

Patients with cross-intolerance (grade 3/4) after switching to nilotinib

Rash / skin

toxicity

Fluid retention

GI intolerance

Liver toxicity

Myalgias / Arthralgias

Cortes et al. Blood :117:5600, 2011

Nilotinib in CML: Dose intensity

800 797 775

Planned Delivered CP 2nd line

Delivered AP 2nd line

800

Delivered BC 2nd line

779

600 597

Delivered CP 1st line

Planned Delivered CP 1st line

0

100

200

300

400

500

600

700

800

Nilo

tinib

Dos

e (m

g/da

y)

n 316 138 136 277 279

Larson et al. J Clin Oncol. 2010;28:487s [abstract 6501]. Hochhaus et al. Haematologica. 2010; 95:459 [abstract 1113].

Giles et al. Haematologica. 2008; 93:161 [abstract 117].

0 6 12 18 24 36 0

20

40

60

80

100

% P

atie

nts

with

MM

R

Time (months)

Nilotinib in CP-CML 2nd line: Dose interruption and time to response (n = 229)

Cumulative dose interruption: No interruption <7 days 7-14 days

14- 28 days ≥ 28 days

Time to MMR vs. dose interruption Time to CCyR vs. dose interruption

P = .0000993*

0 6 12 18 24 36 0

20

40

60

80

100

% P

atie

nts

with

CC

yR

Time (months)

*Log-rank test

P = .00091*

Dose interruptions were 4% of total days of exposure1

Giles et al. Abs 890 ASH 2010

Imatinib Nilotinib Dasatinib ABL ARG BCR-ABL KIT PDGFR DDR1/2 NQO2

ABL ARG BCR-ABL KIT PDGFR DDR1/2 NQO2 MAPK 11/12 EPHA3/A8 ZAK

ABL ARG BCR-ABL KIT PDGFR SRC YES FYN LYN HCK LCK FGR BLK FRK CSK BTK TEC BMX TXK

DDR1/2 ACK ACTR2B ACVR2 BRAF EGFR/ERBB1 EPHA2/A3/A4/A5 FAK GAK GCK HH498/TNNI3K ILK LIMK1 LIMK2 MYT1 NLK PTK6/Brk QIK QSK

RAF1 RET RIPK2 SLK STK36/ULK SYK TAO3 TESK2 TYK2 ZAK

Clinical impact of non-abl kinase modulation?

Dasatinib or Nilotinib versus Imatinib in newly diagnosed CML-CP: Grade 3/4 hematologic adverse events (18 Months)

Study

ENESTnd nilotinib

300 mg BID (n = 279)

ENESTnd nilotinib

400 mg BID (n = 277)

ENESTnd imatinib

400 mg QD (n = 280)

DASISION 100 mg QD

(n = 258)

DASISION imatinib

400 mg QD (n = 258)

%, Heme Grade 3/4 Grade 3/4

Neutropenia 12 10 20 22 20

Thrombo- cytopenia 10 12 9 19 10

Anemia 4 4 5 11 7

Larson et al. Abs 6501. ASCO 2010 Hochhaus et al. Abs 1113. EHA 2010

Shah et al. Abs 206. ASH 2010

Dasatinib and lymphocyte expansion • Mono/oligoclonal T/NK cells increased in CML at diagnosis

• LGL expansion cells – Clonal TCR γ/δ gene rearrangements

• Clones persist low levels in most imatinib-treated patients, markedly expand, resulting in absolute lymphocytosis, in some dasatinib-treated patients

• Most patients with LGL expansions have TCR δ rearrangements, uncommon in those without LGL expansion

• Lymphocytosis associated with both response and severe AE

• Possible predictor of response to Dasatinib?

• Lead for developmental therapeutics : T-cells have profile of late memory cytotoxic lymphocytes - ? enhanced immune reactivity

Rohon et al. Eur J Haem 85; 387, 2010 Kim et al. Haematologica. 2009 94: 135, 2009 Mustjoki et al. Leukemia 23; 1398, 2009 Kreutzman et al. Blood 116: 772, 2010

Dasatinib-related serosal inflammation

• PDGFRß inhibition - receptor on pericytes, involved in angiogenesis regulation of angiogenesis

• PDGFRß blockade with a MoAb associated with severe ascites and pleural effusion

• Src regulates focal adhesions and adherens junctions - subcellular cell-matrix attachment structures key in regulating cell adhesion

• VEGF mediated vascular permeability activity dependent on Src-related kinases Yes and Src

• Occurs in patients with solid tumours

Bergers et al. J Clin Inv 111; 1287, 2003 Hellstrom et al. Develop 126: 3047, 1999 Jayson et al. JCO 23: 973, 2005 Lindahl et al. Scienc 277: 242, 1997 Carragher et al. Curr Biol 13: 1442, 2003 Thomas et al. Ann Rev Cell Dev Biol 13: 513, 1997 Johnson et al. JCO 28: 4609, 2010 Abram et al. Exp Cell Res 254: 1, 2000

71%, P < .0001

67%, P < .0001

44%

By 24 months

100

90

80

70

60

50

40

30

20

10

0

% w

ith M

MR

0 3 6 9 12 15 18 21 24 27 30 33

Time since randomization (Months)

55%, P < .0001

51%, P < .0001

27%

By 12 months

Δ 24%-28%

Δ 23%-27%

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

282 281 283

n

ENESTnd: Cumulative incidence of MMR

44

26

36

2120

10

0

10

20

30

40

50

Best molecular response at any time BCR-ABL ≤ 0.01% (CMR4) and BCR-ABL ≤ 0.0032% (CMR4.5)

% P

atie

nts

With

Res

pons

e

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

P < .0001

P = .0004

P < .0001

P < .0001

BCR-ABL (IS) ≤ 0.01% (4-log reduction: CMR4)

BCR-ABL (IS) ≤ 0.0032% (4.5-log reduction: CMR4.5)

n = 282 n = 281 n = 283 n = 282 n = 281 n = 283

Nilotinib 300 Mg twice daily is highly effective front line treatment of early chronic phase CML: Results of the ICORG 08-02 phase 2 study

M O'Dwyer, RT Swords, FJ Giles, MF McMullin, P le Coutre, A Nagler, S Langabeer, M Wieczorkowska, C McDowell, B Moulton, K Egan, E Conneally

ASH 2011

ENEST1st line RE “Final” Study Design

Secondary Endpoints: • MMR at 3,6,9,12,18 and 24 months • CCyR at 12 months and 24 months • Rate of events after CMR, in year 1 and 2

Study duration 2 years • 18 months to primary endpoint • 6 month follow-up or until early withdrawal of consent or disease progression

Nilotinib 300 mg BID

ENROLL

Newly diagnosed Ph+ CML 1st line patients BCR-ABL pos IM-pre-treat for max 3 Mo

n = 806

Primary Endpoint: CMR at 18 months

18 Months 24 Months

Nilotinib 300 mg BID

6 month follow up

• Stem cell identification, telomere length, interactions with microenvironment

• Pharmacogenomics: genetic prognostic markers, DNA methylation profiling

• PK/ PD and clinical outcome • Compliance • Quality of life • Biomarkers and early predictors

of response

ENEST1st – Intrinsic science studies

A phase IIIb multicentre open-label study of nilotinib in adult patients with newly diagnosed BCR-ABL positive chronic myeloid leukemia in chronic phase: A European clinical Initiative with EUTOS collaboration for standardisation of molecular remission F Giles, G Rosti, GJ Ossenkoppele, M Tulliez, J Stentoft, A Giagounidis, F Nobile, P Le Coutre, N Gattermann, L Griskevicius, NCP Cross, S Hill, P Schuld, A Pellegrino, D Magazzù, A Hochhaus

ASH 2011

Dasatinib or Nilotinib versus Imatinib in newly diagnosed CML CP minimum 24 month follow up

Study

ENESTnd Nilotinib 300 BID (n = 282)

ENESTnd Nilotinib 400 BID (n = 281)

ENESTnd Imatinib 400 QD

(n = 283)

DASISION Dasatinib 100 QD

(n = 259)

DASISION Imatinib 400 QD

(n = 260) MMR by 24 months (%)

71

67

44 64 46

MR4.5 by 24 months (%) 26 21 10 17 8

CCyR by 24 months (%) Confirmed

85 -

85 -

77 -

86 80

82 74

Progression (%) P-value vs imatinib

0.7

0.0059

1.1

0.0196

4.2 -

2.3

5 -

Hochhaus et al. Abs 484. EHA 2011

Hochhaus et al. Abs 1011. ASH 2011 Not statistically significant versus imatinib

ENESTnd: Overall survival*†

Nilotinib 300 mg BID

n = 282

Nilotinib 400 mg BID

n = 281

Imatinib 400 mg QD

n = 283

Total number of deaths 9 6 11 Estimated 24-month rate of OS 97.4% 97.8% 96.3%

P-value (OS) 0.6485 0.2125 –

CML-unrelated 4 3 1 CML-related 5 3 10

Estimated 24-month OS rate of CML deaths 98.9% 98.9% 96.7%

P-value (CML deaths) 0.1930 0.0485 –

*ITT population †Including deaths after discontinuation of study drug

ENESTnd: CML-unrelated deaths Nilotinib

300 mg BID n = 282

Nilotinib 400 mg BID

n = 281

Imatinib 400 mg QD

n = 283

Total number of deaths (n=26)

9 6 11

CML-unrelated (n=8) 4 3 1

Ileus on treatment

Septic shock 9 months after stopping Nil

in survival FU

Renal failure in survival FU

Suicide on treatment

Gastric cancer 6 weeks after study entry

in survival FU

Perisurgical MI on treatment

Death unk cause on treatment

Pneumonia 18 months after stopping Nil

in survival FU

New cases in 2nd yr are in YELLOW

DASISION: Deaths on study

Treated patients, n (%) Dasatinib

100 mg QD N = 258

Imatinib 400 mg QD

N = 258 Total deaths 16 (6) 14 (5)

CML progression 8 (3) 10 (4) Cardiovascular disease 2 (1) 1 (<1) Infection* 5 (2) 1 (<1) Bleeding 0 1 (<1) Other neoplasm 1 (<1) 0 Clinical deterioration 0 1 (<1)

Death on treatment† 7 (3) 4 (2) Death after discontinuation‡ 9 (3) 10 (3) *Deaths due to infection in the dasatinib arm were sepsis/infection (no organism identified; n=3), meningoencephalitis (Klebsiella; n=1), and pneumonia (n=1); 2 of these patients died >30 days after discontinuation from the trial †Within 30 days of last dose ‡Yearly evaluations after discontinuation are currently stipulated by the protocol; additional information on patient status may be provided by investigators at other times

Hochhaus et al. Haematologica. 2011;96(s2):422 [Abs 1011]

Imatinib Nilotinib Dasatinib ABL ARG BCR-ABL KIT PDGFR DDR1/2 NQO2

ABL ARG BCR-ABL KIT PDGFR DDR1/2 NQO2 MAPK 11/12 EPHA3/A8 ZAK

ABL ARG BCR-ABL KIT PDGFR SRC YES FYN LYN HCK LCK FGR BLK FRK CSK BTK TEC BMX TXK

DDR1/2 ACK ACTR2B ACVR2 BRAF EGFR/ERBB1 EPHA2/A3/A4/A5 FAK GAK GCK HH498/TNNI3K ILK LIMK1 LIMK2 MYT1 NLK PTK6/Brk QIK QSK

RAF1 RET RIPK2 SLK STK36/ULK SYK TAO3 TESK2 TYK2 ZAK

Clinical impact of non-abl kinase modulation?

CML: Evolution towards cure

• First do no harm = Give safest most effective drug = Nilotinib for great majority of CML patients

• Monitor to assess speed of response and for signs of non-adherence, resistance

• Aim for cessation of nilotinib therapy = study participation

• Assume nilotinib will not cure everyone • Increase our collaborations