Andrew J. Wagner1, Johanna C. Bendell2, Jeffrey A. Morgan1, James Butrynski1, Suzanne George1, George D. Demetri1, Jill Fredrickson3, Jill Spoerke3, Doris Apt3, Jennifer Lauchle3, Gordon Jayson4, Johann S. de Bono5, Howard A. Burris2, Jean-Charles Soria6

1Dana-Farber Cancer Institute, Boston, MA, USA2Sarah Cannon Research Institute, Nashville, TN, USA3Exploratory Clinical Development, Genentech Inc., South San Francisco, CA, USA4The Christie NHS Foundation Trust, Manchester, UK5Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK6Institut de Cancerologie Gustave Roussy, Villejuif, France

Tolerability and anti-tumor activity of the PI3K/mTOR inhibitor GDC-0980

in patients with GIST and other sarcomas on two Phase I studies

2

2

GDC-0980, a Potent PI3K/mTOR Inhibitor

The PI3K-PTEN-AKT-mTOR signaling pathway is dysregulated in multiple cancers

Multiple mechanisms in GIST and other sarcomas

– Activation of RTKs, RAS, PI3K– Loss of PTEN, NF1, TSC1/2

Kinase Isoform IC50

p110α 4.8 nM

p110β 26.8 nM

p110γ 13.8 nM

p110δ 6.7 nM

mTOR Ki 17.3 nM

GDC-0980 is a potent, selective, oral inhibitor of Class I PI3 and mTOR kinases

Anti-tumor activity demonstrated in several cancer xenograft models

Wallin JJ, et al. Mol Cancer Ther. 2011; 10:2426-36

3

3

Study Design QD Dosing Schedule

Screening

D1

Cycle 1: DLT Assessment (D1-35) Cycle 2

D8 D28 D36D15

FDG-PET

D22 D50

PK PK

D64D56

TumorAssess.

TumorAssess.

PIK3CA, PTEN statusFDG-PETTumor Assessment

Study Objectives: Safety, PK, PD, Anti-tumor activity

Tumor Type Patients (n=115)

GDC-0980 Dose - Schedule

Escalation: All Tumor TypesExpansion: All Tumor Types

5659

2 to 70 mg - QD 21d and 28d30 mg and 40 mg - QD 28d (RP2D)

Sarcoma 11 2 to 40 mg - QD 21d and 28d•5 pts at RP2D

GIST 11 2 to 70 mg - QD 21d and 28d•4 pts at RP2DAssessments

FDG-PET

4

4

Study Design QW Dosing Schedule

Assessments

Study Objectives: Safety, PK, PD, Anti-tumor activity

D-28 D29D22D15D8D1 D43D36 D50 D57

2 x DCE-MRIBiopsyFDG-PETTumor Assessment

DCE-MRI

Biopsy FDG-PET

Tumor Assessment Tumor Assess.FDG-PET

Screening Cycle 1: DLT Assessment Cycle 2

Tumor Type Patients GDC-0980 Dose

All Tumor Types 38 6 to 200 mg

Sarcoma 7 4 pts at 25 to100 mg 3 pts at 150 mg

GIST 6 2 pts at 6 mg4 pts at 150 or 200 mg

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5

Safety and Tolerability QD Schedule

Schedule Dose (mg)

DLTs (n)

DLTs / significant SAEs

21d 2 0/3 -4 0/3 -8 0/3 -

16 0/3 -32 0/7 -50 0/6 G5 colitis (n=1)70 2/8 G3 Rash

G4 HyperglycemiaG3 sympt. Hyperglyc.G2, G3 pneumonitis (1 each)

40 0/4 -28d 40 0/14 G3, G5 pneumonitis

(1 each)50 0/5 -

Dose Escalation Expansion RP2DDrug-related Grade > 3 AEs

40 mg (n=50) Stg. 1 and 2

Any AE 26 (52%) Hyperglycemia 9 (18%) Rash 4 (8%) Diarrhea 5 (10%) Fatigue 2 (4%) Abnormal LFTs 4 (8%) Pneumonia *^ 4*^ (8%) Pneumonitis ^ 4^ (8%) Mucosal inflammation 3 (6%)

Colitis 0 (0%) Nausea 1 (2%) Stomatitis 2 (4%)

• incl. 2 pts with Pneumonocystis jiroveci Pneumonia • ^ Gr 5 AEs: Pneumonitis, Pneumonitis/Pneumonia, Pneumonocystis jiroveci Pneumonia (1 pt each)

Additional Gr ≥3 AEs observed at 40 mg QD in 1 patient each: Alopecia, asthenia, dehydration, dry skin, hyperbilirubinaemia, hypoxia, leucocytoclastic vasculitis, lymphopenia, vomiting

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6

Safety and Tolerability QW Schedule

DLT Assessment

Dose (mg)

DLTs (n)

DLTs

6 0/6 -12 0/5 -25 0/3 -50 0/4 -

100 0/3 -150 1/11 G3 Hyperglycemia*200 1/6 G3 Hyperglycemia*

Drug-related Grade > 3 AEs

150 mg(n=11)

200 mg(n=6)

Hyperglycemia 4 (36.4) 6* (100%)

Dysgeusia 1 (9.1%) -

No Grade ≥3 AE at doses of 6 – 100 mg QW

Adverse Events

* Includes one event of symptomatic Grade 4 hyperglycemia

* defined as a repeated episode of fasting G3 HG that occurred after initiation of oral anti-hyperglycemic therapy

7

7PK Profile and PI3K Pathway InhibitionQD Schedule

# PIK3CA mutant

• Dose-proportional increases in AUC and Cmax, half-life of 6-18 hours

• Decreases in pAKT in PRP of ≥ 90% observed at GDC-0980 doses ≥ 16 mg

• FDG-PET pathway inhibition observed in ~50% pts at RP2D (30 mg, 40 mg)

PK Profile

pAKT in platelet-rich plasmaBest overall FDG-PET response

40 mg Cohort

#

# ##

## #

#

PR # # ##

% M

ean

Cha

nge

SU

Vm

ax

8

8PK Profile and PI3K Pathway InhibitionQW Schedule

Dose-proportional increases in AUC and Cmax, half-life of 8-15 hours

PK Profile PD on Pre-Postdose Biopsies

Robust pathway modulation for both PI3K and mTOR downstream readouts

pS6

H-S

core

Pat

holo

gy S

core

Pat

holo

gy S

core

12 m

g25

mg

50 m

g

pS6 pPRAS40pAKT

9

9

Time on Study Sarcoma Patients

QD Schedule

QW Schedule

PEComaChondrosarcoma

Metastatic Diffuse-Type Giant Cell Tumor (PVNS)

Soft Tissue Sarcoma

Extraskeletal Myxoid ChondrosarcomaLeiomyosarcoma

Soft Tissue Sarcoma

Leiomyosarcoma

Angiosarcoma

MyxofibrosarcomaAlveolar Rhabdomyosarcoma

Solitary Fibrous Tumor

Solitary Fibrous Tumor

Bone SarcomaSynovial Sarcoma

ChondrosarcomaEpithelioid Sarcoma

Leiomyosarcoma

Median ToS2.6m

(1.0-18.1m)

Median ToS 2.9 m

(1.0-11.2m)

PTEN loss

PTEN loss

PTEN loss

PTEN loss

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10

Tumor Response Sarcoma Patients

QD Schedule QW Schedule

PTE

N lo

ss

PTE

N lo

ss

PTE

N lo

ss

PTE

N lo

ss

11

11

Time on Study GIST Patients

QD Schedule

QW Schedule

Median ToS 3.5 m

(1.0-9.9m)

Median ToS 1.4 (0.1-13.9)

SDH-deficient

PDGFRA mutant

Exon 9 mutant

12

12

Tumor Response GIST Patients

QD Schedule QW Schedule

13

13Conclusions: Dual PI3K/mTOR Inhibitor GDC-0980 Safety and Tolerability

– Generally well tolerated with manageable toxicities on QD and QW schedule

PK/PD– Favorable PK profile– Evidence of target modulation at or below recommended Phase II

doses

Activity– Prolonged disease control observed for rare sarcoma and GIST

patients Status Further evaluation in the Phase Ib (QD schedule) and other Phase II

studies (endometrial, renal cell carcinoma) ongoing. Further study in GIST and selected sarcomas needed

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14

Acknowledgements

We thank the patients who participated in the study and their families

We thank the study teams from the participating sites:Dana-Farber Cancer Institute, Boston, MA, USASarah Cannon Research Institute, Nashville, TN, USARoyal Marsden Hospital and Institute of Cancer Research, Sutton, UKThe Christie NHS Foundation Trust, Manchester, UKInstitut de Cancerologie Gustave Roussy, Villejuif, France

We thank the contributors from Genentech Inc:Biostatistics: Ru-Fang YehPharmacology: Joseph R. Ware, Gillian SmelickBiomarker: Mark Lackner, Hartmut Koeppen, Yibing Yan