Abstract #3005

1. First-in-man Phase I study of the oral dual PI3K and mTORC1/2 inhibitor BEZ235 in patients with advanced solid tumors Howard 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

2. Disclosures 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 AG Novartis Pharma AG is the study sponsor Study investigators

3. BEZ235 inhibits the PI3K signaling pathway PI3K BKM120 BEZ235 PIP3 PTEN PDK1 Akt TORC2 Tuberin BEZ235 Rheb TORC1 S6K 4EBP1 S6

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

5. 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 Events ADA, American Diabetes Association

6. BEZ235 Phase I: Study design Single-agent dose-escalation Oral, once-daily BEZ23528-day cycle (N≥24) MTD / safety expansion arm in patients with alterations in PIK3CA/PTEN Oral, once-daily BEZ23528-day cycle Declaration of MTDa Fasted, mg/day 300 400 25 10 50 100 200 Fed, mg/day 300 400 700 1100 Combination with trastuzumab dose escalation arm in patients with HER2+ mBC with a PIK3CA activating mutation • Special safety assessments: • Fasting plasma glucose • 2-hour plasma glucose during a 75 g fasting OGTT • Hemoglobin A1C • 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 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

7. BEZ235 Phase I: Patient characteristics Cut-off date March 2, 2009

8. 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 quality bSNaPshot genotyping, exons 9 and 20 cGenomic DNA sequencing of PTEN exons 1-9, Semiquantitative IHC

9. No DLTs observed in Cycle 1 Median duration of treatment was 8 weeks No relationship observed between treatment duration and dose or administration schedule BEZ235 Phase I: Dose escalation • 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.

10. 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%

11. BEZ235 Phase I: most common AEs suspected to be related to study drug • No drug-related SAEs or treatment-related deaths • No treatment-related disturbances of glucose homeostasis, vital signs, or cardiac function

12. 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 10000 1000 BEZ235 exposure (AUC0-24 - ng.h/mL) 100 10 1 10 50 100 500 1000 Dose (mg) BEZ235 Phase I: clinical pharmacokinetics Individual AUC values Day 1 Day 8 Day 28 Partial response, Max AUC0-24 Partial response, Min AUC0-24

13. 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 50–100 mg 10–25 mg 200–400 mg 30 Number of patients = 9 Number of patients = 8 Number of patients = 28 25 20 C-peptide (ng/ml) 15 Observations at Day 1 Observations at Day 8 Observations at Day 28 10 5 0 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 Time (hours post dose)

14. BEZ235 Phase I: BEZ235 decreases tumor phospho-S6 and Ki-67 levels BEZ235 50 mg/dayCycle 1, Day 28 Baseline Tumor tissue from a patient with esophageal cancer with staining for P-S6

15. 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

16. BEZ235 Phase I: Clinical PR in a patient with ER+ HER2 normal breast cancer BL C1D28 C2D28 CT 18FDG-PET BEZ235 1100 mg/day BL, Baseline; C, Cycle; D, Day

17. BEZ235 Phase I: comparison of TTP for patients with SD for ≥4 months 720 TTP at last prior therapy 660 TTP on BEZ235 treatment according to local review A 600 540 A 480 A 420 Time (Days) 380 300 N 240 A N A A 180 120 Fast 400 mg/d Fast 400 mg/d Fed 300 mg/d Fast 50 mg/d Fed 400 mg/d Fast 25 mg/d Fed 100 mg/d Fast 400 mg/d Fast 400 mg/d Fast 50 mg/d Fast 100 mg/d 60 UNK 0 1 2 3 4 5 6 7 8 9 10 11 Patientsa aAs per data cutoff March 2009 A,Tumor PI3K pathway alteration (PIK3CA / PTEN mutation, low/null PTEN expression); N, No identifiedPI3K pathway alterations TTP, time to progression; UNK, unknown

18. 18 out of 35 evaluable patients had tumor shrinkage as per central review BEZ235 Phase I: reduction in tumor burden as per CT 50 40 Colorectal Breast Colorectal Ovarian Esophageal Breast Mesothelioma Prostate Breast Breast Breast Breast Breast Neuroendocrine Melanoma Breast Breast Lung 30 20 10 Best percent change from baseline in SLD (measurable lesions) 0 –10 –20 –30 Synovial sarcoma Breast Lung Adrenal Colorectal Esophagus Colorectal Colorectal Cholangiocarcinoma Nasopharyngeal Melanoma Colorectal Colorectal Colorectal Lung Melanoma Endometrial –40 –50

19. BEZ235 Phase I: tumor metabolic response as per 18FDG-PETa 60 40 Breast Breast Cholangiocarcinoma Mesothelioma Colorectal Lung Colorectal Breast Renal Esophageal Breast Pancreatic Breast Breast Sarcoma Breast Lung Melanoma 20 Percent change in sSUVmax Baseline – C1D28 0 –20 Colorectal Melanoma Colorectal Colorectal Colorectal Breast Colorectal Colorectal Colorectal Ovarian Colorectal Adrenal Breast Lung Endometrial Breast Lung Colorectal Breast –40 –60 • 18 out of 37 patients demonstrated a detectable decrease in tumor 18FDG-uptake as per central review aEnd of Cycle 1 C, Cycle; D, Day

20. Correlation between CT and PET responses at ≥400 mg/day BEZ235 suggests clinically active exposure levels have been achieved 1.0 0.8 0.6 0.4 0.2 0 –0.2 –0.4 –0.6 –0.8 –1.0 –1.0 –0.8 –0.6 –0.4 –0.2 0 0.2 0.4 0.6 0.8 1.0 BEZ235 Phase I: correlation between single-lesion responses by CT and PET 10–300 mg dose group 10 patients with comparable lesions 400–1100 mg dose group 8 patients with comparable lesions 1.0 y=0.1756x - 0.0563R2=0.0086 y=1.3549x + 0.0822R2=0.4474 0.8 0.6 No correlation Significant correlation 0.4 % change in sSUVmax 0.2 0 –0.2 –0.4 –0.6 –0.8 –1.0 –1.0 -0.5 0 0.5 1.0 % change in SLD

21. 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

22. 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

23. Patients and their families BEZ235 Clinical Study Team Sponsor-Novartis Acknowledgments Nevada Cancer Institute Sarah Cannon Research Institute Johanna Bendell Suzanne Jones MD Anderson Cancer Center Faye Johnson George Blumenschein Justina Price Vall d’Hebron University Hospital Francesco Atzori Gemma Sala Javier Cortes Virtual Scopics S Mahmood

24. Back-up slides

25. BEZ235 Phase I: Patient disposition *Cut-off date March 2, 2009.

26. BEZ235 Phase I: comparison of TTP for patients with SD for ≥4 months 720 PIK3CA: wild-type (WT),mutant (MUT)PTEN: high, medium, low PTEN: wild-type (WT), mutant (MUT) 660 WTMedium MUT 600 MUTLowWT 540 MUTMediumMUT 480 420 Time (Days) 380 WTHighWT 300 WT WT WTHighWT MUTLowWT WTHighMUT 240 MediumMUT Medium 180 120 Fast 400 mg/d Fast 400 mg/d Fed 300 mg/d Fed 400 mg/d Fast 50 mg/d Fast 25 mg/d Fed 100 mg/d Fast 400 mg/d Fast 400 mg/d Fast 50 mg/d Fast 100 mg/d 60 UNK 0 1 2 3 4 5 6 7 8 9 10 11 Patientsa TTP at last prior therapy TTP on BEZ235 treatment according to local review TTP, time to progression; UNK, unknown aAs per data cutoff March 2009