First-in-man Phase I study of the oral dual PI3K and mTORC1/2 inhibitor BEZ235 in patients with advanced solid tumorsHoward Burris1, Jordi Rodon2, Sunil Sharma3, Roy Herbst4, Josep Tabernero2, Jeffrey Infante1, Antonio Silva5, David Demanse5, Wolfgang Hackl5, Jose Baselga2

1Sarah Cannon Research Institute, Nashville, Tennessee, USA; 2Vall d’Hebron University Hospital, Barcelona, Spain; 3Nevada Cancer Institute, Las Vegas, Nevada, USA; 4The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA; 5Novartis Pharma AG, Basel, Switzerland

Abstract #3005

Howard Burris Jordi Rodon Sunil Sharma Roy Herbst Josep Tabernero Jeffrey Infante Jose Baselga

Antonio Silva, David Demanse, and Wolfgang Hackl

are employees of Novartis Pharma AGNovartis Pharma AG is the study sponsor

Disclosures

Study investigators

4EBP14EBP1

PI3K

TORC1TORC1

S6KS6K

Rheb Rheb

S6S6

PIP3PIP3

Tuberin

PTEN

TORC2TORC2 Akt PDK1PDK1

BKM120

BEZ235

BEZ235

BEZ235 inhibits the PI3K signaling pathway

BEZ235: Orally available potent dual inhibitor of PI3K and mTORC1/2

• Potent, specific, oral PI3K and mTORC1/2 inhibitor

• Broad antiproliferative effect across different tumor types

• Pro-apoptotic effect in PI3K-pathway activated tumor models

• Antiangiogenic

Maira et al. Mol Cancer Ther 2008;7:1851–63Serra et al. Cancer Res 2008;68:8022–30

Enzyme IC50 nM/L

Class I PI3K

p110α 4.0 ± 2

P110α-H1047R 4.6 ± 0.8

P110α-E545K 5.7 ± 1.0

p110β 75 ± 45

p110δ 7 ± 6

p110γ 5 ± 4

mTOR 20.7

Panel of 18 other protein kinases >10,000

N

N

N

N

N

O

BEZ235 Phase I: Study objectives• Primary

– MTD of oral BEZ235 administered on a once-daily continuous schedule

• Secondary– Safety and tolerability of BEZ235

• AEs per NCI-CTCAE v3.0, hyperglycemia per ADA guidelines (fasting plasma glucose ≥7.0 mmol/L)

– Pharmacokinetic profile • Days 1, 8, and 28 in Cycle 1

– Biomarker and pharmacodynamic assessments• PIK3CA (mutation) and PTEN (mutation and protein expression) status in

archival tumor samples• Fasting plasma C-peptide levels• Phospho-S6 and Ki-67 levels from pre- and on-treatment biopsies • 18FDG-PET for metabolic anti-tumor activity

– Overall response as per RECIST

NCI-CTCAE, NCI-Common Terminology Criteria for Adverse EventsADA, American Diabetes Association

BEZ235 Phase I: Study design

aDefined as the drug dosage expected to cause a medically unacceptable DLT in >33% of patients during the first treatment cycle; for declaration of MTD, ≥6 patients will have to be treated at this dose level for one treatment cycle OGTT, oral glucose tolerance test

Declaration of MTDa

• Key exclusion criteria:− Treatment with corticosteroids ≤2

weeks before starting study drug− Diabetes mellitus or history of

gestational diabetes− Prior treatment with a PI3K inhibitor

10 25 50 100

200

400

300

300

400

1100

700

Fasted, mg/day

Fed, mg/dayCombination with trastuzumab dose escalation

arm in patients with HER2+ mBC with a PIK3CA activating mutation

Single-agent dose-escalation Oral, once-daily BEZ235

28-day cycle (N≥24) MTD / safety expansion arm in patients with alterations

in PIK3CA/PTENOral, once-daily BEZ235

28-day cycle

• Special safety assessments:− Fasting plasma glucose− 2-hour plasma glucose during a 75 g

fasting OGTT− Hemoglobin A1C

BEZ235 Phase I: Patient characteristics

Characteristic N=59

Median age, years (range)

55 (29–81)

<65 years (%) 47 (80%)

Male / Female 20 (34%) / 39 (66%)

WHO PS, 0/1 29 (49%) / 30 (51%)

Prior antineoplastic therapy

56 (95%)

Median number of regimens (range)

3 (0–18)

Patients with >3 prior regimens

30 (51%)

Primary tumor type N=59

Colorectal 14 (24%)

Breast 13 (22%)

Lung 5 (9%)

Ovarian 4 (7%)

Skin melanoma 4 (7%)

Soft tissue sarcoma 3 (5%)

Prostate 2 (3%)

Endometrial 2 (3%)

Esophageal 2 (3%)

Pancreatic 2 (3%)

Head and neck 2 (3%)

Othera 6 (10%)aOne patient each (1.7%): kidney, adrenal, pleural, choroid, gallbladder, pararenal

Cut-off date March 2, 2009

BEZ235 Phase I: Retrospective analysis of tumor mutation status

a Population enrichment was not employed. Samples available for 51/ 59 patients, some analyses incomplete due to sample quantity or qualitybSNaPshot genotyping, exons 9 and 20cGenomic DNA sequencing of PTEN exons 1-9, Semiquantitative IHC

N=59 n

Tumor samplesa 51 (86%)

Evaluable for PIK3CA Statusb 48

Wild-type 43 (90%)

Mutation 5 (10%)

Evaluable for PTEN Statusc 51

Wild-type 39 (76%)

Mutated 7 (14%)

Protein level low (H-score < 40) 10 (20%)

Protein level medium (H-score 40-90) 12 (24%)

Protein level high (H-score >90) 26 (51%)

Tumors with PI3K pathway activation (any PIK3CA/PTEN alterations)

19 (37%)

BEZ235 Phase I: Dose escalation

ScheduleDose (mg)

Patients Exposure (wks)

>4 >12

Fasted

10 3 2 0

25 6 6 3

50 4 4 4

100 6 5 1

200 5 4 2

300 6 5 0

400 11 8 5

Fed

300 6 5 3

400 3 3 1

700 5 5 2 1100 4 1 1

All 59 48 (81%) 21 (36%)

• No DLTs observed in Cycle 1• Median duration of treatment was 8 weeks

– No relationship observed between treatment duration and dose or administration schedule

DLT definition• Hematologic AEs

−≥Grade 3 neutropenia for >7 consecutive days or febrile neutropenia

−Grade 3 thrombocytopenia for >7 consecutive days or Grade 4 thrombocytopenia

• Non-hematologic AEs− ≥Grade 3 toxicity − Grade 2 hyperglycemia that

cannot be resolved to Grade 0 in ≤14 consecutive daysa

− ≥Grade 2 pancreatitis

aAs per ADA guidelines.

BEZ235 Phase I: AEs in >20% of patients, regardless of causality

• AE incidence was similar in both schedules– Gastrointestinal disorders: 70%– General disorders: 66%– Hematologic disorders: 18%

Fasting, dose in mg Fed, dose in mg

10 n=3

25 n=6

50 n=4

100 n=6

200 n=5

300 n=6

400 n=11

300 n=6

400 n=3

700 n=5

1100 n=4

All n=59n (%)

Total events 3 6 2 6 5 5 11 6 3 5 4 56 (95)

Fatigue/Asthenia

2 1 2 4 3 5 2 3 3 25 (42)

Diarrhea 1 2 3 4 2 4 1 4 2 23 (39)

Nausea 1 2 2 2 3 3 1 2 3 1 20 (34)

Vomiting 1 1 1 2 1 1 3 2 4 1 17 (29)

Anemia 2 2 1 3 1 1 1 1 12 (20)

BEZ235 Phase I: most common AEs suspected to be related to study drug

Preferred Ter m, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Total

Total events 16 (27) 21 (36) 4 (7) – 41(70)

Fatigue / Asthenia 8 (14) 4 (7) 2 (3) – 14 (24)

Diarrhea 13 (22) 1 (2) 1 (2) – 15 (25)

Nausea 9 (15) 3 (5) – – 12 (20)

Vomiting 6 (10) 4 (7) – – 10 (17)

Anemia 1 (2) 3 (5) – – 4 (7)

Abdominal pain 2 (3) – – – 2 (3)

Anorexia 3 (5) 2 (3) – – 5 (9)

• No drug-related SAEs or treatment-related deaths

• No treatment-related disturbances of glucose homeostasis, vital signs, or cardiac function

BEZ235 Phase I: clinical pharmacokinetics

• Non-proportional increase in systemic exposure and Cmax across all doses– High intra- and inter-patient

variability

• Apparent median Tmax 1–7 hrs

• Apparent t½ from 1–14.5 hrs

• No significant food effect on systemic exposure

• Plasma exposure for most patients treated at ≥400 mg/day BEZ235 was within range of steady state exposures in patients with radiologic response Partial response, Max AUC0-24

Partial response, Min AUC0-24

Day 28Day 8Day 1

Dose (mg)B

EZ

235

exp

osu

re (

AU

C0

-24 -

ng

.h/m

L)

10 50 100 500 1000

1

10

100

1000

10000

Individual AUC values

Time (hours post dose)

BEZ235 Phase I: Dose-dependent increases in plasma C-peptide with BEZ235• Dose-dependent increases in plasma C-peptide indicate

pharmacodynamic activity at Day 8 that is sustained at Day 28

Increase relative to 10-25 mg dose

50–100 mg

40% increase

200–400 mg

53% increase

Increase relative to Day 1 52% Day 8 56% Day 28

0

5

10

15

20

25

30

0 1 2 3 4

10–25 mgNumber of patients = 9

0 1 2 3 4

50–100 mg Number of patients = 8

0 1 2 3 4

200–400 mg Number of patients = 28

C-p

eptid

e (n

g/m

l)

Observations at Day 1Observations at Day 8Observations at Day 28

BEZ235 Phase I: BEZ235 decreases tumor phospho-S6 and Ki-67 levels

% Decrease

P-S6 (H-score) 240 120 50%

Ki-67 (% cells+) 15 2 87%

Tumor tissue from a patient with esophageal cancer with staining for P-S6

Baseline BEZ235 50 mg/dayCycle 1, Day 28

BEZ235 Phase I: Clinical activity

• 51 patients were evaluable for response– 2 patients with partial responses

• ER+ HER2 normal breast cancer, unknown PI3K pathway status (1100 mg/day, response duration 9+ months)

• Lung cancer, Cowden syndrome (700 mg/day, response duration 8 months on BEZ235, 10+ months off BEZ235)

– 14 patients (27%) with stable disease for ≥4 months

• 4 patients (29%) had breast cancer• 6 patients (43%) had tumors with alterations in the PI3K

pathway

CT

18F

DG

-PE

T

BL C1D28 C2D28

BEZ235 Phase I: Clinical PR in a patient with ER+ HER2 normal breast cancer

BEZ235 1100 mg/day

BL, Baseline; C, Cycle; D, Day

1 2

540

Tim

e (D

ays

)

0

60

120

180

240

300

380

420

480

600

660

720

3 4 5 6 7 8 9 10 11

TTP at last prior therapy

TTP on BEZ235 treatment according to local review

A,Tumor PI3K pathway alteration (PIK3CA / PTEN mutation, low/null PTEN expression); N, No identified PI3K pathway alterations

Fas

t 40

0 m

g/d

Fas

t 40

0 m

g/d

Fas

t 40

0 m

g/d

Fed

300

mg

/d

Fed

400

mg

/d

Fas

t 25

mg

/d

Fas

t 50

mg

/d

Fas

t 50

mg

/d

Fas

t 10

0 m

g/d

Fed

100

mg

/d

UNK

Patientsa aAs per data cutoff March 2009

Fas

t 40

0 m

g/d

TTP, time to progression; UNK, unknown

A

A

AA

A

A

NN

BEZ235 Phase I: comparison of TTP for patients with SD for ≥4 months

Eso

phag

eal

Col

orec

tal

Adr

enal

Lung

Lung

Col

orec

tal

Bre

ast

Col

orec

tal

Ova

rian

Mel

anom

a

Bre

ast

Bre

ast

Syn

ovia

l sar

com

a

40

20

0

–20

–40

Bes

t p

erce

nt

chan

ge

fro

m b

asel

ine

in S

LD

(m

easu

rab

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Nas

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Mel

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Col

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Mel

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End

omet

rial

Lung

–50

–30

–10

10

30

50

Bre

ast

Bre

ast

Bre

ast

Bre

ast

Neu

roen

docr

ine

Pro

stat

e

Bre

ast

Bre

ast

Mes

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liom

a

BEZ235 Phase I: reduction in tumor burden as per CT

• 18 out of 35 evaluable patients had tumor shrinkage as per central review

Col

orec

tal

60

40

20

0

–20

–40

–60

BEZ235 Phase I: tumor metabolic response as per 18FDG-PETa

Per

cen

t ch

ang

e in

sS

UV

max

B

asel

ine

– C

1D28

Mel

anom

aC

olor

ecta

l

Col

orec

tal

Col

orec

tal

Bre

ast

Col

orec

tal

Col

orec

tal

Col

orec

tal

Ova

rian

Col

orec

tal

Adr

enal

Bre

ast

Lung

End

omet

rial

Bre

ast

Lung

Col

orec

tal

Bre

ast

Bre

ast

Bre

ast

Cho

lang

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oma

Mes

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liom

aC

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Ren

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reas

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Pan

crea

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tB

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arco

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Bre

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Lung

Mel

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a

• 18 out of 37 patients demonstrated a detectable decrease in tumor 18FDG-uptake as per central review

C, Cycle; D, Day

aEnd of Cycle 1

BEZ235 Phase I: correlation between single-lesion responses by CT and PET

• Correlation between CT and PET responses at ≥400 mg/day BEZ235 suggests clinically active exposure levels have been achieved

% change in SLD

% c

han

ge

in s

SU

Vm

ax

10–300 mg dose group 10 patients with comparable lesions

400–1100 mg dose group 8 patients with comparable lesions

y=1.3549x + 0.0822R2=0.4474

y=0.1756x - 0.0563R2=0.0086

–1.0–1.0 -0.5 0 0.5 1.0

–0.8

–0.6

–0.4

–0.2

0

0.2

0.4

0.6

0.8

1.0

No correlation Significant correlation

–1.0

–0.8

–0.6

–0.4

–0.2

0.2

0.4

0.6

0.8

1.0

0

–1.0 –0.8 –0.6 –0.4 –0.2 0 0.2 0.4 0.6 0.8 1.0

BEZ235 Phase I: summary• No DLTs were observed: MTD not identified• SAEs were not reported with BEZ235 treatment• Rapid absorption and highly variable systemic exposure • Evidence of single-agent activity in patients with heavily

pretreated advanced cancer – 2 PRs, 16 cases of tumor shrinkage, 14 SD of ≥4 months

– Activity in patients with and without PI3K pathway alterations

• Pharmacologically active exposure levels reached at doses of BEZ235 400–1100 mg/day – Dose-dependent effects on plasma C-peptide

– Decrease in tumor phospho-S6

– Correlation between CT and PET response

BEZ235 Phase I: conclusions

• BEZ235 is a potent inhibitor of the PI3K pathway

• BEZ235 has a favorable safety profile

• BEZ235 demonstrates clinical activity in patients, including those with alterations in the PI3K pathway

• Ongoing studies include:– A new formulation of BEZ235 with improved bioavailability and

PK properties– Combination treatment with HER2 or MEK-targeted therapies

Acknowledgments• Patients and their families • BEZ235 Clinical Study Team

• Sponsor-Novartis

Sarah Cannon Research InstituteJohanna BendellSuzanne Jones

Nevada Cancer Institute

Vall d’Hebron University HospitalFrancesco Atzori

Gemma SalaJavier Cortes

Virtual ScopicsS Mahmood

MD Anderson Cancer CenterFaye Johnson

George BlumenscheinJustina Price

Back-up slides

BEZ235 Phase I: Patient disposition

Status* N=59

n (%)

On treatment 5 (9%)

Discontinued due to disease progression 46 (78%)

Discontinued due to AE 6 (10%)

Discontinued at the discretion of the treating physician

1 (2%)

Withdrew consent 1 (2%)

*Cut-off date March 2, 2009.

1 2

540

Tim

e (D

ays

)

0

60

120

180

240

300

380

420

480

600

660

720

3 4 5 6 7 8 9 10 11

TTP at last prior therapy

TTP on BEZ235 treatment according to local review

PIK3CA: wild-type (WT), mutant (MUT)PTEN: high, medium, lowPTEN: wild-type (WT), mutant (MUT)

WTHighMUT

MUTMediumMUT

MediumMUT Medium

WTHighWT

WT

WT MUTLowWT

MUTLowWT

WTMediumMUT

WTHighWT

Fas

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g/d

Fas

t 40

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g/d

Fas

t 40

0 m

g/d

Fed

300

mg

/d

Fed

400

mg

/d

Fas

t 25

mg

/d

Fas

t 50

mg

/d

Fas

t 50

mg

/d

Fas

t 10

0 m

g/d

Fed

100

mg

/d

UNK

BEZ235 Phase I: comparison of TTP for patients with SD for ≥4 months

Patientsa

Fas

t 40

0 m

g/d

aAs per data cutoff March 2009TTP, time to progression; UNK, unknown