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

Tolerability and anti-tumor activity of the PI3K/mTOR inhibitor GDC-0980 in patients with GIST and other sarcomas on two Phase I studies.

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

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  1. Tolerability and anti-tumor activity of the PI3K/mTOR inhibitor GDC-0980 in patients with GIST and other sarcomas on two Phase I studies 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, USA 2Sarah Cannon Research Institute, Nashville, TN, USA 3Exploratory Clinical Development, Genentech Inc., South San Francisco, CA, USA 4The Christie NHS Foundation Trust, Manchester, UK 5Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK 6Institut de Cancerologie Gustave Roussy, Villejuif, France

  2. GDC-0980, a Potent PI3K/mTOR Inhibitor • GDC-0980 is a potent, selective, oral inhibitor of Class I PI3 and mTOR kinases • Anti-tumor activity demonstrated in several cancer xenograft models • 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 • Wallin JJ, et al. Mol Cancer Ther. 2011; 10:2426-36

  3. Study Design QD Dosing Schedule Assessments Cycle 2 Cycle 1: DLT Assessment (D1-35) Screening D1 D8 D15 D22 D36 D28 D50 D56 D64 PIK3CA, PTEN status FDG-PET Tumor Assessment PK PK FDG- PET Tumor Assess. Tumor Assess. FDG- PET Study Objectives: Safety, PK, PD, Anti-tumor activity

  4. Study Design QW Dosing Schedule Assessments Study Objectives: Safety, PK, PD, Anti-tumor activity Screening Cycle 1: DLT Assessment Cycle 2 D-28 D1 D8 D15 D22 D29 D36 D43 D50 D57 2 x DCE-MRI Biopsy FDG-PET Tumor Assessment DCE-MRI Tumor Assessment Tumor Assess. FDG-PET Biopsy FDG-PET

  5. Safety and Tolerability QD Schedule Expansion RP2D Dose Escalation • incl. 2 pts with Pneumonocystisjiroveci Pneumonia • ^ Gr 5 AEs: Pneumonitis, Pneumonitis/Pneumonia, Pneumonocystisjiroveci 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. Safety and Tolerability QW Schedule Adverse Events DLT Assessment No Grade ≥3 AE at doses of 6 – 100 mg QW * 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. PK Profile and PI3K Pathway InhibitionQD Schedule PK Profile • 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) Best overall FDG-PET response 40 mg Cohort pAKT in platelet-rich plasma # PIK3CA mutant # # # % Mean Change SUVmax # # # # # # # PR # #

  8. PK Profile and PI3K Pathway InhibitionQW Schedule PD on Pre-Postdose Biopsies PK Profile Dose-proportional increases in AUC and Cmax, half-life of 8-15 hours Robust pathway modulation for both PI3K and mTOR downstream readouts Pathology Score Pathology Score 12 mg pS6 H-Score 25 mg 50 mg pS6 pAKT pPRAS40

  9. Time on Study Sarcoma Patients PEComa Chondrosarcoma Soft Tissue Sarcoma Median ToS 2.6m (1.0-18.1m) Soft Tissue Sarcoma Leiomyosarcoma Extraskeletal Myxoid Chondrosarcoma PTEN loss Angiosarcoma Metastatic Diffuse-Type Giant Cell Tumor (PVNS) Leiomyosarcoma PTEN loss Myxofibrosarcoma QD Schedule PTEN loss Alveolar Rhabdomyosarcoma Solitary Fibrous Tumor QW Schedule Bone Sarcoma Synovial Sarcoma Median ToS 2.9 m (1.0-11.2m) Solitary Fibrous Tumor Chondrosarcoma Epithelioid Sarcoma Leiomyosarcoma PTEN loss

  10. Tumor Response Sarcoma Patients PTEN loss PTEN loss PTEN loss PTEN loss QD Schedule QW Schedule

  11. Time on Study GIST Patients PDGFRA mutant Exon 9 mutant QD Schedule Median ToS 3.5 m (1.0-9.9m) SDH-deficient Median ToS 1.4 (0.1-13.9) QW Schedule

  12. Tumor Response GIST Patients QD Schedule QW 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 • Institutde CancerologieGustaveRoussy, Villejuif, France We thank the contributors from Genentech Inc: • Biostatistics: Ru-Fang Yeh • Pharmacology: Joseph R. Ware, Gillian Smelick • Biomarker: Mark Lackner, HartmutKoeppen, Yibing Yan

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