Andrew J. Wagner 1, Johanna C. Bendell 2, Jeffrey A. Morgan 1, James Butrynski 1, Suzanne George 1, George D. Demetri 1, Jill Fredrickson 3, Jill Spoerke 3, Doris Apt 3, Jennifer Lauchle 3, Gordon Jayson 4, Johann S. de Bono 5, Howard A. Burris 2, Jean-Charles Soria 6 1 Dana-Farber Cancer Institute, Boston, MA, USA 2 Sarah Cannon Research Institute, Nashville, TN, USA 3 Exploratory Clinical Development, Genentech Inc., South San Francisco, CA, USA 4 The Christie NHS Foundation Trust, Manchester, UK 5 Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK 6 Institut 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 IsoformIC 50 p110 α4.8 nM p110β26.8 nM p110γ13.8 nM p110δ6.7 nM mTOR Ki17.3 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:

3 3 Study Design QD Dosing Schedule Screening D1 Cycle 1: DLT Assessment (D1-35) Cycle 2 D8 D28 D36 D15 FDG- PET D22 D50 PK D64D56 Tumor Assess. Tumor Assess. PIK3CA, PTEN status FDG-PET Tumor Assessment Study Objectives: Safety, PK, PD, Anti-tumor activity Tumor TypePatients (n=115) GDC-0980 Dose - Schedule Escalation: All Tumor Types Expansion: All Tumor Types to 70 mg - QD 21d and 28d 30 mg and 40 mg - QD 28d (RP2D) Sarcoma11 2 to 40 mg - QD 21d and 28d 5 pts at RP2D GIST11 2 to 70 mg - QD 21d and 28d 4 pts at RP2D Assessments FDG- PET

4 4 Study Design QW Dosing Schedule Assessments Study Objectives: Safety, PK, PD, Anti-tumor activity D-28D29D22D15D8D1D43D36D50D57 2 x DCE-MRI Biopsy FDG-PET Tumor Assessment DCE-MRI Biopsy FDG-PET Tumor Assessment Tumor Assess. FDG-PET Screening Cycle 1: DLT AssessmentCycle 2 Tumor TypePatientsGDC-0980 Dose All Tumor Types 38 6 to 200 mg Sarcoma7 4 pts at 25 to100 mg 3 pts at 150 mg GIST6 2 pts at 6 mg 4 pts at 150 or 200 mg

5 5 Safety and Tolerability QD Schedule ScheduleDose (mg) DLTs (n) DLTs / significant SAEs 21d20/ /3- 320/7- 500/6G5 colitis (n=1) 702/8G3 Rash G4 Hyperglycemia G3 sympt. Hyperglyc. G2, G3 pneumonitis (1 each) 400/4- 28d400/14G3, G5 pneumonitis (1 each) 500/5- Dose Escalation Expansion RP2D Drug-related Grade > 3 AEs 40 mg (n=50) Stg. 1 and 2 Any AE26 (52%) Hyperglycemia9 (18%) Rash4 (8%) Diarrhea5 (10%) Fatigue2 (4%) Abnormal LFTs4 (8%) Pneumonia *^4*^ (8%) Pneumonitis ^4^ (8%) Mucosal inflammation3 (6%) Colitis0 (0%) Nausea1 (2%) Stomatitis2 (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

6 6 Safety and Tolerability QW Schedule DLT Assessment Dose (mg) DLTs (n) DLTs 60/6- 120/5- 250/3- 500/ / /11G3 Hyperglycemia* 2001/6G3 Hyperglycemia* Drug-related Grade > 3 AEs 150 mg (n=11) 200 mg (n=6) Hyperglycemia4 (36.4)6* (100%) Dysgeusia1 (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 7 PK Profile and PI3K Pathway Inhibition QD 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 plasma Best overall FDG-PET response 40 mg Cohort # # # # # # # # PR # # # # % Mean Change SUVmax

8 8 PK Profile and PI3K Pathway Inhibition QW 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-Score Pathology Score 12 mg 25 mg 50 mg pS6pPRAS40pAKT

9 9 Time on Study Sarcoma Patients QD Schedule QW Schedule PEComa Chondrosarcoma Metastatic Diffuse-Type Giant Cell Tumor (PVNS) Soft Tissue Sarcoma Extraskeletal Myxoid Chondrosarcoma Leiomyosarcoma Soft Tissue Sarcoma Leiomyosarcoma Angiosarcoma Myxofibrosarcoma Alveolar Rhabdomyosarcoma Solitary Fibrous Tumor Bone Sarcoma Synovial Sarcoma Chondrosarcoma Epithelioid Sarcoma Leiomyosarcoma Median ToS 2.6m ( m) Median ToS 2.9 m ( m) PTEN loss

10 Tumor Response Sarcoma Patients QD ScheduleQW Schedule PTEN loss

11 Time on Study GIST Patients QD Schedule QW Schedule Median ToS 3.5 m ( m) Median ToS 1.4 ( ) SDH-deficient PDGFRA mutant Exon 9 mutant

12 Tumor Response GIST Patients QD ScheduleQW Schedule

13 Conclusions: 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

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, USA  Sarah Cannon Research Institute, Nashville, TN, USA  Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK  The Christie NHS Foundation Trust, Manchester, UK  Institut de Cancerologie Gustave Roussy, Villejuif, France We thank the contributors from Genentech Inc:  Biostatistics: Ru-Fang Yeh  Pharmacology: Joseph R. Ware, Gillian Smelick  Biomarker: Mark Lackner, Hartmut Koeppen, Yibing Yan