SUCCESSFUL IMPLEMENTATION OF A NOVEL TRIAL MODEL THE SIGNATURE PROGRAM

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1 SUCCESSFUL IMPLEMENTATION OF A NOVEL TRIAL MODEL THE SIGNATURE PROGRAM Julio A. Peguero, 1 James A. Knost, 2 Todd M. Bauer, 3 Matthew Taylor, Fadi S. Braiteh, 5 Joseph P. Eder, 6 Howard Safran, 7 Bert H. O'Neil, 8 Ajjai S. Alva, 9 Lincoln D. Nadauld, 10 Prashant Joshi, 11 Flora Miranda, 11 Rajinder Sidhu, 11 Joy Ero, 11 Eric D. Slosberg, 11 Claudia Lebedinsky, 11 Barinder Kang, 11 Sudha Parasuraman, 11 Sarina A. Piha-Paul 12 1 Oncology Consultants PA, Houston, TX; 2 Illinois Cancer Care, Peoria, IL; 3 Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; Oregon Health and Science University, Portland, OR; 5 US Oncology Research, and Comprehensive Cancer Centers of Nevada, Las Vegas, NV; 6 Yale University Cancer Center, New Haven, CT; 7 Brown University Oncology Research Group, Providence, RI; 8 Indiana University Simon Cancer Center, Indianapolis, IN; 9 University of Michigan Health System, Ann Arbor, MI; 10 Intermountain Precision Genomics, St George, UT; 11 Novartis Pharmaceuticals, East Hanover, NJ; 12 The University of Texas MD Anderson Cancer Center, Houston, TX

2 Disclosure Information Piha-Paul, Sarina Anne Research Funding: GlaxoSmithKline, Puma Biotechnology, Helix BioPharma, Biomarin, Novartis, Merck Please note: All disclosures are reported as submitted to ASCO and are always available at am.asco.org

3 Signature Program Objectives Rapidly match patients to treatments that target their tumors molecular abnormality Develop a better understanding of the underlying disease biology of the individual patient Discover the clinical potential of pipeline compounds by matching drug mechanism to molecular target in an expedited way Use findings to inform future clinical development

4 Features of the Signature Program Comprised of a series of novel, signal-finding clinical trial protocols No pre-identified clinical trial sites Molecularly driven and histology agnostic

5 Start-Up Process Patients identified via physician-directed local genetic profiling of their tumor and matched to the relevant targeted treatment protocol Brings the protocol to the patient Physician/patient activities prior to trial participation Signature trial-related activities Physician Researchexperienced US site Tissue sample Local CLIAcertified laboratory Genomic profile report Cancer patient Signature protocol package sent to site Research physician contacts Novartis Actionable mutation identified Rapid study start-up process initiated (standard contract & budget; central IRB) Expedited SIV Open study CLIA, Clinical Laboratory Improvement Amendments; IRB, institutional review board; SIV, site initiation visit.

6 Signature Protocol History Program Start March 2013 MEK162 a August 2013 n = 110 BKM120 March 2013 n = 16 TKI258 May 2013 n = 80 LGX818 a November 2013 n= 12 LDE225 November 2013 n = 10 BGJ398 June 201 n= 32 LDK378 July 201 n = 8 LEE011 b July 201 n = 71 Status as of April 2015 Q Q Q Q 2013 Q1 201 Q2 201 Q3 201 Q 201 a Binimetinib (MEK162) and encorafenib (LGX818) are owned by Array BioPharma Inc. b LEE011 was discovered by NIBR in collaboration with Astex Pharmaceuticals. Buparlisib (BKM120): pan PI3Ki Dovitinib (TKI258): RTKi Binimetinib (MEK162): RAS/RAF/MEKi Encorafenib (LGX818): BRAFi Sonidegib (LDE225): SMOi BGJ398: FGFRi Ceritinib (LDK378): ALKi Ribociclib (LEE011): CDK/6i

7 Study Design for Each Protocol Patients with advanced solid and hematologic cancers and no standard therapeutic options excluded for which existing data showed no benefit or key studies were planned/ongoing Central molecular profiling panel of > 280 cancerrelated genes performed retrospectively Tumor cohorts formed when patients of a specific tumor type were enrolled

8 Objectives for Each Study Primary: clinical benefit Endpoint: CR, PR, or SD at 16 weeks Based on local investigator assessment RECIST 1.1 or appropriate hematologic criteria Secondary: Duration of response Progression-free survival Overall survival CR, complete response; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease.

9 Bayesian Adaptive Statistical Model Allows dynamic borrowing of information across cohorts for analysis of clinical benefit with similar historical response rates pooled, thereby allowing smaller sample size for each Frequent interim analyses for each cohort assess futility ( 10 patients) or efficacy ( 15 patients) Berry DA. Mol Oncol. 2015;9(5):

10 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

11 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

12 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

13 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

14 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

15 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

16 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

17 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

18 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

19 Overview of Compounds Evaluated Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Target: Pan-Pl3K Various RTKs RAS/RAF/MEK BRAF PIK3CA mutation or amplification, PTEN mutation/loss, or PIK3R1 mutation FGFR1-3, FLT3, c-kit mutation or amplification; or PDGFRα/β, VEGFR1-2, RET, TrkA (NTRK1), or CSF-1R RAS, RAF, MEK1/MEK2, or NF1 BRAF V600E Endometrial, glioblastoma, NSCLC, prostate, breast Multiple myeloma, urothelial, AML (FLT3+), hepatocellular, endometrial, renal cell, breast cancer (metastatic), squamous NSCLC Pancreatic, biliary, colorectal, ovarian (low-grade serous), melanoma Melanoma, colorectal, primary CNS Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Target: Hedgehog FGFR ALK/ROS1 CDK/6 PTCH1 or SMO FGFR mutation, amplification, or fusion, or translocation of FGFR1- ; or ligand amplification ALK/ROS1 mutation, amplification, translocation, or rearrangement CDK/6 mutation or amplification, cyclin D1/D3 amplification, or p16 mutation/loss Basal cell, pancreatic, medulloblastoma/primary CNS, CML, ALL, AML Urothelial, cholangiocarcinoma, glioblastoma multiforme ALK-positive NSCLC ER+ breast, mantle cell lymphoma, teratoma, liposarcoma, CR prostate cancer, melanoma

Program Enrollment Broad Footprint Academic 20% Network 30% Community

(range) Patients Dosed (N = 69) Research Network 106 (30) 3.1 (1.0-.

1-3.) 165 Median start-up time across 351 sites =.9 weeks (range, 1.0-3.

site. b Average start-up time for phase 2- oncology study: 10.

20 Program Enrollment Broad Footprint Academic 20% Network 30% Community Site 50% Site Type (N = 351) a Sites, n (%) Median Weeks to Trial Start (range) Patients Dosed (N = 69) Research Network 106 (30) 3.1 (1.0-.) 17 Community Site 175 (50).9 ( ) 157 Academic 70 (20) 9.1 (2.1-3.) 165 Median start-up time across 351 sites =.9 weeks (range, weeks) b a 179 individual sites; > 1 module may have been open at a site. b Average start-up time for phase 2- oncology study: 10. months (> 1 weeks) Lamberti MJ, et al. Ther Innov Regul Sci. 2013;7(1):

21 Demographics & Baseline Characteristics a Dosed patients, n Buparlisib (BKM120) Dovitinib (TKI258) Binimetinib (MEK162) Encorafenib (LGX818) Sonidegib (LDE225) BGJ398 Ceritinib (LDK378) Ribociclib (LEE011) Total Median age, y Male, % Caucasian, % ECOG PS 0/1, % b 39/60 50/50 35/66 58/2 20/80 28/69 38/63 39/61 39/60 Median prior lines of therapy (range), n 3 (1-16) 3 (1-1) 3 (1-16) 2 (1-7) (1-10) (1-11) (1-6) 3 (1-6) 3 (1-16) a Data cutoff data: April 6, b May not equal 100% due to rounding. ECOG, Eastern Cooperative Oncology Group; PS, performance status.

22 Diverse Array of Tumor Types Most common tumor types accrued Selected rare tumor types accrued Tumor Type n (%) Colorectal 6 (10) NSCLC adeno 0 (9) Ovarian 35 (8) Sarcoma 29 (6) HNSCC 2 (5) Uterus 19 () Tumor Type n (%) Gallbladder/gallbladder ducts 13 (3) Anal 9 (2) Mesothelioma 5 (1) Vaginal (1) Germ cell tumor 3 (1) Thymus 3 (1) Penile 2 (< 1)

23 Diverse Array of Genetic Alterations Most common genetic alterations a Less frequent (< 1%) genetic alterations a Alteration n (%) RAS 78 (17) PIK3CA 76 (16) p16/cdkn2a 7 (10) PTEN mutation/loss b 30 (6) c-kit 23 (5) NF1 20 () Alteration FGFR2/3, SMO, MEK, CDK, b PDGFRβ, FGFR1, b cyclin D1 b ROS1, FGFR, PIK3R1, cyclin D3 b 3 CSF-1R, TrkA 2 FGFR3/, c CDK6, FGFR b 1 a Mutation unless otherwise specified. b Amplification. c Translocation. n a Mutation unless otherwise specified. b Additional PTEN loss by immunohistochemistry (n = 2).

24 Tumor Cohorts Formed for Analysis As of April 6, 2015, the following cohorts ( patients each) were formed: Agent Buparlisib (BKM120; n = 119) Dovitinib (TKI258; n = 52) Binimetinib (MEK162; n = 82) Encorafenib (LGX818; n = ) BGJ398 (n = 19) Ribociclib (LEE011; n = 60) Cohorts, n a Colorectal b Sarcoma b Ovarian Cervix HNSCC Anal Gallbladder Bladder Gallbladder duct GE junction Liver Skin nonmelanoma Small intestine Thyroid Unknown primary Vaginal GIST Colorectal Ovarian Adenoid cystic HNSCC KRAS NSCLC Ovarian Uterus Appendix Small intestine Sarcoma Thyroid Unknown primary Breast Bladder Thyroid Colorectal Breast Ovarian 9 6 NSCLC (adeno) HNSCC Sarcoma Uterus NSCLC (squamous) Breast Esophagus Gallbladder duct Kidney Mesothelioma Pancreas a No cohorts (defined as patients dosed) for sonidegib (LDE225) or ceritinib (LDK378). b Closed for futility.

25 Summary of Responses a Agent Tumor Type Mutation Prior Lines of Therapy, n Best Response Duration of Treatment, weeks Buparlisib (BKM120) HNSCC PIK3CA E55K and amplification 1 PR 32 Buparlisib (BKM120) Cervix PTEN loss PR 2 Dovitinib (TKI258) Ovary FGFR2 S252W 5 PR 33 Binimetinib (MEK162) AML NRAS G12D, Q61R, and E62K 1 CR 20 Binimetinib (MEK162) Thyroid NRAS Q61K 1 PR 36 Binimetinib (MEK162) Ovary KRAS G12D 5 PR 39+ a Data cutoff data: April 6, 2015; data based on local CLIA testing.

carboplatin/gemcitabine/bevacizumab, doxorubicin, topotecan, and paclitaxel) FGFR2 S252W mutation identified from metastatic

26 Exceptional Response: Ovarian Cancer With FGFR2 S252W Mutation Treated With Dovitinib 7-year-old female patient with poorly differentiated serous ovarian adenocarcinoma Previously treated with 5 lines of therapy (taxol/carboplatin, carboplatin/gemcitabine/bevacizumab, doxorubicin, topotecan, and paclitaxel) FGFR2 S252W mutation identified from metastatic lesion Dovitinib for 33 weeks resulted in PR (56% decrease in target lesion) Courtesy of Dr. Donald Richards, Tyler Cancer Center, US Oncology

Clinical Benefit: Colorectal Cancer With ALK STRN Fusion

poorly differentiated colon adenocarcinoma and peritoneal

cycles), FOLFIRI (8 cycles), and 5-FU (6 cycles) Tumor

STK11, TP53 Patient remains on treatment with ceritinib for

perumbilical node Peritoneal masses are stable in size with

27 Clinical Benefit: Colorectal Cancer With ALK STRN Fusion Treated With Ceritinib 86-year-old female patient with poorly differentiated colon adenocarcinoma and peritoneal carcinomatosis with PD after prior FOLFOX (16 total cycles), FOLFIRI (8 cycles), and 5-FU (6 cycles) Tumor genomic alterations at diagnosis: ALK STRN fusion, KRAS, STK11, TP53 Patient remains on treatment with ceritinib for 19+ weeks Regression of mass protruding through skin from perumbilical node Peritoneal masses are stable in size with resolution of enhancement 12/11/1 5/5/15 Courtesy of Dr. Howard Safran, Brown University

28 Signature Program: Summary Effectively brings the protocol to the patient using a rapid study start-up process Broad participation engaging both academic and community practices Enrolled a wide range of malignancies with multiple tumor histologies and genetic alterations Efficient method for determining activity in multiple tumor types Patient-sparing Bayesian adaptive design allows early assessment of futility or success Detection of clinical activity in rare tumors Continued expansion of the Signature program planned to include combination studies Plan to explore the Signature model in other Novartis-sponsored trials

29 Acknowledgments For assistance with this research and presentation: All the patients and clinical study staff at participating sites August Salvado, Steven Stein, Donald Berry, Theresa White, Stephanie Petrone, Ghulam Warsi, William Chang, John Benedetto, Kert Viele, Lening Zhang, Suzanne Caruso, Tina Grasso, Sebastian Szpakowski, Christopher Corless, Erica Stealey, Linda Karpiak, and Donald Richards Binimetinib (MEK162) and encorafenib (LGX818) are owned by Array BioPharma Inc. Ribociclib (LEE011) was discovered by NIBR in collaboration with Astex Pharmaceuticals. This study was funded by Novartis Pharmaceuticals Corporation

Protocol to Patient (P2P)

Protocol to Patient (P2P) Ghulam Warsi 1, Kert Viele 2, Lebedinsky Claudia 1,, Parasuraman Sudha 1, Eric Slosberg 1, Barinder Kang 1, August Salvado 1, Lening Zhang 1, Donald A. Berry 2 1 Novartis Pharmaceuticals