Pipeline: Oncology - AstraZeneca

Pipeline: OncologySusan Galbraith, Head of Innovative Medicines Oncology iMedMohammed Dar, Vice President, Oncology Clinical Development

AstraZeneca OncologyCommon visionBold ambitionRedefine cancer treatment paradigmRestore patients’ livesEliminate cancer as cause of deathBy 2020, we will be a recognisedleader in oncology, delivering 6new medicines to patients4 core disease areas4 key MoA & platformsCombinationsPersonalised healthcareSmart development crucial to leadership2 – Pipeline: Oncology

Oncology:Combine therapies to change treatment paradigmPD-L1 CTLA-4TORC1/2 FaslodexCombination therapies mayenhance efficacy by:1.5tumour volume (mm3)Tumour volume (cm3)ControlFaslodexAZD20140.5AZD2014 Faslodex0Study daystumour volume (mm3)OX40 CTLA-410Study days20 Establishing synergisticeffects Overcoming resistanceto monotherapy Improving risk / benefitprofileStudy days3 – Pipeline: Oncology Targeting complementarypathways1

Oncology:Personalised healthcare as key driverTissue-basedassaySingle-genemutation analysisCirculatingtumour aIressa / AZD9291Oncology portfolioTumour4 – Pipeline: Oncology

Oncology:Smart development crucial to leadership5 – Pipeline: OncologyAZD9291Potential filing less than 2½ years from first doseMEDI4736(PD-L1)PACIFIC studyLeapfrog competition into early line of therapyIressa / AZD9291First in ctDNA diagnostic testingMEDI4736BRAF / MEKGood combinability enables novel triplet combination

Scientific leadership:Four key platformsTumour driversand resistance Olaparib (PARP) MEDI4736 (PD-L1) Moxetumomab (CD22) Selumetinib (MEK) Cediranib (VEGF)** Tremelimumab (CTLA-4) ADC-Spirogen* AZD2014 (TORC1/2) AZD1775 (Wee1) MEDI0680 (PD-1) ADC-Bispecific* AZD4547 (FGFR) AZD6738 (ATR) MEDI6469 (murine OX40) AZD5363 (AKT) AZD0156 (ATM)* AZD6094 (cMET) AZD2811 (AKB)* MEDI6383 (OX40 FusionProtein) AZD8835 (PI3Kα) MEDI0639 (aDLL4) MEDI-573 (aIGF1/2) AZD9496 (SERD) AZD5312 (AR antisense)6 – Pipeline: OncologyImmunotherapy AZD9291 (EGFRm) AZD8186 (PI3Kβ)* Preclinical** Combination with DDRDNA damage repairAntibody drugconjugates MEDI0562 (OX40 humanisedmAb) AZD9150 (STAT3) AZD5069 (CXCR2)

Scientific leadership:Tumour drivers & resistance Highly altered signallingpathways in cancer Interconnected pathwaysallow resistance / escapemechanisms Multiple targets identified aspotential tumour drivermutationsTumour7 – Pipeline: Oncology

AZD9291:EGFR mutant selective inhibitor in lung cancerStrong evidence of monotherapy activityBest percentage change from baseline in target lesion* Potentially first irreversibleselective inhibitor of doubleEGFR mutations Awarded FDA BreakthroughTherapy Designation FSI 1st line Phase III Q42014, data expected 2017 Combinations with MEDI4736(PD-L1), MET (cMET) andselumetinib (MEK) ongoing(FSI Q3 2014)US NDA submission expected Q2 2015 in NSCLC 2L* ESMO 20148 – Pipeline: OncologyTumour driversand resistance

AZD9291:Early efficacy in 1st line EGFRm NSCLC1st line EGFRmTumour driversand resistancePreliminary evidence of activityin NSCLC brain metsA)A)A B))B)Overall disease control rate (CR PR SD) 95%Clinical activity of AZD9291 in brain mets hasbeen observed in a Phase I study in patients withacquired resistance to current EGFR-TKIs.FLAURA: Phase III NSCLC 1L EGFRm H2H vs 1st gen. TKI to start Q4 20149 – Pipeline: Oncology

AZD2014:Dual TORC1/2 inhibitorStrong evidence of activityDual TORC1/2 paclitaxel*Tumour driversand resistanceDifferentiated clinical activity Broad potential in breast, lung,ovarian cancer and lymphoma Dual TORC1/2 and intermittentweekly dosing schedule to deliverbetter efficacy and tolerability25 mg 3/750 mg 3/775 mg 3/7 Potential accelerated Phase IIIinvestment decision in 2015100 mg 2/775 mg 2/7Combination with Faslodex in ER breast cancer to be submitted forpresentation in 2015*Basu et al ESMO 201410 – Pipeline: Oncology

AZD6094:Potent, selective cMET inhibitor of MET-driven tumoursBest tumour assessment change from baseline (%)Activity in MET-drivenpapillary renal cell cancer (PRCC)Gan et al ASCO 201411 – Pipeline: Oncology Active in MET amplified and METmutant settings First-in-class opportunity in papillaryrenal cell cancer (PRCC) Phase II trial in PRCC ongoing Phase II trial in MET-amplifiedgastric and lung cancer ongoing Combination with AZD9291 in2nd line EGFR mutant lungcancer ongoingTumour driversand resistance

AZD9496:Oral selective estrogen receptor degrader (SERD)Greater tumour inhibitionthan FaslodexUndosed ControlsPEG/Captisol vehicleUndosed control vehiclesPeanut oil vehicleFaslodex 5 mg x3 weekly s.c.Tamoxifen 10 mg/kg p.o. once dailyOral SERD 5 mg/kg p.o. once daily2.0Mean Tumour Volume (cm3)1.81.61.4Tamoxifen1.21.0Faslodex0.80.6 Oral formulation Clinical development startedQ4 2014AZD94960.40.20204060Days of Dosing12 – Pipeline: Oncology Improved potency andbioavailability allows greaterestrogen receptor (ER) knockdown80100120 Pharmacological data submittedfor AACR 2015Tumour driversand resistance

DNA Damage Repair (DDR):Targeting the Achilles heel of cancer Highly altered pathwaysin cancer Traditional chemotherapiesdepend on DDR pathways Most extensive portfolio ofDDR agents in the industry13 – Pipeline: Oncology

Lynparza (olaparib):First-in-class PARP inhibitorDNA damagerepairClinical benefit in BRCAmovarian cancerProportion of patients progression-freeMedianOngoing Phase III programmesOlaparib, n 74Placebo, n 6211.2 mo4.3 moHR 0.18 95% CI (0.10, 0.31); P 0.000011.0 BRCAm ovarian cancer: SOLO-2(2015*), SOLO-1 (2016*) BRCAm breast cancer: OlympiAD(2016*)0.90.80.7 Gastric cancer: GOLD (2017*)0.60.5 BRCAm pancreatic cancer:POLO (FSI Q4 2014)0.40.30.2Olaparib BRCAm0.1Placebo BRCAm0036Months91215 Promising activity in late-stageprostate cancer (10/30 RR,ESMO 2014)EU: Positive CHMP opinionUS: PDUFA 3 January 2015*Data available14 – Pipeline: Oncology

AZD1775:Wee1 inhibitor; encouraging data in ovarian cancerWee1: Role in cell cycle progressionand DNA damage checkpoints 11/14 RECIST responsesG2/Mcheckpoint PFS 10.8 months 13/14 GCIG responses(includes CA125 responses)Wee1S phasecheckpointPlatinum-sensitive relapsedovarian cancerG1/Scheckpoint Phase II study in ovarian;Lynparza combination due tostart Q1 2015 Phase I/II trials in NSCLCPhase III ovarian cancer investment decision expected 201515 – Pipeline: OncologyDNA damagerepair

AZD2811:Aurora Kinase B inhibitor (AKBi): AML proof of conceptPhase II: AKBi vs low-dose cytarabine(LDAC) in elderly unfit AMLOverall SurvivalAKBi vs LDACOCRR ( Cheson) 30%Overall Survival (HR)0.88 (0.49-1.58)AKBi 1200mg(n 48)LDAC 400mg(n 26)Differentiated profile Novel mechanism of action:Regulates mitosis andchromosomal segregation Nanoparticle formulation indevelopment* Potential in DLBCL and AML Plan to discuss further steps withregulators early in 2015Kantarjian et al Cancer 2013;119:2611-19* In collaboration with BIND Therapeutics16 – Pipeline: OncologyDNA damagerepair

Immuno-oncology (IO):Changing the treatment paradigms for cancer An effective immuneresponse is durable possibly life-long Cancer hijacks manyimmune pathways toescape destruction Our robust pipeline allowsidentification ofcombinations that restorethe immune response17 – Pipeline: Oncology

Immuno-oncology (IO):Three major components to cancer immune response2. Optimizing T cellfunction andmemory1. 4NME-4NME-53. Inhibition bymicroenvironmentHPV 8 – Pipeline: OncologyPreclinical* Clinical collaborations

MEDI4736 (PD-L1):Triplet w/dabrafenib and trametinib in BRAFm melanomaBRAFi/MEKi treatment effectPotential for well-tolerated, durablebenefit in BRAFm melanomaIncrease in CD8 Tumour Infiltrated Lymphocytes (TILs) Clinical data for BRAFi/MEKiprovide rationale for “triplet”combinationIncrease in PD-L1 expression Potential for durable response in1L BRAFm melanoma patients Phase I “triplet” combination welltolerated at full monotherapydoses; MTD not reachedFrederick et al, 2013Presentation of Phase I “triplet” combination planned for H1 2015In collaboration with GSK19 – Pipeline: OncologyImmunotherapy

MEDI6383 (OX40):Pathway drives potent, durable anti-tumour T cell immunityMurine OX40: Phase I evidence of activityBest tumour assessment change from baseline (%)10080603 unique OX40 molecules withdistinctive biologyPD on day 56SD on day 56 Murine anti-human OX40(active in monotherapy;in combination withMEDI4736 now)40200-20-40Stimulatory activity in periphery Human OX40L fusion protein(currently in dose escalation) OX40 (FSI Q1 2015)20 – Pipeline: OncologyImmunotherapy

AZD9150:STAT3 and roles in tumour microenvironmentSTAT3 inhibition decreases immunetolerance in tumour microenvironmentNature Reviews Immunology 7, 41-51Durable responses in Phase Imonotherapy studiesA CR and PRs lasting 1year in lymphoma and liver cancer studiesPhase I oral presentation in plenary session at EORTC 19 Nov 2014STAT3 MEDI4736 Phase I study start H1 201521 – Pipeline: OncologyImmunotherapy

AZD5069:CXCR2 affects myeloid-derived suppressor cell trafficking First-in-class CXCR2antagonist in oncology Potential synergisticactivity with MEDI4736(PD-L1) Phase I combination studyof CXCR2 MEDI4736(PD-L1) expected to startin H1 201522 – Pipeline: OncologyImmunotherapy

Immuno-oncology (IO): Combinations address multiple immune pathwaysAntigen presentationPD-L1EGFRT-cell activation combined with increased tumour visibilityPD-L1MEK/BRAFT-cell activation combined with increased antigen presentationPD-L1HPV VaccineT-cell activation combined with increased primingT-cell killing and memoryCTLA-4PD-L1Increased T-cell activation through blocking multiple inhibitory pathwaysPD-1PD-L1Increased T-cell activation through complete blockade of thePD-1/PD-L1 axisPD-L1/CTLA-4OX40Increasing T cell number, function and memoryTumour microenvironmentPD-L1IDOT-cell activation combined with removal of inhibitionPD-L1CCR4T-cell activation combined with T-reg depletionPD-L1CXCR2T-cell activation combined with reduced MDSC suppressionPD-L1STAT3T-cell activation combined with myeloid reprogrammingEnables precise identification, location and relationship betweenmultiple components of tumour microenvironment23 – Pipeline: Oncology

Immuno-oncology (IO):Unique indications, novel combos, speed of execution12SpeedQuickest path to approvalMonotherapy MEDI4736(PD-L1) Late-stage NSCLC 2L head/neck (SCCHN)MEDI4736 (PD-L1) /tremelimumab combo Late-stage NSCLC 2L head/neck (SCCHN)24 – Pipeline: OncologyImmunotherapy3Differentiation Rapid program expansion Adaptive decision-making Patient selectionDifferentiated tumour typesand biomarker subsetsHigh value leapfrogindications: Stage 3 unresectable NSCLC Adjuvant NSCLCLeadershipFirst or best-in-classagentsCombinations MEDI4736 (PD-L1) tremelimumab MEDI4736 (PD-L1) AZD9291Three OX-40 antibodies Murine, humanised, fusion Monotherapy, combination

MEDI4736 (PD-L1):Monotherapy; early, durable activity in multiple tumours*ImmunotherapyTotal study population(10 mg/kg q2w)Ongoing responders92% (33/36)TotalRECIST responsePD-L1 22% (18/81)PD-L1-5% (12/233)Total10% (36/352)Disease control rate at 12 weeksTime (weeks)Treatment stopped at 52weeks* Patients with baseline and 1 on-treatment scan; disease assessment at 6 weeks, 12 weeks, 16 weeks, and then every 8 weeksData cut-off: 21 August, 201425 – Pipeline: OncologyPD-L1 47% (38/81)PD-L1-28% (64/233)Total33% (115/352)

MEDI4736 (PD-L1) tremelimumab:Encouraging efficacy for combination in ortcohort(n 18)(n 18)26 – Pipeline: OncologyImmunotherapyBest change in tumour size bydose cohort (n 18)All patientsORRStable diseaseMEDI4736 tremelimumab28% (5/18)28% (5/18)