ASCO Investor & Analyst Briefing June 3, 2017
Safe Harbor Statement To the extent that statements contained in this press release are not descriptions of historical facts regarding TESARO, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "anticipate," "estimate," "intend," and similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. Examples of forward-looking statements contained in this press release include, among others, statements regarding the expected timing of the approval and launch of VARUBI IV in the U.S., the expected timing of approval and commercial launch of ZEJULA in Europe, the expected timing of availability of additional TOPACIO data in the second half of 2017, our expected BLA submission and request for accelerated approval of TSR-042, our expectation to enroll more patients in our European EAP program for ZEJULA, and the design and expected timing of our various planned niraparib, TSR-042 and combination studies and other ongoing clinical trials. Forward-looking statements in this release involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the execution and completion of clinical trials, uncertainties surrounding the timing of availability of data from clinical trials, uncertainties surrounding our ongoing discussions with and potential actions by regulatory authorities, uncertainties regarding regulatory approvals, including with respect to the ultimate approval and indication for niraparib in Europe, uncertainties regarding certain expenditures, risks related to manufacturing and supply, risks related to intellectual property, and other matters that could affect our development plans, the availability or commercial potential of our drug candidates. TESARO undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forwardlooking statements, as well as risks relating to the business of the Company in general, see TESARO's Annual Report on Form 10-K for the year ended December 31, 2016 and Quarterly Report on Form 10-Q for the quarter ended March 31, 2017. 2
Agenda ZEJULA and VARUBI/Y Updates Niraparib Development Programs Immuno-Oncology Portfolio Q&A 3
ZEJULA : U.S. Launch Off to a Strong Start Over 800 new patient starts since FDA approval More than 600 unique prescribers Growing brand awareness and broad utilization across patient populations Rapid adoption by payers Source: Specialty Pharmacy and Specialty Distributor data 4
ZEJULA : Initial Demographics Indicate Broad Utilization Gynecologic Oncologists ~1/3 Medical Oncologists ~2/3 Clinic 45% Hospital 55% Prescribed by both medical and gynecologic oncologists Utilized in hospital and community settings Data indicate prescriptions for women with ovarian, fallopian tube, & peritoneal cancers 20 30 40 50 60 70 80 90 Source: Specialty Pharmacy and Specialty Distributor data Distribution of Patient Ages Other Peritoneal 10% 5% Fallopian 5% 80% Ovarian 5
ZEJULA : Strength of Clinical Data and Broad Label Support Rapid and Comprehensive Coverage Medicare Medicaid 4% 30% Other 6% 60% ZEJULA is being reimbursed per label by Commercial, Medicare and Medicaid carriers 75% of commercial-paid prescriptions have been adjudicated by the top 4 PBMs Top 4 cover ~ 200 million lives or >90% of commercially covered lives Commercial Pay 75% of Medicare Part D prescriptions have been adjudicated by top 4 Medicare Part D providers Top 4 cover ~25 million Medicare enrollees or ~60% of Part D plan beneficiaries Source: Specialty Pharmacy data 6
TESARO: Our Patient Support Program: TOGETHER with TESARO PROGRAM GOALS Patient-centric Solution-oriented A resource for patients and healthcare professionals Single point of contact Automated connectivity where feasible Focused on patient and HCP experience Solutions to Insurance Related Delays PA support Quick Start Bridge Appeal support Solutions for Uninsured and Underinsured Enhanced Coverage Support PAP Program Affordable Copays Commercial Copay Program via online portal Referrals to 501(c)3 organizations 7
TESARO: U.S. Commercial Execution Field Management ~170 Field-based Associates Full-scale Oncology Commercial & Medical Affairs Organizations Area Managers and Health Systems Managers Medical Science Liaisons Oncology Nurse Educators Sales Leadership Key Customer Account Teams Sales Training Product Marketing 8
TESARO: Global Commercial Execution Six offices to support product launches in 17 countries Team of ~100 associates London Paris Zug Madrid Rome Munich European ZEJULA approval anticipated by year-end; Early Access Program off to a strong start First product launch now underway in Germany 9
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VARUBI: Building a Brand Franchise in CINV Volume 3,370 3,179 2,786 1,515 1,391 NOT YET AVAILABLE January February March April May June Solid growth of VARUBI Oral indicates clinician acceptance of the product profile IV formulation of VARUBI will enable reach into largest CINV market segment (90%) VARUBI IV PDUFA date is October 25 Source: IMS and Specialty Pharmacy data 11
TESARO: A Balanced Portfolio of Product Candidates Compound Therapeutic Area Discovery Pre-clinical Ph 1 Ph 2 Ph 3 Registration VARUBI IV (rolapitant) Niraparib PARP Inhibitor Niraparib + anti-pd-1 mab Niraparib + bevacizumab Niraparib + anti-pd-1 mab Niraparib + anti-pd-1 mab Niraparib + bevacizumab Niraparib + anti-pd-1 mab Niraparib + pembrolizumab TSR-042 Anti-PD-1 mab TSR-022 Anti-TIM-3 mab TSR-033 Anti-LAG-3 mab Anti-LAG-3/PD-1 bi-specific mab Undisclosed small molecule I-O candidates Chemotherapy-Induced Nausea & Vomiting (CINV) Recurrent Ovarian Cancer (NOVA)* 1L Ovarian Cancer (PRIMA) Ovarian Cancer Treatment (QUADRA) 1L Ovarian Cancer (OvCa 3000-03-003) First Recurrence (OvCa 3000-03-002) Advanced Triple Negative Breast Cancer (TNBC 3000-03-004) Advanced NSCLC with high PDL-1 (Lung 3000-03-01) Ovarian Cancer (AVANOVA)* Advanced NSCLC, Advanced squamous cell carcinoma of the lung (Lung 3000-02-01) Ovarian Cancer/Triple-negative Breast Cancer (TOPACIO) MSI-H Tumors, including metastatic Endometrial Cancer Various tumor types Various tumor types Various tumor types Various tumor types Registrational trial To be initiated To be initiated To be initiated To be initiated To be initiated Registrational trial PDUFA 10/25/17 FDA EMA *In collaboration with ENGOT, the European Network for Gynaecological Oncological Trial groups FDA: Food and Drug Administration; EMA: European Medicines Agency; PARP: Poly ADP-ribose Polymerase; mab: monoclonal antibody 12
Mary Lynne Hedley, Ph.D. President & COO
ZEJULA : Now Available in the US and Coming Soon to the EU-17 1 Highly selective PARP 1/2 inhibitor; once per day, oral dosing 2 3 Unsurpassed efficacy in patients with BRCA mutations; unprecedented activity in patients without BRCA mutations FDA Approved; Patients with ovarian, fallopian tube, and peritoneal cancer in response to platinum based therapy. No biomarker test required 4 MAA under review, EU organization preparing for launch 5 6 Ongoing and planned trials to establish market leader position in 1 st line and recurrent OC representing a $4.0Bn opportunity globally Franchise expansion plan in place to expand in solid tumor markets representing a $4.5Bn opportunity globally 7 IP: Composition of Matter through 2030 AE: Adverse Event; N&V: Nausea & Vomiting; NDA: New Drug Application; MAA: Marketing Authorisation Application. 14
A Robust Differentiation Platform to Position ZEJULA as a Unique PARP Inhibitor Biochemical/ Pharmacologic Properties Pre-clinical Evidence High Bioavailability High Permeability Stronger Tumor Regression than with Olaparib in Platinum-sensitive PDX Model Long Half-life Large Volume of Distribution Anti-tumor Effect Following Tumor Growth on Olaparib ZEJULA is concentrated in the tumor relative to plasma, delivering selective, greater than 90%, durable PARP inhibition, and a persistent anti-tumor effect Pre-clinical data demonstrates unique activity of ZEJULA 15
Expanding the Impact of ZEJULA Combination Approaches to Grow the Value of Niraparib 16
Potential Mechanisms by which Niraparib may Enhance Anti-PD-1 Therapy Anti-PD-1 Therapy Approved Indications chl CRC- MSI-H Melanoma NSCLC Renal HNC Bladder Gastric HCC SCLC Ovarian Breast PD1/L1 Mono ORR Range 65 70% 25 57% 30 40% 20 30% 25% 13 18% 16 30% 15 22% 19% 13% 11 15% 10 18% Immunologically COLD Tumor PARP Inhibition PARP/DNA complexes produce cydna, and cell death Immunologically HOT Tumor STING mediated immune activation Absence or limited tumor infiltrating lymphocytes Infiltration of Activated T cells Presence of tumor infiltrating lymphocytes 17
Niraparib Induces DNA Damage Niraparib Induced DNA Damage DNA Damage Activates DDR Signature Endogenous (Loss of DNA Repair) Loss of FA or BRCA genes Loss of Checkpoint genes, inhibition of DNA- PK1, CHK1 Mismatch repair deficiency Exogenous DNA Damage S Phase specific: Cisplatin, Mitomycin, Etoposide Thymidine block Double DNA strands breaks: Bleomycin, Radiation DNA repair inhibitors (PARPi) 18
STING Activation Increases HOT Tumor Phenotype STING Immune Activation Pathway Increased chemokine expression Increased lymphocyte infiltration Increased PDL-1 expression DDRD positive tumors have heavy lymphocyte infiltrate PDL1+ tumors are DDR positive 19
Niraparib Mediated Increase in Tumor Infiltrating CD8 + T Cells B6-ApcMin/J immunocompetent Breast BRCA wt model CD8 Vehicle CD8 Niraparib Veh PD-1 Nira Combo Veh PD-1 Nira Combo CD8 Syngeneic Immunocompetent model: C57BL/6J-ApcMin/J heterozygous carries a mutation on Apc resulting an early stop codon. Report MSK6005 20
Niraparib Treatment Prevents Growth of Tumors on Re-challenge Indicative of Immune Memory Niraparib + anti-pd-1 Allogenic BRKras-luc, BRCA1null 1,2 All niraparib and anti-pd-1 treated mice achieved a complete response Upon re-challenge, mice treated with niraparib monotherapy or combination therapy with anti- PD-1 rejected tumors Supportive of a hypothesis that niraparib triggers a memory immune response against tumor Rechallenge Study EO322-I1509 21
Niraparib Combination with Anti-PD-1 Increases Complete Regressions in MC38 Colorectal Cancer model Isotype Control (0.5 mg/kg) + Vehicle Anti-PD-1 (0.5 mg/kg) + Vehicle Tumor Volume (mm 3 ) 1500 1000 500 0 2/10 animals tumor free 1 3 7 10 14 17 21 24 27 31 35 38 42 45 48 1500 1000 500 0 3/10 animals tumor free 1 3 7 10 14 17 21 24 27 31 35 38 42 45 48 Isotype Control (0.5 mg/kg) + Niraparib (50 mg/kg) Anti-PD-1 (0.5 mg/kg) + Niraparib (50 mg/kg) Tumor Volume (mm 3 ) 1500 1000 500 0 1 3 7 10 14 17 21 24 27 31 35 38 42 45 48 0/10 animals tumor free 1500 1000 500 0 1 3 7 10 14 17 21 24 27 31 35 38 42 45 48 6/10 animals tumor free Days Post Randomization Days Post Randomization MC38 CRC Syngeneic Mouse Model/10 animals/group. Treatment began when tumors reach an average size of 50-100 mm³/ Anti-PD-1/isotype control dosed ip. Days 1, 4, 8, 14. Niraparib/vehicle dosed po. qd. 22
Niraparib: Nonclinical Summary Niraparib is Concentrated in the Tumor, Delivering Selective, >90% Durable PARP Inhibition, and a Persistent Anti-tumor Effect Niraparib: Has favorable physiochemical/pk properties; wide distribution to tumor Induces persistent PARP/DNA complexes Induces accumulation of DNA damage Produces PARP dependent effective killing of tumor cells regardless of BRCA mutations Increases infiltration of CD8+ T cells into tumor environment In combination with IO agents, increases anti-tumor activity resulting in enhanced tumor regression 23
ZEJULA (niraparib) Ovarian Cancer Strategy 24
TESARO s Plan to Establish Leadership in Ovarian Cancer 1L Ovarian Cancer Therapeutic Area Discovery Pre-clinical Ph 1 Ph 2 Ph 3 Registration Approved PRIMA (Maintenance Treatment post response to platinum) OvCa 3000-03-003 (Niraparib + PD1 maintenance Treatment) P2 Single arm (Niraparib + bevacizumab) Recurrent Ovarian Cancer Platinum Resistant Ovarian Cancer NOVA (Maintenance Treatment post response to platinum) OvCa 3000-03-002 First Recurrence (Niraparib + bevacizumab) QUADRA (Treatment at recurrence) AVANOVA 1 (Niraparib + bevacizumab) TOPACIO (Niraparib + KEYTRUDA (pembrolizumab) OPAL Exploratory doublets and triplets REGISTRATIONAL Phase 2 To be initiated in next 6 9 months 1. In collaboration with ENGOT, the European Network for Gynaecological Oncological Trial groups. 25
Recurrent Ovarian Cancer: Maintenance Treatment Study Designs NOVA Analyses Non - g BRCA mut 3 1 2 g BRCA mut HRDpos HRDneg ARIEL3 Analyses All - comers 3 2 1 t BRCA mut LOHpos LOHneg 2 Cohorts: gbrca mutant and nongbrcamutant Separate analysis for cohorts Primary efficacy analysis of HRDpos Pooled patient population Nested step down analysis BRCA mutant population represents >30-100% of the efficacy population for each analysis 26
NOVA: Unsurpassed and Unprecedented Efficacy Progression free Survival (%) Niraparib is the only PARP inhibitor to show clinically meaningful benefit in patients with and without BRCA mutations 100 75 50 25 gbrcamut Niraparib Placebo Progression free Survival (%) 100 75 50 25 Non-gBRCAmut Niraparib Placebo 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time Since Randomization (months) 74% reduction in the risk of disease progression or death versus placebo HR = 0.26 (95% CI, 0.17-0.41; p=<0.0001) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time Since Randomization (months) 55% reduction in the risk of disease progression or death versus placebo HR = 0.45 (95% CI, 0.34-0.61; p=<0.0001) Probability of patients remaining progression free at ~24 mths post initiation of chemotherapy: 50% for niraparib vs 16% for placebo PFS=progression-free survival; CI=confidence interval. Mirza MR et al. N Engl J Med. 2016;375:2154-2164. Probability of patients remaining progression free at ~24 mths post initiation of chemotherapy: 30% for niraparib vs 12% for placebo 27
NOVA: Summary of Adverse Events Event % (n) Grade 3/4 Events 1 (N=367) % Incidence Grade 3/4 Events That Occurred After Month 2 2 Any Grade Treatment Discontinuations (N=367) 1,2, 3 Thrombocytopenia a 29% 1% 3% Anemia b 25% 10% 1% Neutropenia c 20% 8.8% at Month 3, <1% afterwards Fatigue d 8% 1.5% 3% Hypertension 9% -- <1% Nausea 3% <1% 2% Vomiting 2% <1% <1% 2% 100 Incidence of Grades 3 or 4 Thrombocytopenia 100 Prevalence of Grades 3 or 4 Thrombocytopenia Percent of Patients 75 50 25 0 27.5 4.7 0 0 1.2 0 0.3 0 0 0 Month 1 Month 2 Month 3 Month 4 Month 5 Percent of Patients 75 50 25 0 27.5 22.3 5.8 0 0 0 1.3 0 0.7 0 Month 1 Month 2 Month 3 Month 4 Month 5 a Data contained in ZEJULA 1. Prescribing Information; 2. Data on file at TESARO; 3. Data presented at SGO 2017. 28
ZEJULA : Now Approved by the U.S. FDA Indications and Usage ZEJULA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. 29
ZEJULA Franchise Expansion 30
Potential Future OC Treatment Landscape (2018 2020): Expand into First Line Diagnosis 1L* W&W Platinum Doublet Olaparib (BRCAmut +/- bev) Niraparib Platinum Doublet + Bevacizumab* Bevacizumab Platinum Response and Duration of Response >6 mos No response or response duration of <6 mos 2L* W&W Platinum Doublet Niraparib Olaparib (gbrca Only) Rucaparib Platinum Doublet + Bevacizumab Bevacizumab Single agent chemotherapy Platinum Response and Duration of Response >6 mos No response or response duration of <6 mos 3L Platinum Doublet Olaparib (gbrca Only) Platinum Doublet + Bev W&W Niraparib Rucaparib Bevacizumab Rucaparib (tbrca Only) Olaparib (gbrca Only) Single agent chemotherapy 4L Non-platinum Singlet Rucaparib (tbrca Only) Olaparib (gbrca Only) Niraparib *Other cytotoxics and vaccines are in development across first and second line treatment. Rucaparib is supporting an IST for 1st line maintenance Olaparib and rucaparib are in multiple trials in phase 2 in combination with PD1, PDL1 or anti-ctla or triple combinations of PARP + PD1 + CTLA4. 31
PRIMA: Registration Trial of Niraparib for First Line Ovarian Cancer Ovarian Cancer with high risk for progression, Stage 3 or 4 (N=330) CR or PR following platinum based chemotherapy Stratify on HRD (mychoice) Niraparib 300 mg Daily Treatment Placebo 300 mg Daily Treatment Endpoint assessment Primary Endpoint Hierarchical Testing for PFS (radiologic, central review) PFS in HRDpos population (HR 0.5) PFS in ITT population (HR 0.65) Key Secondary Endpoints OS PFS2 PRO (FOSI, European Quality of Life scale-5-dimensions, Neuropathy questionnaire) Safety & Tolerability Time to CA-125 progression 32
PRIMA: A Winning Strategy Observations from trials of approved agents inform strategy Activity of efficacious agents is maintained moving from recurrent to first line (carboplatin/taxane and bevacizumab) Benefit in recurrent setting for bevacizumab was similar to that observed in first line Optimize for success Clinical enrichment for niraparib sensitive patients: include platinum responsive patients Exclude patients with microscopic only disease (very slow to progress) Conservative power assumptions relative to results observed in NOVA Bevacizumab Trials First line Recurrent Resistant GOG218*** 14.7 v 10.6m; HR 0.7 ICON7 Stage IV: 13.5 v 10.1; HR 0.74 Stage III** 10.1 v 16.9; HR 0.67 GOG 213 13.8 v 10.4m; HR 0.61 Oceans: 12.4 v 8.4m; HR 0.46 Aurelia 6.8 v 3.4m; HR 0.38 Stage III* 17.1 v 19.3; HR 0.89 Bevacizumab USPI and SmPC GOG218: *** included 20% of patients Stage I or IIA ICON 7: * Stage III optimally debulked vs ** Stage 33 III not optimally debulked Bookman JCO 2009
Establish Leadership in First-Line Ovarian Cancer Phase 3 Study with Niraparib + anti-pd-1 chemotherapy Tx CR, PR and SD NIR + IV placebo 1 st Line, OvCa chemotherapy Tx + anti-pd-1 CR, PR and SD NIR+anti-PD-1 Bevacizumab Combinations Phase 2 for continual data generation and landmark analyses 1 st Line, OvCa Chemotherapy CR, PR and SD NIR+bev + bev 34
Potential Future OC Treatment Landscape Based on Ongoing Studies (2018-2020): Expand in Recurrent OC Diagnosis 1L* W&W Platinum Doublet Olaparib (BRCAmut +/- bev) Niraparib Platinum Doublet + Bevacizumab* Bevacizumab Platinum Response and Duration of Response >6 mos No response or response duration of <6 mos 2L* W&W Platinum Doublet Niraparib Olaparib (gbrca Only) Rucaparib Niraparib + Bevacizumab Platinum Doublet + Bevacizumab Niraparib + PD1 Single agent chemotherapy Platinum Response and Duration of Response >6 mos No response or response duration of <6 mos 3L Platinum Doublet Olaparib (gbrca Only) Platinum Doublet + Bev W&W Niraparib Rucaparib Bevacizumab Rucaparib (tbrca Only) Olaparib (gbrca Only) Single agent chemotherapy 4L Non-platinum Singlet Rucaparib (tbrca Only) Olaparib (gbrca Only) Niraparib *Other cytotoxics and vaccines are in development across first and second line treatment. Rucaparib is supporting an IST for 1st line maintenance Olaparib and rucaparib are in multiple trials in phase 2 in combination with PD1, PDL1 or anti-ctla or triple combinations of PARP + PD1 + CTLA4. 35
AVANOVA: Niraparib Combination with Bevacizumab Recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer w/high-grade serous/endometrioid histology Phase 2, N=94 Stratify on HRD and PFI (>6-12 months or 12+ months) Objectives Phase 1/2 AVANOVA Trial Niraparib + Bevacizumab Niraparib + Bevacizumab Phase 1, N = 12 Niraparib Phase 1: Safety and tolerability of bevacizumabniraparib combination Phase 2: Progression-Free Survival (PFS) in Niraparib vs. niraparib + bevacizumab Potentially synergistic activity via simultaneous inhibition of anti-angiogenesis and DNA repair Goal to improve PFS with bevacizumab or niraparib monotherapy Supported by VEGFi + PARPi exploratory work (Avastin and others) Promising initial combination activity observed in AVANOVA Safety/tolerability established in Phase 1 4 HRD+ (3 BRCA mut ) (75% CR/PR + 1 SD) 5/12 (42%) ORR Median duration of treatment in all patients 41.7weeks (91% of patients without progression; ASCO 2016) Phase 2 is ongoing 80% power for HR 0.57 (8 vs. 14 months) Update at upcoming medical meeting Initial data presented at ASCO 2016, abstract 5555. AVANOVA is an Investigator Sponsored Trial (IST). 36
QUADRA: Registration Trial of Niraparib for Treatment of Ovarian Cancer QUADRA Treatment Trial Recurrent Ovarian Cancer Received 3 or More Lines of Chemotherapy Niraparib 300 mg Daily Treatment Endpoint Assessment Primary Endpoint Overall Response Rate (ORR) and DOR HRDpos, HRDneg, BRCAmut 37
Historical Response Rates to PARPi and anti-pd-1 Antibodies Platinum resistant OC TNBC PARP inhibitor BRCAmut Parp inhibitor BRCAwt Pembro Nivolumab Olaparib + durvalumab 25-30% 1 Niraparib:16% Others: <5% 1 11.5% 2 15% 2 PFS 3.5m 0 4 0 4 5-18.5% 5 Median PFS:1.9m 20% 3 Aurelia 6 (patients with no more than 2 prior chemotherapies) CT v CT+ bevacizumab: Median PFS 3.4 v 6.7 months 1. Konecny, SGO 2017, Matulonis, Annal Onc 2016, Gelmon et al Lancet Onc 201; Rucbraca package insert. Sandhu et al Lancet Onc 2013 2. ASCO 2015 (n=26 for pembro) ; JCO 2015 33.4015; n=20 evaluable ptt, median 4 prior therapies, plat resist = DOR<6m to last platinum; 80% PDL1+ 3. Lee et al JCO 2017 4. Gelmon, Lancet Onc 2011, 12.852 5. JCO 2016 34.2460; Keynote 12, 27 evaluable pts, all= PDL1 >1%; med prior therapies =2, TNBC= 60% PDL1+; ASCO 2017 6. US package insert 38
TOPACIO: Niraparib Combination with Anti-PD-1 mab Phase 1/2 TOPACIO Trial niraparib + pembrolizumab Triple-negative breast cancer (TNBC) and Recurrent, Platinum-Resistant Ovarian Cancer Eligibility: Ovarian Cancer, platinum resistant, <5 previous lines therapy or TNBC, treated with 4 prior lines of chemotherapy Dose escalation phase evaluable pts: 8 OC and 5 TNBC Phase 1 Cohorts: OC and TNBC; 48 Patients each DL2: 6 patients N: 300 mg d1-21 P: 200 mg d1 DL1: 6 patients N: 200 mg d1-21 P: 200 mg d1 Phase 2 Study: 42 Ovarian Pts 48 TNBC pts Objectives Phase 1: Evaluate DLTs and establish Phase 2 dose Phase 2: Response rate by RECIST Exploratory biomarker work planned 39
TOPACIO: Niraparib Combination with Anti-PD-1 mab Eligibility: Ovarian Cancer, platinum resistant, <5 previous lines therapy or TNBC, treated with 4 prior lines of chemotherapy Dose escalation phase evaluable pts: 8 OC and 5 TNBC OC: 4 PR/CR + 4 SD (100% DCR) TNBC: 1 of 5 with SD (>10m) Best Response OvCa (N=8) Time on Study (Cycle) BRCA status PR 13+ BRCA1 mut CR 11+ WT PR 9 BRCA2 mut PR 8 WT SD 6 WT SD 6 WT SD 5 Unknown SD 3 WT 40
Expansion into NSCLC 41
Niraparib in NSCLC: A Staged Approach Mitigate Risk and Build Opportunity to Address Larger Population Rationale NSCLC Phase 2 Study Niraparib is effective in platinum responsive ovarian cancer (OC); lung cancer is a platinum responsive disease Like OC, lung cancer has high rate of HRD and other mutations that infer platinum and PARPi sensitivity 1 Niraparib demonstrated activity in preclinical lung cancer models and 2 of 2 NSCLC patients in Phase 1 had clinical benefit, even at low dose of niraparib (40mg, 316d; 110mg 175d) 2 Niraparib demonstrated positive effect on immune system and combination activity with anti-pd-1 in non-clinical models shows activity TOPACIO data indicative of positive clinical benefit from combination Supportive of 1L NSCLC + anti-pd-1 mab Phase 3 Study NSCLC Niraparib + anti-pd-1 mab (1L) (PD-L1 >50%) NSCLC Niraparib + anti-pd-1 mab (1L) (PD-L1 1-49%) SqNSCLC Niraparib (2/3L) (Post Plat/Post PD-1) Mutation Frequency ERCC1 low NSCLC Further Sensitized to Niraparib TCGA HRD by Marquand et al Phase 2 > Phase 3 Low BRCA1/2 a 69% Low ERCC1 b 50% ATM loss c 40% PTEN loss d 20-30% Low MSH2 b 18-38% FA methylation 14% Provides supportive data; informs Phase 3 design 2 cohorts based on PDL-1 expression 1 cohort sqnsclc due to high frequency of DNA repair mutations Utilize same trial sites for Phase 2 and Phase 3 1. Marquard et al, Postel-Vinay Nature Rev Clin Onc 9:144 2012; Postel-Vinay Oncogene 2013 1-11, Lee et al Clin Can Res 13:832; 2. Sandhu et al Lancet Onc 2013; a. Clin Cancer Res 2007 13.832; b. Nat Rev Clin Onc 9:144 2012, c, oncotarget 2016 Villaruz et al, d, Rehman et al Nat Rev Clin Onc 7:718 2010, e, Oncogene 23:1000 2004. 42
Phase 3 1 st Line NSCLC: anti-pd-1 +/- Niraparib Trial Design Primary Endpoint: Progression Free Survival (PFS) Secondary Endpoints: ORR (Overall response rate), Duration of Response (DOR), Disease Control Rate (DCR), Overall Survival (OS), PFS2, PRO Target Population: Patients with metastatic NSCLC with no EGFR, ROS, or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC Anti-PD-1 plus Niraparib Metastatic NSCLC No prior systemic chemotherapy Screening (28 days) Randomized 1:1 N=500 OS Follow-up Anti-PD-1 plus Placebo Futility 1/3 PFS events LPI Final Analysis PFS events 43
Immuno-Oncology 44
Advancing the I-O Pipeline Current Status Compound Indication Preclinical Ph 1 Ph 2 Ph 3 TSR-042 Anti-PD-1 mab Various tumor types Registration strategy initiated TSR-022 Anti-TIM-3 mab TSR-033 Anti-LAG-3 mab Various tumor types Various tumor types Enrolling last dose level (10.0 mg/kg) Initiated anti-pd-1 combination IND cleared Anti-LAG-3/PD-1 dual reactive mab Various tumor types Lead candidate identified Undisclosed small molecules Various tumor types Lead candidate identified 45
TSR-042 (anti-pd-1 antibody) 46
Role of PD-1 Signaling in T Cell Exhaustion Several proposed mechanisms by which PD1 expression suppresses T- cell function Antigen-Bearing Cell (APC Tumor Cell) A. Recruitment of phosphatases to block TCR signaling B. Modulate PI3K/mTor signaling regulating survival C. Reduced Ras signaling, regulating proliferation D. Induce BATF* that negatively regulates transcription of effector genes (cytokines, granzyme) E. Altered T-cell motility *BATF prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved Staron et al., Immunity, 2014; Yokusuda et al., J. Exp. Med., 2012; Chemnitz et al., J. Immunol., 2004; Patsoukis et al., Sci. Signal, 2012; Quigley et al., Nat. Med., 2010; Honda et al., Immunity, 2014; Zinselmeyer et al., J. Exp. Med., 2013 47
Phase 1 TSR-042 (Anti-PD-1): Expansion Initiated to Support Registration Part 1: DLT Based Dose Escalation (All Comers): 21 Enrolled Part 2a: Fixed Dose Safety Cohort: 12 Enrolled Expansion Cohorts (Part 2b) N~65 Registrational Intent (AA Strategy) Endometrial Cancer (MSI H**) <1/3 DLT 1mg/kg 6 enrolled <1/3 DLT 3mg/kg* 3 enrolled 10mg/kg 12 enrolled Part 2a Fixed dose safety cohorts (all comers) 500 mg Q3W 1000 mg Q6W N=12 DLT period complete; Dose/Schedule selected Endometrial Cancer (MSS) Other MSI-H & NSCLC Anti-PD-1 antibody Phase 1 data Nivolumab (JCO 2010) n=39 ORR 8%: 1 CR (CRC); 2 PRs (RCC, Melanoma) First endometrial patient in cohort expansions dosed April 2017 Pembrolizumab (CCR 2015) n=32 ORR 16%: 2 CR (merkel, melanoma); 3 PRs (melanoma) *Expansion to be initiated after confirmation of PK and safety of the fixed doses. **Current accelerated approval opportunity. 48
TSR-042 (Anti-PD-1): Dose Escalation Summary Phase 1 Dose Escalation (n=21) Complete through 10 mg/kg Q2W, no DLTs 2 PR: ovarian cancer (3mg/kg ), SCLC (10 mg/kg) 5 SDs: parotid gland carcinoma(1mg/kg), anal cancer (1mg/kg), fallopian tube cancer (3mg/kg), 2 ovarian cancer (10mg/kg), duration of 4-11 months Safety Most of AEs were grade 1-2 and frequently observed AEs include fatigue, nausea, decreased appetite, and dehydration. TESAEs (17) from Part 1 and one event: Grade 3 AST/ALT elevation was assessed as related. Observed safety data reflects the population of heavily pretreated advanced solid tumors and is comparable to the safety profile of approved anti PD-1 antibodies. 49
TSR-022 (anti-tim-3 antibody) 50
Loss of T Cell Function Associated with Progressive Expression of Checkpoint Molecules Elimination of antigen CTL IFNγ IL-2 TNFα Poly-functional memory cell PD-1 Tim-3 PD-1 LAG-3 Tim-3 PD-1 CTL Prolife ration IFNγ IL-2 TNFα IFNγ Exhausted Naïve CD8 T cell Persistent stimulation + inflammation Progressive acquisition of checkpoints associated with reduced functionality PD-1 is One of Several Checkpoints Associated with Exhausted T-cells with e.g., Reduced Proliferative and Cytokine Releasing Capacity Wherry, Nat Immunol. 2011; Wherry et al., Immunity, 2007; Blackburn et al., Nat Immunol., 2009; Paley et al., Science, 2012. 51
TIM-3 is a Key Immune Checkpoint and a Next Generation Cancer Immunotherapy Target TIM-3 biology Has Been Implicated in T Cell Exhaustion AND Immune Suppression Mediated by Regulatory T Cells and Myeloid Cells CD4/8+ T Cell Exhaustion Myeloid Cells TIM-3 is expressed on macrophages and can also influence MDSC activity in TME* Dendritic Cells Regulatory T Cells T-cell TIM-3 negatively regulates T cell activation and is a marker of exhausted T cells TIM-3 is expressed on regulatory T cells and promotes survival and suppressive activity TIM-3 is expressed on tumor associated dendritic cells and may negatively regulate DC activation *TME = tumor microenvironment. Adapted from Anderson, A. Cancer Immunology Research. 2014. 52
TIM-3 is Induced Concomitantly with Emergence of Resistance to anti-pd1 in NSCLC Model Treatment with anti-tim-3 monotherapy after the emergence of resistance restores T-cell activation and increases survival PD-1 resistance is associated with increased TIM-3 expression Akbay et. Al. (DFCI), EORTC 2015 53
Human Cancer is Characterized by Fully Exhausted T-cell Infiltrates with High Levels of TIM-3 CD8+ %CD45+CD3+CD8+ PD-1+ PD-1+, TIM-3+ PD-1+, LAG-3+ PD-1+, TIM-3+, LAG-3+ CD4+ %CD45+CD3+CD4+ 54
TSR-022: Enhances the Activity of Anti-PD-1 Combination Treatment Enhances T Cell response Combination Treatment Reduces M2 immunosuppressive macrophages IL-2 Concentration (pg/ml) 3000 2000 1000 +20 ng/ml anti-pd-1 +2 ng/ml anti-pd-1 0 0.001 0.01 0.1 1 10 100 [Antibody] (µg/ml) Lead antibody Isotype control TSR042 TSR-022 TSR-033 TSR-042+ TSR-022 TSR-042+ TSR-033 TSR-042+ TSR-022+ TSR-033 *p 0.05; **p 0.01 Student s T-test 55
TSR-022: Phase 1 Dose Escalation as Monotherapy and in Combination Setting Dose Escalation: Monotherapy Starting dose: 0.03 mg/kg 4 week DLT period Dose Escalation Combination (TSR-042) Starting at RP2D of TSR-022 Flat dosing for TSR022 + TSR-042 <1/3 DLT <1/3 DLT DL2: 0.1mg/kg n=3+3 <1/3 DLT DL3: 0.3mg/kg n=3+3 <1/3 DLT DL4: 1.0 mg/kg n=3+3 <1/3 DLT DL5: 3.0 mg/kg n=3+3 CDL1: TSR-022 + anti-pd-1 n=3+3 DL6: 10.0 mg/kg n=3+3 <1/3 DLT <1/3 DLT CDL2: TSR-022 + anti-pd-1 n=3+3 CDL3: TSR-022 + anti-pd-1 n=3+3 Part 2: Expansion Cohorts DL1: 0.03mg/kg n=3+3 56
TSR-022: Initial Registration Strategy Phase 1 Dose Escalation Mono and Combo with Anti-PD-1 Phase 1 Expansion Cohorts (Mono and Combo) Pts Post Anti-PD-1/PDL-1: Melanoma, NSCLC Pts Typically Refractory to Anti-PD 1/PDL-1 Pts naïve to Anti-PD-1: NSCLC Dose Escalation TSR-022 mono* TSR-022 + TSR-042 Accelerated Approval *Parallel testing of monotherapy and combination therapy to test the potential for anti-tim-3 to act as monotherapy and trump the PD-1 expression on T cells as well as generate additional monotherapy safety data. 57
TSR-033 (anti-lag-3 antibody) anti-pd-1 / LAG-3 58
Loss of T Cell Function Associated with Progressive Expression of Checkpoint Molecules Elimination of antigen CTL IFNγ IL-2 TNFα Poly-functional memory cell PD-1 TIM-3 PD-1 LAG-3 TIM-3 PD-1 CTL Prolife ration IFNγ IL-2 TNFα IFNγ Exhausted Naïve CD8 T cell Persistent stimulation + inflammation Progressive acquisition of checkpoints associated with reduced functionality PD-1 is One of Several Checkpoints Associated with Exhausted T-cells with e.g., Reduced Proliferative and Cytokine Releasing Capacity Wherry, Nat Immunol. 2011; Wherry et al., Immunity, 2007; Blackburn et al., Nat Immunol., 2009; Paley et al., Science, 2012. 59
Broad Utility for TSR-033 Supported by TIL Profiling and Emerging TIL Functional Data Dual LAG-3 and PD-1 Blockade Increases IFNγ Production in CD8+ TILs from Patients with Ovarian Tumors In house IHC data (Kurt Schalper, Yale collaboration) Matsuzaki et al. PNAS. 2010 60
LAG3 Expression on TILs in Human Tumors LAG-3 is Co-Expressed with PD-1 on CD8+T cells % CD45+/CD3+/CD8 cells expressing receptors 80 60 40 20 0 (N=57) 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 PD1-/LAG3+ PD1+/LAG3+ PD1+/LAG3- PD-1-lag-3+/CD8 - PD-1+lag-3+/CD8 - PD-1+lag-3-/CD8-61
Durable Tumor Regression and T cell Memory Induced by Combination Anti-LAG-3 and Anti-PD-1 PBS Anti-PD-1 Anti-LAG-3 2000 2000 2000 Tumor Volume (mm3) 1500 1000 500 0 0 5 10 15 20 25 30 35 40 45 50 55 Tumor Volume (mm3) 1500 1000 500 0 0 5 10 15 20 25 30 35 40 45 50 55 Tumor Volume (mm3) 1500 1000 500 0 0 5 10 15 20 25 30 35 40 45 50 55 Days Post Tumor Inoculation Days Post Tumor Inoculation Days Post Tumor Inoculation Anti-LAG-3 + Anti-PD-1 Tumor Volume (mm3) 400 350 300 250 200 150 100 50 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Days Post Tumor Inoculation Tumor Re-challenge Day 85 = Dosing Days. Note: Each antibody dosed at 10mg/kg on days 4, 7, 11 and 14. Similar results obtained in the MC38 model. Anti-mPD1 (RMP1-14, rat IgG2a), Nakanishi Y et al., 2004 J Immunol 172:2530. Anti-mLAG3 (C9B7W, rat IgG1), Workman CJ et al., 2002 Eur J Immunol 32:2255. 62
TSR-033 Potentiates anti-pd-1 Activity Mixed Lymphocyte Reaction TSR-033 (anti-lag-3) IL-2 Concentration (pg/ml) 3,000 2,000 1,000 0 0.01 0.1 1 10 100 [Antibody] (nm) Anti-LAG-3 alone EC 50 Values LAG-3 0.83 nm +2 ng/ml anti-pd-1 0.18 nm +20 ng/ml anti-pd-1 0.023 nm H. Toni Jun, Patricia McNeeley, Jean dasilva 63
Phase 1 Evaluation of TSR-033 (Anti-LAG-3): Dose Escalation and Expansion Part 1: DLT Based Dose Escalation (all comers) Monotherapy: Q3 2017-Q1 2018 Combination with TSR-042: Q4 2017-Q2 2018 Expansion Cohort Placeholders (Part 2) Q2 2018 <1/3 DLT 240 mg n=6 Cancer 1 Cancer 2 <1/3 DLT 80 mg n=6 240 mg TSR-033 + TSR-042 n=3-6 Cancer 3 20 mg n= 3+3 80 mg TSR-033 + TSR-042 n=3-6 Expansion cohort indications will be finalized in late Q3 to allow for a protocol amendment and seamless transition from dose escalation to expansion 64
Bispecific PD-1/LAG-3 Antibody Lead Candidate Identified for IND Enabling Studies Similar levels of T cell activation as combination of TSR-042 and TSR-033 Antibodies PD-1 LAG-3 PD-1 LAG-3 + TSR-042 TSR-033 Bispecific Candidate Macrogenics DART * Normalization allows for inter-donor averaging. Drug responses are relative. *In combination, both antibodies were used at the specified 65 concentration (ie 50nM each of 042 and 033), single treatment used at the specified concentration (ie 50nM of the bispecific or DART)
Advancing the I-O Pipeline Current Status Compound Indication Preclinical Ph 1 Ph 2 Ph 3 TSR-042 Anti-PD-1 mab Various tumor types Registration strategy initiated TSR-022 Anti-TIM-3 mab Various tumor types Enrolling last dose level (10.0 mg/kg) TSR-033 Anti-LAG-3 mab Various tumor types Initiated anti-pd-1 combination IND cleared Anti-LAG-3/PD-1 dual reactive mab Various tumor types Lead candidate identified Undisclosed small molecules Various tumor types Lead candidate identified 66
ASCO Investor & Analyst Briefing June 3, 2017