Targeting the genetic and immunological drivers of cancer

Transcription

1 NASDAQ: MRTX Targeting the genetic and immunological drivers of cancer Corporate Presentation January

2 Safe Harbor Statement Certain statements contained in this presentation, other than statements of fact that are independently verifiable at the date hereof, are "forward-looking" statements, within the meaning of the Private Securities Litigation Reform Act of 1955, that involve significant risks and uncertainties. Forward looking statements can be identified by the use of forward looking words such as believes, expects, hopes, may, will, plan, intends, estimates, could, should, would, continue, seeks, pro forma, or anticipates, or other similar words (including their use in the negative), or by discussions of future matters such as the development of current or future product candidates, timing of potential development activities and milestones, business plans and strategies, possible changes in legislation and other statements that are not historical. Forward-looking statements are based on current expectations of management and on what management believes to be reasonable assumptions based on information currently available to them, and are subject to risks and uncertainties. Such risks and uncertainties may cause actual results to differ materially from those anticipated in the forward-looking statements. Such risks and uncertainties include without limitation potential delays in development timelines, negative clinical trial results, reliance on third parties for development efforts, changes in the competitive landscape, changes in the standard of care, as well as other risks detailed in Mirati's recent filings on Forms 10-K and 10-Q with the U.S. Securities and Exchange Commission. Except as required by law, Mirati undertakes no obligation to update any forward-looking statements to reflect new information, events or circumstances, or to reflect the occurrence of unanticipated events. 2 January 4, 2018

3 Mirati s Leadership Team Applying Proven Approaches to Oncology Development Charles M. Baum, M.D., Ph.D. CHIEF EXECUTIVE OFFICER SVP Clinical Research, Pfizer Leader of Key Oncology Programs: Ibrance, Xalkori, Sutent, Inlyta, Temodar Oncology Experience Isan Chen, M.D. CHIEF MEDICAL OFFICER CMO at Aragon Pharmaceuticals Previously VP at Pfizer with Ibrance, Xalkori, Sutent, Inlyta James Christensen, Ph.D. CHIEF SCIENTIFIC OFFICER Head of Precision Research, Oncology Research Unit, Pfizer Deep experience in precision oncology with Ibrance, Xalkori, Sutent, Inlyta Chris LeMasters CHIEF BUSINESS OFFICER CBO at Tragara Pharmaceuticals, Cabrellis, Conforma; Business Development at Eli Lilly Led successful sales of two clinical-stage oncology companies Jamie Donadio CHIEF FINANCIAL OFFICER Corporate Finance lead at Amylin Pharmaceuticals Significant capital markets transaction experience. Participated in sale to BMS for $7 Billion Mirati s leadership is supported by an operational team with deep oncology drug development expertise across all disciplines 3

4 Mirati s Development Programs Indication Preclinical Phase 1/1b Phase 2 Phase 3 Current Status NSCLC Phase 3 Expected to be Initiated 1H 2019 Immuno-oncology Sitravatinib + checkpoint inhibitor Bladder Phase 2 Initiated September 2018 Sitravatinib Oral Multi Kinase Inhibitor MOA Trials RCC, Head & Neck Mechanism of Action Trials Initiated September 2018 BeiGene Sitravatinib + Tislelizumab (anti-pd-1) NSCLC, RCC, HCC, Gastric, Ovarian, other BeiGene-led Trials Initiated November 2018 Targeted Single Agent CBL mutations NSCLC Melanoma Phase 1b Focusing on CBL in NSCLC and Melanoma KRAS Oral KRAS Inhibitors Targeted Single Agent MRTX849 G12C mutations Targeted Single Agent G12D mutations NSCLC CRC CRC, NSCLC, Pancreatic 1 st Patient Expected January 2019 Clinical Candidate Identification Underway 4 NSCLC = non-small cell lung cancer; CRC = colorectal cancer; RCC = renal cell cancer; HCC = hepatocellular cancer; IND = Investigational New Drug application; Tislelizumab (BeiGene s anti PD-1) MOA = Mechanism of Action

5 Immuno-Oncology Combinations Sitravatinib + Checkpoint Inhibitors 5 5

6 6 Sitravatinib in the Tumor Microenvironment May Restore Immune Response

7 Sitravatinib + Checkpoint Inhibitors Phase 2 Trial of Sitravatinib + Nivolumab in Checkpoint Refractory NSCLC Maximum % Change from Baseline 70% 60% 50% 40% 30% 20% 10% 0% -10% -20% -30% -40% -50% -60% -70% -80% -90% -100% * On study as of 27-Aug-18 Complete response (1 target lymph node) BEST RESPONSE 1 (Evaluable Patients, N=56) Confirmed Response Stable Disease Progressive Disease 42/56 (75%) Clinical Benefit (SD+PR+CR) 18/56 (32%) Tumor Regression >30% * 11/56 (20%) Confirmed CR/PR 7 Study cycles of 28 days, with disease assessment scans every 2 cycles 1. Data cut-off: 27-Aug-2018; presented at ESMO 2018 Congress. Response data per investigator assessment, response confirmations updated after data cut-off.

8 Sitravatinib + Checkpoint Inhibitors Phase 2 Trial of Sitravatinib + Nivolumab in Checkpoint Refractory NSCLC DURATION OF TREATMENT (Evaluable Patients, N=56) 50 * Confirmed Response Stable Disease Progressive Disease 40 Response first achieved 30 on study On study as of 27-Aug-18 Off study Complete response (1 target lymph node) 20 * Preliminary Kaplan-Meier Estimate of Median Duration of Response: 9.2 months Weeks Study cycles of 28 days, with disease assessment scans every 2 cycles 1. Data cut-off: 27-Aug-2018; presented at ESMO 2018 Congress. Response data per investigator assessment, response confirmations updated after data cut-off.

9 Clinical Practice in 1 st Line NSCLC has Changed The checkpoint refractory population is now in 2 nd line Sitravatinib + Checkpoint Inhibitors Prior Standard of Care No/Low PD-L1 High PD-L1 Stage IV Non-Squamous NSCLC Treatment Paradigm New Standard of Care No/Low PD-L1 High PD-L1 1L Platinum Doublet PD-1 1L PD-1 + Chemo PD-1 2L PD-(L)1 Platinum Doublet 2L Checkpoint Refractory Patients Platinum Doublet 3L Checkpoint Refractory Patients Docetaxel 3L 3 rd line population is diminishing Docetaxel By 2020 It is estimated that >50,000 patients in US/EU will be 2 nd line Checkpoint Refractory Kantar Health CancerMPact Treatment Architecture, Kantar Health projections. Excludes patients with addressable driver mutations

10 Sitravatinib + Checkpoint Inhibitors Phase 3 Randomized Trial in 2 nd Line NSCLC Two Opportunities for Approval in 2 nd Line NSCLC Interim Analysis: ORR, for Accelerated Approval Primary Analysis: OS, for Full Approval Preliminary Study Design Key Inclusion/Exclusion Criteria: Advanced, Non-Squamous NSCLC Checkpoint Refractory 2 nd Line NSCLC Documented Tumor Progression RANDOMIZATION 1:1 Sitravatinib + Checkpoint Inhibitor Docetaxel Primary Analysis OS N:~620 pts Progression on or following first line combination of PD-(L)1 inhibitor plus chemotherapy Excludes patients with known driver mutations Endpoints: Interim: ORR (for potential Subpart H accelerated approval) Primary: OS (for potential full approval) Secondary: PFS, duration of response, safety, tolerability Interim Analysis ORR Projected Phase 3 Timing: Study Initiation: 1H 2019 Interim ORR Analysis: Year End 2020 Primary OS Analysis: Year End

11 Sitravatinib + Checkpoint Inhibitors Docetaxel: A Favorable Efficacy Comparator in Prior 2 nd Line NSCLC Trials Advanced NSCLC 2 nd Line or Subsequent Therapy Trial Compound Pts ORR, % DOR, Mos PFS, Mos (Range) SD, % CBR, % (CR+PR+SD) OS, Mos (Range) 057 [1] Docetaxel n=290 12% ( ) 42% 54% 9.4 ( ) CheckMate Nivolumab n=292 19% ( ) 25% 44% 12.2 ( ) Checkpoint Naïve Patients Atezolizumab n=425 14% ( ) 35% 49% 13.8 ( ) Docetaxel n=425 13% ( ) 42% 55% 9.6 ( ) Not yet Pembrolizumab n=345 18% KEYNOTE reported 3.9 ( ) 10.4 ( ) 010 [3] Docetaxel n=343 9% ( ) 8.5 ( ) Checkpoint Refractory Patients MRTX-500 [4] Sitravatinib + Nivolumab n=56 20% 9.2* 6.8* 66% 75% 15.1* Borghaei H, et al. N Engl J Med. 2015;373: Rittmeyer A, et al. Lancet. 2017;389: Herbst RS, et al. Lancet. 2016;387: Mirati ESMO 2018 Congress Data presented is from separate studies and does not reflect results that might have been obtained from head-to-head studies. Results from Mirati's planned Phase 3 trial comparing sitravatinib + nivolumab to docetaxel may differ materially from prior studies presented. ORR = Overall Response Rate DOR = Duration of Response CBR = Clinical Benefit Rate (CR + PR + SD>14 weeks) * Preliminary Kaplan-Meier Estimate

12 Sitravatinib + Checkpoint Inhibitors Sitravatinib Value Creation and Expansion Strategy Mirati Development Activities 1 Advance Sitravatinib Towards Registration NSCLC Phase 3: 2 nd line checkpoint refractory Interim Analysis for Potential Accelerated Approval End of Extend Proof of Concept into Other Tumor Types Bladder Phase 2: checkpoint refractory Initial Proof of Concept Clinical Data Expected 2H Expand Mechanism of Action Data RCC Pre-surgical study HNSCC Pre-surgical study Early Mechanism of Action Data Expected 1H NSCLC = non-small cell lung cancer; RCC: renal cell cancer; HNSCC: head & neck squamous cell cancer Note: HNSCC pre-surgical mechanism of action study is investigator-sponsored

13 BeiGene / Mirati Collaboration: Expanding the Value of Sitravatinib Sitravatinib + Checkpoint Inhibitors BeiGene Development Activities Generate Additional Proof of Concept Data in New Indications and With Another PD-1 Inhibitor BeiGene-Sponsored Clinical Trials 1 (in China and Australia) NSCLC: checkpoint naïve & refractory Independent confirmation in NSCLC with another PD-1 inhibitor RCC: checkpoint naïve & refractory Ovarian: checkpoint naïve HCC: checkpoint naïve & refractory Gastric: checkpoint naïve Initial Proof of Concept Clinical Data Expected 2H 2019 Initial Proof of Concept Clinical Data Expected 1H 2020 BeiGene will Fund and Conduct Multiple I/O Combination Trials with Sitravatinib 250+ Patients Across 5 Tumor Types in Initial Proof of Concept Trials Leverages BeiGene s Considerable Clinical Development Capabilities Access to Difficult-to-Enroll Patient Populations in China Provides Further Proof of Concept with Another PD-1 Inhibitor: Tislelizumab Sitravatinib is licensed to BeiGene, Ltd. in China, Asia (less Japan, Russia and India), Australia and New Zealand NSCLC = non-small cell lung cancer; RCC: renal cell cancer; HNSCC: head & neck squamous cell cancer

14 Sitravatinib + Checkpoint Inhibitors Sitravatinib I/O Combinations Summary Positive Phase 2 Efficacy Data in Checkpoint Refractory NSCLC 1 (n=56) 42/56 (75%) demonstrated Clinical Benefit (Stable Disease, Partial Response or Complete Response) 11/56 (20%) achieved a confirmed Partial or Complete Response Preliminary Kaplan-Meier estimates Median Duration of Response: 9.2 months Median Progression Free Survival: 6.8 months Median Overall Survival: 15.1 months Registration Path: FDA Agrees to Phase 3 Design with Accelerated Approval Opportunity Phase 3 randomized trial planned to be initiated in 1H with two opportunities for approval: Interim analysis based on ORR by Year End 2020 (potential Accelerated Approval) Final analysis based on OS by Year End 2021 (for potential Full Approval) Phase 2 Clinical Trials in Expanded/Other Indications Checkpoint Refractory Bladder Cancer: Initial Phase 2 Proof of Concept data expected in 2H 2019 BeiGene-funded Phase 2 Trials: Initial Phase 2 proof of concept data expected in 2H 2019 / 1H Data presented at ESMO 2018 Congress; Data cut-off: 27-Aug-2018; Response data per investigator assessment, response confirmations updated after data cut-off.

15 Targeted Oncology Sitravatinib Single Agent: CBL Loss of Function Mutations 15 15

16 Sitravatinib: Rationale For Targeting CBL Mutations Inhibiting hyperactivated TYRO/AXL/MER, PDGFR, KIT, MET Single Agent Sitravatinib Loss of function (LOF) mutations in CBL result in increased target RTK activation in tumor cells that may act as oncogenic drivers Key CBL Targets Unique binding motifs Sitravatinib Oral Administration A549 NSCLC CDX model X Early Endosome Sorting Endosome X X X Proteasome Lysosome Late Endosome Tumor volume (mm 3 ) Time (Days) Vehicle Sitravatinib 20mg/kg QD * 16 * Adapted from B. Mohapatra et al, Biochim Biophys Acta (2013) 1833:

17 Single Agent Sitravatinib Phase 1b Trial of Single Agent Sitravatinib in Patients with CBL Mutations Summary of On-going Trial Initial Clinical Activity 1 in CBL Mutations is Encouraging 1/2 confirmed Partial Response in NSCLC 1/2 confirmed Partial Response in Melanoma (mucosal) (non-uv form which does not respond well to other treatments) Phase 1b Expansion Trial Design Patients with CBL Loss of Function Mutations Expansion Criteria (PRs) Stage 1 Stage 2 Expansion Criteria (PRs) Stage 3 Single Agent Sitravatinib Has Been Well Tolerated with Manageable Side Effects NSCLC Melanoma CBL Loss of Function Mutation (via NGS) n=8 2 PR 7 PR n=16 n=46 Single Agent Sitravatinib Program Focused on CBL in NSCLC and Melanoma Circulating tumor DNA assay (liquid biopsy) is now available to identify CBL loss of function mutations Clinical update expected in 2H 2019 to define single agent registration pathway Key Inclusion Criteria: Malignancy harboring loss of function CBL mutation Advanced metastatic or unresectable solid tumor malignancy Adequate bone marrow and organ function Key Exclusion Criteria: Symptomatic or uncontrolled brain metastases Endpoints: Safety, PK/PD Clinical Activity (ORR, DR, PFS, OS) Presented at ESMO 2018 Congress; data cut-off 4-Sep-2018

18 Targeted Oncology MRTX849: KRAS G12C Inhibitor 18 18

19 MRTX849 KRAS G12C Inhibitor KRAS: The Holy Grail of Mutated Oncogene Targets KRAS Signaling A Key Regulator of Cell Growth and Survival 1 KRAS Mutations Prevalent in the Top 3 Cancer Types 2 with High Mortality Pancreas Colorectal NSCLC 98% 45% 30% Image from Genetics Home Reference 2. Bos, Johannes L. Ras oncogenes in human cancer: a review. Cancer Res (1989):

20 MRTX849 KRAS G12C Inhibitor Mutant KRAS is an Oncogenic Tumor Driver KRAS mutations occur early in tumor genesis and do not overlap with other tumor drivers Mutational Prevalence and Overlap in 1,357 Lung Adenocarcinomas 1 Mutant KRAS signaling is required for tumor cell survival Sensitivity of Cancer Cell Lines to shrna Knockdown of KRAS 2 HER2 (44) RET Fusion (20) KRAS G13 (37) EGFR L858R (109) BRAF (65) KRAS G12 (346) EGFR Exon 19 Deletion (102) KRAS Q61 (18) MET (47) ROS1 (29) ALK Fusion (42) Sensitivity Score Wild Type KRAS Cancer Cell Lines Mutant KRAS Zehir A et al, Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6): McDonald et al, Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening, Cell 2017

21 MRTX849 KRAS G12C Inhibitor Mirati s KRAS Program: Targeting KRAS G12C Mutations KRAS G12C Can Be Inhibited Covalently KRAS G12C Codon 12 Mutation 1. KRAS G12C has a cysteine present in its inactive form Switch II pocket 3. Inhibitor covalently binds to the cysteine and the induced Switch II pocket Cysteine Single amino acid substitution at codon 12 in the KRAS protein Glycine Cysteine KRAS G12C 2. Binding to the cysteine opens an adjacent Switch II pocket KRAS G12C Inactive 4. KRAS G12C is irreversibly locked in the inactive state KRAS tumor cell death 21

22 KRAS G12C Mutations Occur Frequently in Multiple Tumor Types MRTX849 KRAS G12C Inhibitor KRAS G12C Mutation Frequency 1 G12C (14%) NSCLC adenocarcinoma Colorectal G12C (5%) G12C (5%) Endometrial Pancreatic G12C (1%) U.S Addressable Patients 2 : ~28, Campbell et al, Nature Genetics 2016 Distinct patterns of somatic genome alterations in lung adenocarcinomas ; Waters, Der et al, Cold Spring Harb Perspect Med 2018 KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer ; Krakstad et al, PLoS One 2012 High-throughput mutation profiling of primary and metastatic endometrial cancers ; MSKCC Cancer Hot Spots database; NIH TCGA: The Cancer Genome Atlas 2. Mirati estimate based upon frequency data from sources above and epidemiology data from Globocan 2022 incidence projections (accessed January 2019) ; Total includes additional histologies

23 MRTX849 KRAS G12C Inhibitor KRAS G12C Mutations are Prevalent in a Large Population of Patients No Targeted Treatments Available for Patients with KRAS G12C+ Tumors 30,000 Addressable U.S. Patient Populations 2 KRAS G12C vs. ALK, RET and TRK Significant Commercial Opportunity In NSCLC alone, KRAS G12C population is 2X the size of the ALK inhibitor population (ALK projected to be a $3B market by 2022) 1 Diagnosed by Approved Assays Both tissue and liquid biopsy tests are commercially available Testing common in NSCLC and CRC U.S. Patient Population 25,000 20,000 15,000 10,000 5,000 0 KRAS G12C ALK RET TRK NSCLC CRC Other Major-market commercial sales projection (2020) for ALK inhibitors in NSCLC (Decision Resources NSCLC Forecast published Dec 2017) 2. Mirati estimates based on epidemiology data reported in Globocan 2022 incidence projections (accessed January 2019); Note: RET population estimate does not include thyroid cancer

24 MRTX849 KRAS G12C Inhibitor MRTX849: A Potent and Selective KRAS G12C Inhibitor Potent Selective Antiproliferation IC50s MRTX849, 3D format Cysteine Selectivity in H358 Cells MRTX849 (3 µm) IC50 (um) KRAS G12C cell lines Treated/Control Peptide Ratio 5,700 other cysteine peptides Ratio of significance Only modified cysteine is KRAS G12C Cervix Colon Pancreas Urinary Lung Peptide 24

25 MRTX849: Significant In Vivo Antitumor Activity Complete tumor regressions observed following oral administration in preclinical models MRTX849 KRAS G12C Inhibitor Tumor Volume(mm 3 ) MRTX849 Oral Administration CDX pancreatic model (MIA PaCa-2) Vehicle 1mg/kg 3mg/kg Vehicle 1 mg/kg Vehicle 1mg/kg 3mg/kg 10mg/kg 30mg/kg 100mg/kg 3 mg/kg 10 mg/kg 30 mg/kg 100 mg/kg 10mg/kg Dose-Dependent Regressions Observed In Vivo Durable and complete responses seen at 30mg/kg and 100mg/kg doses Tumor response continued following cessation of treatment MRTX849 Tested in More than 20 In Vivo Models Profound tumor regressions observed in ~80% of all KRAS G12C in vivo models tested Similar activity seen in both cell-derived and patientderived tumor models S tart D osing End Dosing Day 30 & 100mg/kg* Preclinical Data Increase Likelihood of Single Agent Clinical Activity Supports pursuit of an accelerated single agent development pathway based on response rate * Tumors did not recur despite cessation of treatment, indicating durable and complete responses 25

26 MRTX849 KRAS G12C Inhibitor Phase 1/2 Clinical Trial of MRTX849 in KRAS G12C+ Tumors Phase 1 Dose Escalation Phase 2 Expansion NSCLC Enrolling Only Patients with KRAS G12C+ Tumors KRAS G12C+ Tumors 1 pt Intra-patient Dose Escalation 1 pt 1 pt 3 pt RP2D Phase 1b Early Expansions CRC Others Accelerated Dose Escalation Design Wide preclinical therapeutic index supports starting dose close to predicted active exposure Single patient cohorts initially with intra-patient dose escalations Phase 1b Expansion Cohorts Opportunity to enroll additional patients based on early efficacy signals while still escalating to MTD Genomic Testing Accelerated Titration Phase 2 Expansion Cohorts Protocol allows expansion directly into Phase 2 registration-enabling cohorts Clinical Sites Open to Enrollment ClinicalTrials.gov Identifier: NCT

27 MRTX849 KRAS G12C Inhibitor MRTX849: Phase 1/2 Clinical Trial Now Open Summary Potent: 1-20 nm potency in cellular assays Selective: 1,000 fold selective for KRAS G12C mutations over KRASwild type Orally Bioavailable: PK profile consistent with once daily oral dosing Highly Active in vivo: Complete durable regressions in KRAS G12C models Wide Therapeutic Index: Preclinical toxicology studies suggest a favorable safety profile Strong Patent Estate: First program patent issued in December 2018 Accelerated Phase 1/2 Clinical Trial Design Initiated Accelerated Titration design with single patient cohorts and intra-patient dose escalation Phase 2 expansion cohorts with potential for early proof of concept in 2019 First patient expected to be dosed in early January

28 Targeted Oncology KRAS G12D Program 28 28

29 KRAS G12D Discovery Program Mirati s Next KRAS Program: KRAS G12D KRAS G12D is a Driver Mutation Early oncogenic event Non-overlapping with other driver mutations, including KRAS G12C Large Patient Population Highly prevalent in pancreatic cancer (ductal adenocarcinomas) No targeted treatment options for patients with KRAS G12D+ tumors Leveraging Learnings from G12C Applying knowledge gained from designed targeting KRAS G12C Identified KRAS G12D leads with cellular potency approaching 100nm G12D (35%) G12D (5%) KRAS G12D Mutation Frequency 1 Pancreatic Endometrial Colorectal NSCLC adenocarcinoma U.S Addressable Patients 2 : ~46,000 G12D (12%) G12D (5%) Sources: Zehir, Ahmet et al. Nature Med Mutational Landscape of Metastatic Cancer ; Krakstad et al. PLoS One 2012, High-Throughput Mutation Profiling of Primary and Metastatic Endometrial Cancers ; NIH TCGA: The Cancer Genome Atlas 2. Mirati estimate based upon frequency data from sources above and epidemiology data from Globocan 2022 incidence projections (accessed January 2019)

30 Mirati Therapeutics: Potential Value-Driving Catalysts in 2019 Sitravatinib Initiating Phase 3 Registrational Trial in NSCLC Sitravatinib + Nivolumab in Checkpoint Refractory NSCLC Phase 3 Trial Initiation 1H 2019 Extending Proof of Concept into Additional Tumor Types Sitravatinib + Nivolumab in Checkpoint Refractory Bladder Phase 2 Initial Proof of Concept Data Sitravatinib + Tislelizumab in NSCLC, RCC, Ovarian Phase 2 Initial Proof of Concept Data (BeiGene) 2H H 2019 Expanding Clinical Mechanism of Action Data Sitravatinib + Nivolumab in Pre-Surgical RCC, HNSCC Initial Mechanism of Action Data 2H 2019 MRTX849 KRAS G12C Generating Clinical Data with Potential Best-in-Class KRAS G12C Inhibitor MRTX849 in KRAS G12C+ Tumors Phase 1/2 Early Proof of Concept Data 2H 2019 KRAS G12D Program Expanding KRAS Franchise into KRAS G12D KRAS G12D Program Lead Candidate Identification Q

31 Company Financials NASDAQ MRTX Cash (Q3 18)* $242.6M Shares Outstanding** 44.3M * Reported cash and investments as of September 30, ** As of September 30, 2018, includes 32.5 million shares of common stock and pre-funded warrants to purchase a total of 11.8 million shares of common stock. The pre-funded warrants have a per share exercise price of $0.001.

32 NASDAQ: MRTX Targeting the genetic and immunological drivers of cancer Corporate Presentation January