Corporate Presentation. November 2017

Transcription

1 v Corporate Presentation November 2017

2 Safe Harbor Statement Certain statements contained in this presentation, other than statements of fact that are independently verifiable at the date hereof, contain "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. These statements include but are not limited to statements under the captions Business, Risk Factors and Management s Discussion and Analysis of Financial Condition and Results of Operations and in other sections incorporated by reference from our Annual Report on Form 10-K and Quarterly Reports on Form 10-Q, as applicable, as well as our other filings with the SEC. You should be aware that the occurrence of any of the events discussed under the heading Risk Factors in any applicable prospectus supplement and any documents incorporated by reference herein or therein could substantially harm our business, operating results and financial condition and that if any of these events occurs, it could adversely affect the value of an investment in our securities. 2

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 Clinical Programs Targeted Agents and Immuno-Oncology Combinations Indication Preclinical Phase 1/1b Phase 2 Sponsor Anticipated 2018 Milestones Sitravatinib Oral Kinase Inhibitor Immuno-oncology Combination with nivolumab Targeted Agent CBL, CHR4q12 and RET alterations NSCLC NSCLC Stage 2 Data (n=34) in Checkpoint Refractory Mid-2018 Updated Phase 1b Data Mid-2018 Mocetinostat Oral HDAC Class I & IV Immuno-oncology Combination with durvalumab Immuno-oncology Combination with pembrolizumab and guadecitabine* NSCLC NSCLC Stage 1 Data (n=18) in Checkpoint Refractory Mid-2018 Enrollment and Early Data Update H KRAS Oral KRAS G12C Inhibitor Targeted Agent G12C mutations NSCLC CRC IND Filing Q nivolumab owned by BMS, durvalumab owned by AstraZeneca, pembrolizumab owned by Merck, guadecitabine owned by Astex NSCLC = non-small cell lung cancer; CRC = colorectal cancer; IND = Investigational New Drug application * Trial is sponsored by Memorial Sloan Kettering Cancer Center and funded with support from Merck and Stand Up To Cancer 4

5 Targeting Underserved Populations with Significant Commercial Potential Sitravatinib Mocetinostat Sitravatinib KRAS Checkpoint Inhibitor Combinations CBL, CHR4Q12, RET KRAS G12C Target Population Checkpoint Failures Selected Patients Selected Patients 3 rd Line NSCLC 40,000+ pts in US 5.5% of NSCLC 14% of NSCLC adenocarcinoma Currently Approved Treatment Options none none none Comparably Sized NSCLC Market I/O 2 nd line NSCLC $5-10 Billion WW Alk + NSCLC $1.0+ Billion WW EGFR + NSCLC $2.5+ Billion WW Patient Expansion Opportunities Bladder, RCC, HCC, HNSCC Melanoma, Sarcoma, Cancer of Unknown Primary CRC (5%) Population Data: NCI SEER; Market Size Data: Evaluate Pharma, I/O 2 nd NSCLC estimate based on projections by Decisions Resources for market size by 2022 Incidence Data: COSMIC 8.0 NSCLC = non-small cell lung cancer; CRC = colorectal cancer; RCC = Renal Cell Cancer; HCC = Hepatocellular Cancer; HNSCC = Head & Neck Cancer WW = World Wide; I/O = immuno-oncology 5

6 Sitravatinib v Spectrum Selective Kinase Inhibitor 6

7 Sitravatinib Target Profile Spectrum Selective Kinase Inhibitor Kinases Inhibited by Sitravatinib Tumor Driver Targets Immuno-supportive Targets Tyro/Axl/Mer (IC 50 : <1nM) VEGFR/PDGFR KIT (IC 50 : <10nM) MET (IC 50 : 25nM) RET (IC 50 : 20nM) VEGFR/PDGFR KIT (IC 50 : <10nM) Split Family Kinases Tyro/Axl/Mer (IC 50 : <1nM) TAM Family Kinases CBL Mutations CHR4Q12 Alterations RET Fusions Depletes Tregs and MDSCs, Shifts tumor macrophage type to M1 Single Agent Sitravatinib Targeted Therapy Genomically Selected Patients Sitravatinib + Checkpoint Inhibitors Combination Therapy Checkpoint Refractory Patients 7

8 Immuno-Oncology Sitravatinib + Nivolumab v Checkpoint Refractory NSCLC

9 Sitravatinib in the Tumor Microenvironment Multi-targeted modulation of immunotherapy resistance mechanisms VEGFR2, KIT SITRAVATINIB Tyro, Axl, Mer Treg MDSC Treg MDSC Treg M2 TAM M1 TAM CD4 Targeting VEGFR2 reduces Tregs and MDSCs Targeting KIT depletes MDSCs Releases brakes for expansion of CD8+ T cells via PD-1 inhibition MDSC Targeting MERTK & Axl shifts tumor associated macrophage (TAM) type to M1 M1 macrophages secrete cytokines that enhance immune response (IL-12, TNF) Both TAM & VEGFR2/KIT cooperate: idc mdc To increase dendritic cell maturity and antigen presentation capacity To increase NK cell response To increase T cell trafficking into tumors CD8 CD4 9

10 TAM receptors regulate immune cell function and may synergize with immune checkpoint inhibitors TAM receptors negatively regulate immune response via multiple mechanisms MERTK suppresses pro-inflammatory macrophage function (M1) & induces immune suppressive macrophage phenotype (M2) Axl required for terminating the inflammatory response in dendritic cells Inhibition of TAM receptors increases CD8+ CTL and inhibits tumor growth Nat. Rev. Canc. (2014) Cancer Imm Res,

11 Sitravatinib + PD-1 Exhibits Marked Anti-tumor Activity %CD4+ Lymphocytes CD4+ T Lymphocytes Expansion Control Sitra Control Sitra Day 9 Day 6 Significant tumor growth inhibition and durable response for PD-1 + sitravatinib combination arm Expansion of systemic CD4 & CD8 T effector cells observed by Day 9 Depletion of systemic myeloid-derived suppressor cells (MDSCs) by Day 6 %MDSC+ CD11b/Gr MDSC CD11b/Gr1+ (Systemic) Depletion Control Sitra Control Sitra Day 9 Day 6 11

12 MRTX500: Phase 2 Sitravatinib + Nivolumab in NSCLC Stage 1 expansion criteria met in both checkpoint refractory cohorts Prior Therapy with Checkpoint Inhibitor (PD-L1 or PD-1) Documented Tumor Progression No Selection for PD-L1 Status Sitravatinib + Nivolumab Phase 2 NSCLC Prior Clinical Benefit from Checkpoint No Prior Clinical Benefit from Checkpoint Criteria (PRs) Stage 1 Stage 2 Enrolling 9 pts PR: 1/6 evaluable* Enrolling 9 pts PRs: 2/5 evaluable* Stage 1 evaluation still underway Advancement 1 PR 1 PR Enrolling 8 pts Enrolling 8 pts Checkpoint Inhibitor Naïve (after platinum doublet) PD-L1 Status Selection PD-L1 Low PD-L1 High Enrolling 9 pts Enrolling 17 pts 1 PR 6 PR Sitravatinib: Dose 120mg daily Nivolumab: Dose 3mg/kg every 2 weeks (full labeled dose) Study cycles of 28 days, with disease assessment scans every 2 cycles Data presented at IASLC 18 th World Conference on Lung Cancer, October

13 MRTX500: Safety and Adverse Events Combination of sitravatinib + nivolumab has been well tolerated Most frequent (>20%) treatment emergent, treatment related (sitravatinib) Adverse Events Adverse Event (Preferred Term) Fatigue 5 (50%) Frequency N=10 All Grades Grade >3* Diarrhea 4 (40%) 1 (10%) Aspartate aminotransferase increase 3 (30%) Dysphonia 3 (30%) Palmar-plantar (erythrodysaesthesia) 3 (30%) 1 (10%) Lipase increase 2 (20%) Weight decrease 2 (20%) Nausea 2 (20%) Vomiting 2 (20%) Decreased appetite 2 (20%) Hyponatremia 2 (20%) Hypertension 2 (20%) 2 (20%) Hypothyroidism 2 (20%) Blood pressure increase 1 (10%) 1 (10%) *No Grade 4 or 5 events Safety cut off date = 26-Jun-17 13

14 MRTX500: Sitravatinib + Nivolumab NSCLC Phase 2 Presented at IASLC 18 th World Conference on Lung Cancer, October 2017 Maximum Response in NSCLC Patients Who Failed Prior Checkpoint Therapy (evaluable patients) 60% PB 40% 36% Confirmed PR 20% 0% PB 13% NPB 0% PD New Lesion NPB PB NPB PB PB NPB NPB PB -2% Unconfirmed PR SD PD On Study as of 10-Aug-17 RECIST Cutoff for PR, 30% -20% -13% -17% -19% -40% -60% -28% -33% -48% -58% 3/11 Confirmed PR 8/11 Tumor Regression Prior Tx Days from Prior Tx Durva Nivo Nivo Nivo Nivo Nivo Nivo Pemb Nivo Nivo Pemb 232d 19d 30d 40d 14d 44d 22d 63d 40d 25d 63d Study cycles of 28 days, with disease assessment scans every 2 cycles Data presented at IASLC 18 th World Conference on Lung Cancer, October 2017 PB: Prior Benefit Cohort NPB: No Prior Benefit Cohort CONFIDENTIAL 14

15 MRTX-500: Sitravatinib + Nivolumab NSCLC Phase 2 Presented at IASLC 18 th World Conference on Lung Cancer, October 2017 Prior Tx Days from Prior Tx Duration in NSCLC Patients Who Failed Prior Checkpoint Therapy (evaluable patients) Nivo 22d PB Pembro 63d PB Nivo 25d NPB Nivo 14d PB Pembro 63d PB Nivo 40d NPB Nivo 40d NPB Nivo 44d NPB Objective PD Nivo 19d PB Objective PD Nivo 30d NPB Objective PD Durva 232d PB Objective PD Weeks Study cycles of 28 days, with disease assessment scans every 2 cycles Data presented at IASLC 18 th World Conference on Lung Cancer, October 2017 PB: Prior Benefit Cohort NPB: No Prior Benefit Cohort 15

16 MRTX500: Tumor Regressions in NSCLC Patients Activity of sitravatinib + nivolumab after progression on prior checkpoint therapy Patient Details: 71 year-old female metastatic adenocarcinoma, diagnosed in May 2014 Previous therapies: cisplatin/etoposide, paclitaxel, carboplatin, pemetrexed, docetaxel, pembrolizumab (stable disease) Documented progression following pembrolizumab treatment Best response sitravatinib+nivolumab: Confirmed Partial Response: -58% Presented at IASLC 18 th World Conference on Lung Cancer 16

17 2 nd Line NSCLC Checkpoint Inhibitor Activity Response rates and PFS are relatively low 1L 2017 ASCO NSCLC Treatment Guidelines Stage IV NSCLC *No actionable mutation* Pembrolizumab Platinum Doublet 2 nd Line Checkpoint Inhibitor Therapy after chemotherapy ORR mpfs (mons) 2L Platinum Doublet Checkpoint Inhibitor Nivolumab Atezolizumab Any PD-L1 status 19% 2.3 Any PD-L1 status 14% NR 3L No Approved 3 rd Line Therapy 3 rd Line Standard of Care Single Agent Chemo (Taxanes) Low response rates, short durations After Progression on Checkpoint Sitravatinib + Nivolumab MRTX500 Phase 2 Trial Any PD-L1 status ORR: 3/11* Nivolumab data: CheckMate-026, CheckMate-057, CheckMate-017, drug label Atezolizumab data: BIRCH, OAK, drug label Nishino et al, Clin Can Res 2017 * Preliminary data presented at IASLC 18th World Conference on Lung Cancer, October

18 Immuno-Oncology: Expansion Opportunities Multiple opportunities for expansion into other lines and tumor types Sitravatinib + Nivolumab Phase 2 NSCLC Indication Expansion Opportunities Sitravatinib s mechanism may support combinations in many other tumors where checkpoint inhibitors are active BLADDER RENAL CELL RCC HEPATOCELLULAR HCC OTHER TUMORS 18

19 Sitravatinib Immuno-Oncology Summary Promising Early Data Sitravatinib combined with nivolumab in checkpoint refractory NSCLC Patients had disease progression on prior checkpoint therapy before enrollment 3/11 Confirmed Partial Responses 8/11 Clinical benefit with durable tumor regressions Meaningful Milestone Anticipated in 2018 Stage 2 checkpoint refractory (n=34) data in 2H 2018 Potential for Rapid Registration Pathway* Possibility for single arm surrogate endpoint accelerated approval in checkpoint refractory NSCLC patients Opportunity for Broad Label Expansion Broadly applicable immuno-oncology mechanism (TAM + VEGF) Opportunities in other tumor types where checkpoint inhibitors are active: Bladder, RCC, HCC, among others * Current company perspective on potential registration pathway; subject to FDA review and approval 19

20 Mocetinostat: Class I and IV HDAC Inhibitor Immuno-supportive effects in the Tumor Microenvironment (TME) Immunosuppressive TME Mocetinostat Immune-stimulated TME MDSC Treg IMMUNE CELL EFFECTS CD8 Treg Treg Treg Treg Treg CD8 CD8 CD8 CD8 CD4 MDSC CD4 MDSC MDSC MDSC Tregs and MDSCs decreased by mocetinostat MDSC CD4 CD8 CD8 CD8 increased by mocetinostat TUMOR CELL EFFECTS PD-L1 and antigen presentation machinery upregulated by mocetinostat in tumor cells 20

21 Mocetinostat + PD-L1 Exhibits Marked Anti-tumor Activity CT26 Model (colon) %CD3 cells Tregs Depletion Vehicle Moce PD-L1 Moce + PD- L1 Mocetinostat significantly improved the ratio of CD8+ T cells to Treg cells Mocetinostat also significantly increases T-cell clonality and T-cell fraction The combination of mocetinostat and anti-pd-l1 antibody produces greater antitumor activity than either agent alone %CD3 cells Ratio CD8/Tregs CD8+ T cells Expansion Vehicle Moce PD-L1 Moce + PD- L1 CD8/Tregs Ratio Vehicle Moce PD-L1 Moce + PD- L1 21

22 Mocetinostat + Durvalumab Phase 2 in NSCLC Similar design opportunity to select the best I/O combination partner Prior Therapy with Checkpoint Inhibitor (PD-L1 or PD-1) Documented Tumor Progression Mocetinostat + Durvalumab Phase 2 NSCLC No Selection for PD-L1 Status Prior Clinical Benefit from Checkpoint No Prior Clinical Benefit from Checkpoint Criteria (PRs) Stage 1 Stage 2 Enrolling 9 pts Enrolling 9 pts Stage 1 evaluation still underway Advancement 1 PR 1 PR Will enroll 8 pts If criteria is met, will enroll 8 pts Checkpoint Inhibitor Naïve (after platinum doublet) PD-L1 Status Selection PD-L1 Low PD-L1 High Enrolling 9 pts Enrolling 17 pts 1 PR 6 PR If criteria is met, will enroll 8 pts If criteria is met, will enroll 27 pts Stage 1 Update In Checkpoint Refractory Planned Q Mocetinostat: Dose 70mg three times a weekly Durvalumab: Dose 1500mg every 4 weeks (full labeled dose) 22

23 Targeted Oncology Sitravatinib Single Agent v Genomically Selected Patients

24 Sitravatinib: A Novel Kinase Inhibitor Sitravatinib targets genetic alterations in up to 5.5% of NSCLC patients CBL mutations 1.5% CHR4q12 amplicons 2% RET fusions 2% TrkA/C fusions TrkB/C mutations <1% DDR2 mutations <1% ALK 4% CBL CBL mutations 1.5% MET Exon 14del 2% MET Gene amp 2% CHR4q12 RET CHR4q12 amplicons RET fusions 2% 2% Other and Unknown 42% EGFR 15% KRAS 15% An et al 2012, Ding et al 2008, Doebele et al, 2014; Eguchi et al 1999, Euhus el al 2002, Greco et al 2010, Hammerman et al 2011, Harada et al 2011, Kohno et al 2012, Lipson et al 2012, Marchetti et al 2008, Phay et al 2010, Sheng et al 2001, TCGA 2014, Tan et al 2010, Ramos et al

25 Sitravatinib: Rationale For Targeting CBL Mutations Inhibiting hyperactivated PDGFR, KIT, MET, Tyro/Axl/Mer CBL Key CBL Targets Unique binding motifs X X Proteasome Early Endosome Sorting Endosome X X Lysosome Late Endosome CBL is an E3-ubiquitin ligase that regulates the internalization and degradation of multiple activated RTKs including PDGFRA, MET, KIT, & Tyro/Axl/Mer Loss of function mutations in CBL result in increased target RTK activation in tumor cells that may act as oncogenic drivers 25

26 Tumor Regressions in CBL Tumor Models CBL Mutations Models CBL A549 NSCLC CDX NCI-H1734 NSCLC CDX LU11713 NSCLC PDX Study Days Vehicle sitravatinib 20mg/kg QD Study Days Vehicle sitravatinib 20mg/kg QD Study Days Vehicle sitravatinib 20mg/kg QD Dosing initiated with first measurement 26

27 CHR4q12 Sitravatinib: Rationale For Targeting CHR4q12 Inhibiting overexpressed PDGFRα, KIT and KDR CHR4q12 amplification increases expression of multiple driver kinases PDGFR, KIT and KDR Present in 2% of lung adenocarcinomas Sitravatinib potently inhibits these kinases Cellular IC 50 values ~10 nm Sitravatinib is active in tumors with CHR4q12 amplification Tumor regression in CHR4q12 amplified NSCLC models at 20 mg/kg Dose administered in mouse model yields exposure comparable to expected human clinical use Tumor volume (mm 3 ) CHR4q12 Gene Amplification (PDGFRα / KIT / KDR) NCI H2073 NSCLC CDX Start of treatment Time (Days) Vehicle Sitravatinib 20mg/kg QD

28 Sitravatinib: Rationale For Targeting RET Fusions Directly inhibiting RET RET RET is a known oncogenic driver Present in 2% of lung adenocarcinoma Sitravatinib is a Potent RET Inhibitor Inhibits RET activity in cellular assays with IC 50 values of ~20-30 nm Also blocks RET V804M gatekeeper mutation, implicated in resistance Sitravatinib is active in tumors with RET rearrangements Tumor regression in multiple RET rearrangement positive NSCLC models at 20 mg/kg Active in models of KIF5B RET fusion Dose administered in mouse model yields exposure comparable to expected human clinical use Tumor volume (mm 3 ) Active in KIF5B (75% of RET Fusions) KIF5B-RET Fusion Positive NSCLC PDX Start of treatment Time (Days) Vehicle Sitravatinib 20mg/kg QD

29 : Sitravatinib Phase 1b Single Agent Trial NSCLC and Basket of other solid tumors Selection Criteria Tumor Type Cohort CBL mutations CHR4q12 amplicons RET fusions NSCLC Other solid tumors Cohort 1: NSCLC 2nd-line or later Cohort 2: Basket 2nd-line or later 35 sites in US and Korea Phase 1b dose: 150mg QD Primary objectives: safety, PK, clinical activity Secondary objectives: PD, metabolites, tumor molecular markers ClinTrials.gov identifier: NCT

30 : Safety and Adverse Events Single Agent Safety Summary Most frequent (>10%) Treatment Emergent, Treatment-Related Adverse Events Adverse Event Term Frequency N = 86 All Grades Grade >3* Fatigue 38 (44%) Diarrhea 30 (35%) 9 (11%) Hypertension 29 (34%) 16 (19%) Nausea 21 (24%) Decreased appetite 19 (22%) Vomiting 19 (22%) Weight decreased 15 (17%) Palmar-plantar erythrodysaesthesia syndrome 11 (13%) Hypothyroidism 10 (12%) *No Grade 5 events Safety cut off date = 26-Jun-17 30

31 CBL CBL: Tumor Regression in First Evaluable NSCLC Patient Patient Details: 77 year-old female non-smoker, metastatic adenocarcinoma Previous therapies: carboplatin/pemetrexed, erlotinib, rociletinib, osimertinib, Enrolled March 15, 2017 Confirmed Partial Response: -77% Source: Poster #78, IASLC 2017 Chicago Multidisciplinary Symposium in Thoracic Oncology 31

32 RET NSCLC Patients with RET Fusions Early data reported in January 2017 cohort enrollment continues Best Response unknown unknown non-kif5b KIF5B Total enrolled patients 6 Patients with no scan data 2 1 patient with 0 scans to date 1 patient withdrew before 1 st scan 4 patients on study Duration Initial Indication of Response (n=4) ORR (confirmed & unconfirmed) 50% (2/4) Tumor Regression 100% (4/4) *Data cutoff: 9-Dec-2016 Weeks **Investigator-reported activity data 32

33 v KRAS Inhibitor G12C Mutant Selective

34 Mirati s KRAS Inhibitor Program KRAS: A Common Driver Mutation First well-defined driver mutation in oncology and most commonly mutated oncogene KRAS mutation associated with poor prognosis and resistance to therapy KRAS G12C mutations: 14% of NSCLC and 5% CRC KRAS is difficult to target due to high affinity for GTP and lack of binding pocket Shokat (UCSF) indicated that KRAS G12C can be targeted via covalent modification strategies Figure: The Biology of Cancer (Garland Science 2007) KRAS mutation testing is already customary Approved PCR-based testing is already standard for many cancer patients Current practice to disqualify for other therapies (where KRAS patients will not respond) 34

35 Mirati KRAS G12C Inhibitors: Potent and Selective Potent Target Inhibition KRAS clinical leads inhibit downstream signaling and cell survival in KRAS-dependent cancer cells at low nanomolar concentrations Highly Selective for KRAS G12C KRAS inhibitors are >1000-fold selective for inhibition of cell survival in KRAS-dependent cancer cells vs KRAS non-g12c cells Clinical leads demonstrated >1,000-fold selectivity for modification of KRAS G12C at 3 µm vs rest of cellular proteome MRTX-A Growth IC50 (um) MRTX Compound A Cell Viability EC 50 (mm) 1 KRAS G12C Non- KRAS G12C Cysteine Selectivity in H358 Cells (3 µm MRTX Compound B) In Vivo Pharmacodynamics Robust dose-dependent KRAS protein modification (covalent binding) & inhibition of KRAS-dependent signaling demonstrated in G12C tumors implanted in mice 35

36 Dose Dependent In Vivo Antitumor Activity Full tumor regressions observed following oral administration 1500 MRTX Compound A Oral Administration MIA PaCa-2 G12C xenograft model MIA PaCa-2 G12C xenograft model 1400 Vehicle 1300 MRTX-A 1mg/kg 1200 MRTX-A 3mg/kg MRTX-A 10mg/kg Tumor Volume (mm 3 ) MRTX-A 30mg/kg MRTX-A 100mg/kg Vehicle 1mg/kg Study Day 3mg/kg Dosing stopped Dosing started Day 52 Day 24 10mg/kg 30 & 100mg/kg 36

37 KRAS Attributes of Clinical Leads Parameter Target Criteria Mirati KRAS Lead Compounds Cell IC 50 (nm) <100nM 1-20 nm Proteome Selectivity ADME No clinically concerning off target activity In Range of Marketed Irreversible Inhibitors High proteome/cellular selectivity (1000X) Hepatic and extrahepatic clearance comparable or better than marketed irreversible drugs* Minimal expected drug interaction risk Solubility >10 µg/ml at ph 7 All tested compounds high >> 500 ph 7 PK >30%F & acceptable projected human T 1/2 for daily admin >30-75 % oral bioavailability in nonclinical species and projected human half-life >12 hours Efficacy 30mpk Regressions at PO dose levels < 10 mg/kg Safety Well-tolerated in preclinical models Well-tolerated in rodents with > 10X therapeutic index * Based on published data; no head-to-head trials have been conducted 37

38 Historical Challenges in Targeting the KRAS Pathway Upstream Inhibitors Blocking Ras Membrane localization Farnesyl transferase inhibitors have proven ineffective at blocking KRAS localization Downstream Effector Inhibitors Raf / MEK and PI3K / AKT / mtor Limited effectiveness in KRAS+ tumors Incomplete inhibition of KRAS mut Inhibition of KRAS wt resulting in low therapeutic index KRAS Direct Inhibitors Direct targeting of RAS mut challenging due to small & undefined catalytic site & high affinity for GTP However, this issue can be overcome with irreversible inhibitors Direct Inhibition of KRAS G12C Covalent binding to neo-cysteine in KRAS G12C variant Expansion of closed binding pocket Effective and irreversible inhibition 38

39 KRAS: An Attractive Development Opportunity KRAS G12C is a Large Unserved Market Significant KRAS G12C patient populations in NSCLC and Colorectal Cancer First-in-class opportunity: no direct KRAS inhibitors in clinical development Simple genetic patient selection; most patients are already typed for KRAS KRAS G12C Mutations NSCLC adenocarcinoma all KRAS 25% KRAS G12C (14%) Discovery Collaboration with Array BioPharma, Led by Mirati Access to Array s well-regarded chemistry and crystallography capabilities Mirati has full worldwide rights to the program and related compounds Modest milestones and royalties due to Array upon program success Colorectal all KRAS 50% KRAS G12C (5%) KRAS incidence source: COSMIC v.80 39

40 KRAS G12C Program Summary KRAS: Difficult Target, Meaningful Population Historically, KRAS has been extremely difficult to inhibit directly Patients with KRAS mutations have poor prognosis and limited treatment options KRAS G12C mutations are tumor drivers in substantial patient populations (14% of NSCLC, 5% of Colorectal Cancer) Lead Compounds Identified in Mirati s KRAS G12C Program Covalent irreversible inhibitors that target KRAS G12C mutations Highly potent compounds: 1-20 nm potency in cellular assays 1,000 fold selective for KRAS G12C mutations over other KRAS Potent, Dose Dependent In Vivo Antitumor Activity Observed Tumor regressions at doses as low as 3 mg/kg in KRAS G12C tumor models in vivo Complete durable regressions at 30 mg/kg Tumor regressions appear to be maintained after dosing is discontinued Program Advancing Into IND-enabling Preclinical Studies IND filing planned by Q4 2018, with Phase 1 studies in patients expected to follow 40

41 Mirati s Clinical Programs Targeted Agents and Immuno-Oncology Combinations Indication Preclinical Phase 1/1b Phase 2 Sponsor Anticipated 2018 Milestones Sitravatinib Oral Kinase Inhibitor Immuno-oncology Combination with nivolumab Targeted Agent CBL, CHR4q12 and RET alterations NSCLC NSCLC Stage 2 Data (n=34) in Checkpoint Refractory Mid-2018 Updated Phase 1b Data Mid-2018 Mocetinostat Oral HDAC Class I & IV Immuno-oncology Combination with durvalumab Immuno-oncology Combination with pembrolizumab and guadecitabine* NSCLC NSCLC Stage 1 Data (n=18) in Checkpoint Refractory Mid-2018 Enrollment and Early Data Update H KRAS Oral KRAS G12C Inhibitor Targeted Agent G12C mutations NSCLC CRC IND Filing Q nivolumab owned by BMS, durvalumab owned by AstraZeneca, pembrolizumab owned by Merck, guadecitabine owned by Astex NSCLC = non-small cell lung cancer; CRC = colorectal cancer; IND = Investigational New Drug application * Trial is sponsored by Memorial Sloan Kettering Cancer Center and funded with support from Merck and Stand Up To Cancer 41

42 Company Financials NASDAQ: MRTX Cash Q3 2017*: Cash Plus November 2017 Offering: $75.0M $161.6M Shares Outstanding** 39.9M * Reported cash as of September 30, ** Shares outstanding as of November 20, Including pre-funded warrants to purchase a total of 11.4M which have a per share exercise price of $

43 Back-Up Slides v 43

44 VEGFR2 / KIT inhibition reduces Tregs and MDSCs in preclinical models Anti-VEGF antibody reduces Tregs in CT26 model Terme, Cancer Res, (2013) Anti-KIT antibody decreases M-MDSCs and is synergistic with checkpoint inh therapy Garton, A, MCT,

45 VEGF Inhibitors + Checkpoint Inhibitors Emerging data is supportive of VEGF I/O combinations Tumor VEGF Inhibitor Combo Partner ORR VEGF alone Checkpoint alone RCC (naïve) Axinitib Pembro 67% (35/52) 47% - RCC (2 nd line) Sunitinib Nivo 52% (17/33) 34% 19% RCC (2 nd line) Pazopanib Nivo 45% (9/20) 34% 19% NSCLC (2 nd line) Ramucirumab VEGFR2 Pembro 38% (10/26) <10% 20% Sitravatinib inhibits both VEGF and TAM receptors, which may further enhance the immuno-supportive effects observed 45