Corporate Overview Presentation November 2021 Exhibit 99.1
This presentation contains certain forward-looking statements regarding the business of Mirati Therapeutics, Inc. (“Mirati”). Any statement describing Mirati’s goals, expectations, financial or other projections, intentions or beliefs, development plans and the commercial potential of Mirati’s drug development pipeline, including without limitation adagrasib (MRTX849), sitravatinib, MRTX1133 and MRTX1719 is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to risks and uncertainties, particularly those challenges inherent in the process of discovering, developing and commercialization of new drug products that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. Mirati’s forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Mirati’s forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Mirati. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Mirati’s programs are described in additional detail in Mirati’s quarterly reports on Form 10-Q and annual reports on Form 10-K, which are on file with the U.S. Securities and Exchange Commission (the “SEC”) available at the SEC’s Internet site (www.sec.gov). Mirati assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. November 8, 2021 Safe Harbor Statement
Operational and commercial synergies across portfolio, particularly in NSCLC $1.2 billion in cash, cash equivalents and short-term investments as of 9/30/21 NSCLC = non-small cell lung cancer; CRC = colorectal cancer; IO = immuno-oncology; IND = investigational new drug; P = phase; MTA = methylthioadenosine; MTAP = methylthioadenosine phosphorylase Developing Novel Oncology Therapies, Including Two Registration-Enabling Programs in Large NSCLC Patient Populations IO Resistance Adagrasib (MRTX849) G12C selective inhibitor KRAS Selective Inhibition G12D selective (MRTX1133) and other KRAS selective inhibitors Compelling Phase 2 data in combination with a PD-1 support and inform SAPPHIRE Phase 3 approach in NSCLC Potential first-in-class G12D inhibitor advancing in IND-enabling studies Compelling efficacy and favorable tolerability with broad development in both monotherapy and combinations Sitravatinib Inhibitor of TAM and VEGFR2 NSCLC NSCLC CRC Pancreatic CRC Others Others Others Synthetic Lethality Internally discovered synthetic lethal PRMT5/MTA cooperative program for MTAP-deleted cancers with IND submission by year end MRTX1719 MTA Cooperative PRMT5 Inhibitor Others NSCLC Pancreatic & Bladder Advancing targeted novel oncology research platform: KRAS mutant inhibition and KRAS signaling modifiers (e.g., SOS1)
K = KRYSTAL (adagrasib trials); POC = proof of concept; NSCLC = non-small cell lung cancer; CRC = colorectal cancer; OS = overall survival; IND = investigational new drug; NDA = new drug application; TPS = tumor proportion score; MTAP = methylthioadenosine phosphorylase. 1. BeiGene is currently conducting certain combination studies of sitravatinib + tislelizumab for solid tumor indications in their Territory in Asia (ex-Japan). These trials include a P3 trial in non-squamous and squamous NSCLC randomized vs. docetaxel, as well as proof-of-concept trials in hepatocellular carcinoma, renal cell carcinoma, ovarian cancer and gastric cancers. Compound Indication Development Approach Lead Optimization IND-enabling Phase 1/1b Phase 2 Phase 3 Status / Near-Term Catalysts Adagrasib KRAS G12C Inhibitor 2L NSCLC Monotherapy NDA submission in Q4:2021 Phase 2 NSCLC data in early 2022 ahead of expected US commercial launch 2L NSCLC POC Combo: SHP2, SOS1, CDK4/6, Pan-EGFR, EGFR POC combos ongoing; pan-EGFR planned 1L NSCLC Monotherapy: STK11 co-mutations and TPS <1% Potentially registration-enabling: STK11 cohort initiated Q1:2021 and TPS <1% initiated Q4 2021 1L NSCLC Combo: Pembrolizumab (PD-1) Phase 2 enrollment on-going at 400mg BID 2L CRC Combo: Cetuximab (EGFR) Phase 3 initiated in 1H:2021 3L+ CRC and Pancreatic Monotherapy Combo: Cetuximab (EGFR) On-going potentially registration-enabling 3rd Line+ CRC cohorts; clarify next steps for tumors other than NSCLC and CRC in 1H:2022 Sitravatinib Multi Kinase Inhibitor 2/3L NS-NSCLC PD-1 Phase 3 interim analysis of OS in 2H:2022 2/3L S + NS-NSCLC PD-1 Phase 3 initiated Q3:2021 by BeiGene MRTX1719 MTA cooperative PRMT5 Inhibitor MTAP-deleted Cancers Monotherapy IND by Year End 2021 MRTX1133 KRAS G12D Inhibitor Pancreatic, CRC, NSCLC Monotherapy and combination IND in 2022 Additional KRAS pathway preclinical programs Solid Tumors SOS1 Inhibitor Solid Tumors Other KRAS mutations Mirati’s Pipeline Spans Multiple Novel Oncology Programs and Tumor Types K-10: combination with cetuximab vs. FOLFIRI or FOLFOX Multiple: POC combination trials K-12: P3 confirmatory trial, randomized vs. docetaxel K-7 (2 Arms): <1% TPS and ≥1% TPS SAPPHIRE – Combination with Nivolumab vs. docetaxel K-1: STK11 co-mutations K-1: P2 registration-enabling Tislelizumab Combinations (BeiGene)(1) K-1: P1b and P2 monotherapy K-1: P1b and P2 combination K-7 (1 Arm): <1% TPS
KRAS mutations are generally associated with poor prognosis The absence of known binding pockets made KRAS historically undruggable; discovery of the switch II binding pocket by Shokat et al has changed this Mirati: Deep Commitment to Addressing Cancers With High Unmet Needs KRAS Prevalence in Tumors With High Unmet Needs1-3 Pancreatic Cancer CRC Key: KRASG12C KRASG12D Other KRASmut KRASmt Total KRASG12C KRASG12D ~90% ~2% ~36% KRASmt Total KRASG12C KRASG12D ~35% 3-4% ~12% KRAS: Drugging the Undruggable Prevalence of Oncogenic Mutations in Lung Adenocarcinoma4 NSCLC Adenocarcinoma KRASmt Total KRASG12C KRASG12D ~25% ~14% ~4% KRASG12C occurs in ~14% of patients with NSCLC, comparable to the prevalence of all EGFR mutations4,5 Other: 57% KRASG12C: 14% EGFR: 15% ALK: 5% ROS1: 2% BRAF: 2% NTRK: 1% KRASG12D: ~4% WT KRAS 1. Zehir A, et al. Nat Med. 2017;23(6)703-713. 2. Krakstad C, et al. PLoS One. 2012;7(12):e52795. 3. NIH TCGA: The Cancer Genome Atlas. February 11, 2021. https://www.cbioportal.org. 4. Biernacka A, et al. Cancer Genet. 2016;209(5):195-198. 5. Pakkala S, Ramalingam SS. JCI Insight. 2018;3(15):e120858.
Adagrasib (MRTX849): KRASG12C Selective Inhibitor
Molecular profile, including differentiated pharmacokinetic properties, long half-life and CNS penetration Encouraging preclinical and early clinical evidence of activity in the brain NSCLC: potentially best-in-class 2nd Line+ NSCLC: differentiated response rate and initial durability in heavily pretreated patients CRC: potentially first-in-class and best-in-class 3rd Line+: Response rate and initial durability in heavily pretreated patients Both in monotherapy and in combination with cetuximab 2nd Line: Phase 3 randomized trial in combination with cetuximab is ongoing Other solid tumors Encouraging preliminary results in pancreatic cancer Assessing adagrasib in additional solid tumor settings Adagrasib: Potentially Differentiated Therapy in NSCLC, CRC and Other Tumors for Patients with KRASG12C Mutations Adagrasib (MRTX849) KRASG12C Inhibitor CNS = central nervous system; NSCLC = Non-Small Cell Lung Cancer; CRC = colorectal cancer
Adagrasib: Multiple Paths to Potential Commercialization Adagrasib (MRTX849) KRASG12C Inhibitor Tumor Type Development Status NSCLC NDA filing Q4:2021 (accelerated approval) Phase 3 confirmatory study in 2nd Line (randomized to docetaxel) initiated Q1:2021 Potentially registration-enabling Phase 2 initiated Q1:2021 Phase 2 TPS <1% initiated in Q4 2021 Phase 2 pembrolizumab combination: enrollment ongoing at 400mg BID Multiple POC trials ongoing or to be initiated with SHP2, SOS1, pan-EGFR and CDK4/6 Potentially registration-enabling Phase 2 cohorts in monotherapy initiated Q2:2021 and combination initiated in Q4:2021 Phase 3 cetuximab combination in 2nd line (randomized to chemotherapy) initiated in 1H:2021 CRC KRASG12C Patient Population 2nd line and beyond 1st line stratified by TPS score 1st line with STK11 co-mutation 2nd line and beyond 2nd line ≥ 3rd line Combination: PD-1 Development Approach Monotherapy Monotherapy Combination: other Monotherapy and Combination (EGFR) Combination: EGFR *Mirati and Zai Lab have a collaboration and license agreement under which Zai obtains the right to research, develop, manufacture and exclusively commercialize adagrasib in Greater China (mainland China, Hong Kong, Macau and Taiwan). Zai also has obligations to support enrollment in Mirati’s adagrasib global registrational studies. Mirati has an option to co-commercialize in Greater China and retains full and exclusive rights to adagrasib in all countries outside of Greater China. NSCLC = non-small cell lung cancer; NDA = new drug application; TPS = tumor proportion score; POC = proof of concept 1st line with TPS < 1% Monotherapy
Maximize systemic exposure for duration of dosing Extensive volume of tissue distribution ensures optimal target coverage throughout dosing interval Long half-life ensures pathway maximally inhibited throughout entire dosing interval Comprehensive target coverage combats new KRAS protein synthesis (half-life ~ 24h) and reactivation of signaling2 Extensive Tissue Distribution Long Half Life NSCLC = non-small cell lung cancer; CSF = cerebrospinal fluid; CNS = central nervous system; POC = proof of concept; PK = pharmacokinetic Presented at the 32nd EORTC-NCI-AACR Symposium, October 24-25, 2019; 2. Stites and Shaw, CPT Pharmacometrics Syst. Pharmacol. (2018); 3. Estimated from nonclinical data and PBPK modeling; Adagrasib: Desired Properties Include Complete Inhibition of KRASG12C for Full Dosing Interval, Long Half-Life, CNS Penetrance and Dose-Dependent PK Estimated Human Volume of Distribution (>10 L/Kg3) Human Half Life ~24 hours1 CNS Penetrant Dose-dependent PK and emerging exposure-response relationship for adagrasib supports dose modification schema and selected combination strategies PK Profile / dosing Encouraging and clinically meaningful adagrasib exposure in patients Clinical POC: heavily pre-treated NSCLC patient had 63% reduction of primary tumor and disappearance of active brain metastases Human Half Life ~24 hours1 Estimated Human Volume of Distribution (>10 L/Kg3) Encouraging CSF/CNS penetration Dose Dependent PK Exposure Response Adagrasib (MRTX849) KRASG12C Inhibitor
Adagrasib (MRTX849): Advanced Non-Small Cell Lung Cancer
Topline results from Phase 2 cohort of KRYSTAL-1 study in 2nd Line+ NSCLC patients with the KRASG12C mutation evaluating adagrasib at 600mg BID: Intent-to-treat population Data cut off: June 15, 2021 Median follow-up: 9 months 43% ORR (confirmed based on central independent review) 98.3% of patients received adagrasib following treatment with both immunotherapy and platinum chemotherapy Safety and tolerability profile consistent with previously reported findings for adagrasib in patients with advanced NSCLC NDA submission status First adagrasib data package submitted as a part of Real-Time Oncology Review (RTOR) pilot program Completion of NDA submission in Q4:2021 Adagrasib Phase 2 Topline Monotherapy Data in NSCLC ORR = Objective Response Rate; NSCLC = Non-Small Cell Lung Cancer; NDA = New Drug Application; BID = dosing two times a day KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in NSCLC
Preliminary findings in limited number of patients support moving forward with 400 mg BID dose of adagrasib in combination with full dose pembrolizumab in 1st Line NSCLC Adagrasib 400mg BID plus pembrolizumab in Phase 1b study preliminarily show a manageable tolerability profile No TRAEs leading to treatment discontinuation and no Grade 4 or Grade 5 AEs observed 4 of 7 patients had a confirmed PR One additional patient experienced 49% tumor regression, which allowed for tumor resection prior to achieving RECIST-defined confirmed response DCR of 100% All 7 patients exhibited tumor regression ranging from 37% – 92% KEYNOTE-189 (pembrolizumab + chemotherapy) approved in 1st Line NSCLC with ORR of 47.6% across all TPS scores Median follow up of 9.9 months 5 of the 7 patients remained on treatment as of the data cut off and had been on treatment for 8 to 11 months 400 mg BID dose of adagrasib with pembrolizumab being evaluated in the ongoing Phase 2 KRYSTAL-7 study Preliminary Phase 1b Adagrasib + Pembrolizumab Data in 1st Line NSCLC Data cut off date is October 21, 2021; NSCLC = non-small cell lung cancer; BID = dosing two times a day; TRAEs = treatment related adverse events; AE = adverse event; PR = partial response; ORR = overall response rate; DCR = disease control rate; TPS = tumor proportion score KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor + Pembrolizumab in 1st Line NSCLC
NSCLC: Phase 1/1b 2nd Line and Beyond: Best Overall Response Includes All Monotherapy Phase 1/1b 2nd Line+ Patients Enrolled at 600mg BID (n=19) Maximum % Change From Baseline Evaluable Patients 40 20 0 -20 -40 -60 -80 -100 SD PD SD SD SD SD SD PR uPR PR PR PR uPR PR PR PR SD PR PR Best Tumor Change From Baseline in All Patients Treated With Adagrasib 600 mg BID (n=19) Heavily pretreated (median of 2 prior lines of treatment), investigator-assessed ORR of 58%, including 2 responses that occurred after being on treatment for > 10 monthsa aTwo unconfirmed responses subsequently both confirmed; Data cut off: June 15, 2021; NSCLC = non-small cell lung cancer; BID = dosing two times a day; ORR = overall response rate KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in NSCLC
Data cutoff June 15, 2021; NSCLC = non-small cell lung cancer; BID = dosing two times a day; ORR = overall response rate NSCLC: Phase 1/1b in the 2nd Line+ Setting: Duration of Treatment 4 8 12 2 4 0 10 14 16 18 20 22 24 Evaluable Patients Duration of Treatment, months First response Progression Treatment ongoing Death PR PR PR uPR PR PR PR SD PR PR SD SD PR SD uPR SD SD SD PD Duration of Treatment in All Patients Treated With Adagrasib 600 mg BID (n=19) Endpoint Median (months) (range/95%CI) Median Follow Up 17.3 Duration of Treatment 9.5 (2.6, NE) mDOR 12.6 (3.1, NE) mPFS 8.3 (2.8, NE) KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in NSCLC
KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in NSCLC Adagrasib Clinical Activity in NSCLC Patients with Brain Metastases Clinical activity in NSCLC patients with brain metastases with brain and CSF exposure in preclinical and clinical studies Preclinical research demonstrates adagrasib has dose dependent drug penetration in the CNS Brain concentrations >IC90 achieved with dose comparable to human dose Heavily pre-treated KRASG12C mutated NSCLC patient with active brain metastases was evaluated following several cycles of adagrasib therapy Patient experienced 63% reduction in size of primary lung tumor and disappearance of the active brain metastases Enrolling cohort of patients to assess adagrasib in NSCLC patients with a G12C mutation and active brain metastases Cellular IC90 Mean plasma Mean brain Mean Plasma and Brain Concentrations of Adagrasib After a Single 100 mg/kg Oral Dose in Mice Cellular IC50 1Kpuu is the concentration ratio of unbound drug in CSF to blood, to, as a measure of brain penetration NSCLC: non-small cell lung cancer; CSF = cerebrospinal fluid; CNS = central nervous system Presented at the 32nd EORTC-NCI-AACR Symposium, October 24-25, 2020 Kpuu1 Comparison Osimertinib 0.3 Adagrasib preclinical 0.4 Preliminary adagrasib clinical 0.47
KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in NSCLC Adagrasib Clinical Activity in NSCLC in Patients with KRASG12C and STK11 Co-Mutations Co-mutations in KRAS and STK11 in NSCLC Patients KRAS and STK11 co-mutations comprise approximately 30% of KRASG12C mutant NSCLC The co-occurrence of KRAS and STK11 mutations may cooperate to create an immune-suppressed tumor microenvironment Initial adagrasib clinical activity shows promising response Potentially registration enabling Phase 2 monotherapy study in 1st line NSCLC patients with STK11 co-mutation initiated in Q1:2021 Best Tumor Change From Baseline for Patients Harboring KRASG12C and STK11 Co-mutations Shows 64% (9 of 14 patients) ORR Evaluable Patients Maximum % From Baseline -100 -80 -60 -40 -20 0 20 40 60 80 SD SD SD PR PD PR PR PR PR PR PR PR PR SD Presented at the 32nd EORTC-NCI-AACR Symposium, October 24-25, 2020 NSCLC: non-small cell lung cancer; ORR = overall response rate
Ricciuti et al. Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019); Skouldis et al. Cancer Discovery. 2018 Jul;8(7):822-835; Zehir et al. Nat Med. 2017 Aug 4;23(8):1004. NSCLC = non-small cell lung cancer; CI = checkpoint inhibitor KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in NSCLC Co-mutations in KRAS and STK11 are Associated with Poor Prognosis and Outcomes on Checkpoint Inhibitor Therapy in NSCLC Progression Free Survival Overall Survival
Adagrasib (MRTX849): Heavily Pretreated Colorectal Cancer
Prognosis on Standard of Care in CRC with KRASG12C Mutations Have Historically Been Worse Than the Broader CRC Population 1 Obermannová R, et al. Ann Oncol. 2016;27(11):2082-2090. 2 Grothey A, et al. Lancet. 2013;381(9863):303-312. 3 Mayer RJ, et al. N Engl J Med. 2015;372(20):1909-1919. 3Van Cutsem E, et al. Eur J Cancer. 2018;90:63-72.; CRC = colorectal cancer; Patient outcomes in CRC have historically been poor and progressively worse in later lines of therapy KRAS-mutant CRC patients tend to have worse outcomes than the broader CRC patient population Population Historical Efficacy Outcomes 3rd Line and Beyond KRAS-agnostic Regorafenib1 or Trifluridine/Tipiracil2,3: ORR: 1-2% mPFS: 1.9-2.0 months mOS: 6.4-8.0 months KRAS-mutant Trifluridine/Tipiracil3: KRAS-mut mOS = 6.5 months KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in CRC
Studied CRC patients Were Heavily Pretreated; 90% of Patients in Combination Treatment Were 3rd Line or Beyond aAdagrasib monotherapy was administered at a dose of 600 mg BID. bAdagrasib was administered at a dose of 600 mg BID. Cetuximab was administered IV at a dose of 400 mg/m2 followed by 250 mg/m2 QW, or 500 mg/m2 Q2W (Phase 1b). cMolecular status includes patients with conclusively evaluable test results. Data as of 25 May 2021 for monotherapy (median follow-up: 8.9 months). Data as of 9 July 2021 for the cetuximab combination (median follow-up: 7 months).; CRC = colorectal cancer Presented at the European Society for Medical Oncology (ESMO) Congress, 19 September 2021 KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in CRC
No apparent association between response rate and molecular status was shown in an exploratory analysis Response rate was 22% (10/45), including 1 unconfirmed PR (unconfirmed response remains unconfirmed)e SD was observed in 64% (29/45) of patientse Clinical benefit (DCR) was observed in 87% (39/45) of patientse Adagrasib Monotherapy in Patients With Advanced CRC: Best Overall Response Maximum % Change From Baseline Evaluable Patients 40 20 0 -20 -40 -60 -80 PD PD PD SD PD SD SD SD SD SD SDc SD SD SD SD PD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD PD PR PRd PR PR PR PR PR PRc PR PR SD aAll results are based on investigator assessments. bEfficacy evaluable population (n=45) excludes 1 patient who withdrew consent prior to the first scan. cPhase 1/1b. dAt the time of the 25 May 2021 data cutoff, the patient had uPR, After a follow-up scan after the data cut off, this response still remains unconfirmed, and the patient is still on therapy and will be evaluated with the next scan. eAmong all enrolled Phase 1/2 monotherapy patients (n=46), ORR was 22% (10/46). Data as of 25 May 2021 for monotherapy (median follow-up: 8.9 months); ORR = overall response rate; CRC = colorectal cancer; DCR = disease control rate; PR = partial response; SD = stable disease Best Tumor Change From Baseline (n=45)a,b KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in CRC Presented at the European Society for Medical Oncology (ESMO) Congress, 19 September 2021
Adagrasib Monotherapy in Patients With Advanced CRC: Duration of Treatment aAll results are based on investigator assessments. bAt the time of the 25 May 2021 data cutoff, the patient had uPR. cPatients who crossed over to receive adagrasib + cetuximab. dPhase 1/1b. eMedian duration of response is based on 9 confirmed responses. Data as of 25 May 2021 for monotherapy (median follow-up: 8.9 months); ORR = overall response rate; PFS = progression free survival; CRC = colorectal cancer; DOR = duration of response; PR = partial response; SD = stable disease; PD = progressive disease Median time to response was 1.4 months Median DOR was 4.2 months Median PFS was 5.6 months At time of analysis, 40% (18/45) of patients remain on treatment 4 2 0 6 8 10 12 14 16 Evaluable Patients Progression First Response Treatment Ongoing Death SD SD PR PR SD SD SD SD SD PRb PR PRc SDc SD SD SD SD SDc PRc SD SD SD PD SD PRd PR PR PR SD SD SDc SD SD SD PD SD SD SDc SDd SD SD PD PD PD PD Duration of Treatment (n=45)a KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in CRC Presented at the European Society for Medical Oncology (ESMO) Congress, 19 September 2021 HISTORICAL DATA: 3L Standard of care (regorafenib and LONSURF®), regardless of KRAS, status show median ORR of ~1-2% PFS of ~2 months OS of 6-8 months Time, Months
Response rate was 43% (12/28), including 2 unconfirmed PRsc Confirmed ORR of 39% (11/28) in the efficacy eligible and heavily pretreated population SD was observed in 57% (16/28) of patients Clinical benefit (DCR) was observed in 100% (28/28) of patients Best Tumor Change From Baseline (n=28)a,b Adagrasib + Cetuximab in Patients with Advanced CRC: Best Overall Response Maximum % Change From Baseline Evaluable Patients 20 0 -20 -40 -60 -80 -100 SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD PRc PRc PR PR PR PR SD PR PR PR PR PR PR aAll results are based on investigator assessments. b Evaluable population (n=28) excludes 4 patients who withdrew consent prior to the first scan (1 withdrew due to unrelated pneumonia, 2 withdrew related to cetuximab, and 1 withdrew related to mailese from both cetuximab and adagrasib); cAt the time of the 9 July 2021 data cutoff, 2 patients had uPRs (1 patient subsequently confirmed and 1 patient subsequently had progressive disease). dAmong all enrolled Phase 1b combination patients (n=32). Data as of 9 July 2021 (median follow-up: 7 months); PR = partial response; CRC = colorectal cancer; ORR = overall response rate; SD = stable disease; DCR = disease control rate KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor + Cetuximab in CRC Presented at the European Society for Medical Oncology (ESMO) Congress, 19 September 2021
4 2 0 6 8 10 12 14 Evaluable Patients Progression First Response Treatment Ongoing Death SD SD SD SD SD SD SD PR PR SD SD PR SD PR PR PR PR PR PR SD PR SD SD SD SD PRb PRb SD Duration of Treatment (n=28)a aAll results are based on investigator assessments. bAt the time of the 9 July 2021 data cutoff, 2 patients had uPRs. Data as of 9 July 2021 (median follow-up: 7 months); CRC = colorectal cancer; ORR = overall response rate; PFS = progression free survival; OS = overall survival; SD = stable disease; PR = partial response Time, Months Adagrasib + Cetuximab in Patients with Advanced CRC: Duration of Treatment 16 Median time to response was 1.3 months At time of analysis, 71% (20/28) of patients remain on treatment KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor + Cetuximab in CRC Presented at the European Society for Medical Oncology (ESMO) Congress, 19 September 2021 HISTORICAL DATA: 3L Standard of care (regorafenib and LONSURF®), regardless of KRAS, status show median ORR of ~1-2% PFS of ~2 months OS of 6-8 months
Most Frequent TRAEs Adagrasib Monotherapya (n=46) Adagrasib + Cetuximabb (n=32) TRAEs,c,d % Any Grade Grades 3-4 Any Grade Grades 3-4 Any TRAEs 91% 30% 100% 16% Most frequent TRAEs, % Diarrhea 63% 7% 56% 3% Nausea 57% 0% 63% 0% Fatigue 46% 4% 47% 0% Vomiting 46% 0% 50% 0% Decreased appetite 15% 0% 16% 0% Peripheral edema 15% 0% 19% 0% AST increase 13% 4% 6% 0% QT prolongation 13% 2% 16% 3% ALT increase 11% 4% 13% 0% Anemia 11% 2% 9% 0% Dermatitis acneiform 0% 0% 44% 3% Rash maculopapular 2% 0% 22% 0% Infusion-related reaction NA NA 19% 3% Adagrasib +/- Cetuximab in Patients With Advanced CRC: Treatment-Related Adverse Events aAdagrasib monotherapy was administered at a dose of 600 mg BID. bAdagrasib was administered at a dose of 600 mg BID + cetuximab was administered IV at a dose of 400 mg/m2 followed by 250 mg/m2 QW, or 500 mg/m2 Q2W. cOccurred in ≥10% of patients treated with adagrasib monotherapy and select TRAEs of interest in patients treated with adagrasib + cetuximab combination. dIncludes events reported between the first dose and 25 May 2021 for adagrasib monotherapy (median follow-up: 8.9 months). Includes events reported between the first dose and 9 July 2021 for adagrasib + cetuximab combination (median follow-up: 7 months). eTRAEs leading to discontinuation were grade 2 treatment-related malaise and grade 2 cetuximab-related infusion-related reaction. KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor ± Cetuximab in CRC Presented at the European Society for Medical Oncology (ESMO) Congress, 18 September 2021 Adagrasib Monotherapy No Grade 5 TRAEs No TRAEs that led to discontinuation Adagrasib + Cetuximab Combination No Grade 5 TRAEs 6% (n=2) of TRAEs led to discontinuation of treatmente
Adagrasib (MRTX849): Pancreatic Ductal Adenocarcinoma Cancer
Adagrasib was administered at a dose of 600mg BID in this cohort. At the time of the 10 September 2021 data cutoff, 2 of the 12 enrolled patients had discontinued treatment prior to 1st scan due to unrelated adverse events and were not evaluable for clinical activity; aTreatment ongoing; SD = stable disease; PR = partial response; DCR = disease control rate Promising Proof of Concept Data from Adagrasib in Pancreatic Ductal Adenocarcinoma Best Tumor Change From Baseline in Patients (n=10) Preliminary response rate per investigator assessment was 50% (5/10), including 1 unconfirmed PR Clinical benefit (DCR) was observed in 100% (10/10) of patients All patients received gemcitabine-based regimens and 10/12 received prior fluoropyrimidine-based regimens Maximum % Change from Baseline Evaluable Patients 40 60 20 0 -20 -40 -60 -80 -100 SD SDa SDa SD PRa PRa uPRa SD PR PR (n=12) Median age, y (range) 67 (40-80) Female, n (%) 4 (33%) ECOG PS, n (%) 0 0 (0%) 1 12 (100%) Prior lines of systemic therapy, median (range) 3 (1-4) Prior lines of systemic therapy, % 1 2 3 ≥4 8% 42% 33% 17% Selected Patient Demographics Presented at the AACR-NCI-EORTC Mlecular Targets and Cancer Therapeutics Congress, 9 October 2021 KRYSTAL-1: Adagrasib (MRTX849) KRASG12C Inhibitor in Pancreatic Cancer
MRTX1133: KRASG12D Selective Inhibitor
MRTX1133 is a small molecule that selectively & reversibly binds to & inhibits KRASG12D in both active & inactive states MRTX1133 demonstrates selective inhibition of cell viability of KRASG12D mutant, but not KRAS wild-type, tumor cells MRTX1133: Potential First-in-Class KRASG12D Selective Inhibitor Assay Criteria MRTX1133 KRASG12D cell activity <10nM ~5 nM Selectivity over KRASWT >100-fold >1,000-fold Predicted human half-life >24 hours ~50 hours Low risk for hERG/off-target pharmacology >10µM ✓ Drug-drug interaction (CYPs) Low risk ✓ IC50 = 5 nM Active GTP-Loaded KRASG12D Assay MRTX1133 KRAS G12D Inhibitor
MRTX1133: Clinical Development Path and Design Principles Optimizing target coverage throughout the dosing interval is important for maximizing antitumor activity in KRAS mutated cancers Evaluation of long-acting IV formulations, including liposomal strategies, to maximize the extent and duration of target coverage is ongoing IV injectable route of administration commercially attractive and compatible with development as a monotherapy or in combination with standard of care regimens IND filing planned for 2022 MRTX1133 KRASG12D Inhibitor Multi-cohort Phase 1 monotherapy trial comparable to adagrasib Rapid dose escalation strategies to define a tolerated and active dose Multiple expansion cohorts for pancreatic, colorectal, lung and other G12D patients Rational combination approaches are similar to G12C and enabled in first-in-human clinical trials PATH TO CLINICAL DEVELOPMENT CLINICAL TRIAL DESIGN PRINCIPLES IND: investigational new drug; IV = intravenous
Sitravatinib + Checkpoint Inhibitors
Pircher et al., Synergies of Targeting Tumor Angiogenesis and Immune Checkpoints. Int J Mol Sci, 2017. 18(11). Garton et al., Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression. Mol Cancer Ther, 2017. 16(4) Akalu, Y.T., C.V. Rothlin, and S. Ghosh, TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev, 2017. 276(1) Graham, D.K., D. DeRyckere, K.D. Davies, and H.S. Earp, The TAM family. Nat Rev Cancer, 2014. 14(12) Du, W., Huang, H., Sorrelle, N., & Brekken, R. A. (2018). Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight, 3(21). Sitravatinib + Checkpoint Inhibitors Sitravatinib Inhibits TAM (TYRO3, AXL and MER), VEGFR2, and KIT Receptors and May Restore Immune Response Increase dendritic cell maturity & antigen presentation capacity Increase NK cell response Increase T cell expansion & trafficking into tumors Rationale for Targeting TAM & Split RTKs to Enhance Immune Response to Checkpoint Inhibitors Targeting VEGFR2 reduces Tregs & MDSCs Targeting KIT also depletes MDSCs Releases brakes for expansion of CD8+ T cells via PD-1 inhibition Both TAM & Split RTKs cooperate to: Targeting MERTK & AXL shifts tumor associated macrophage (TAM) type to M1 M1 macrophages secrete cytokines that enhance immune response (IL-12, TNF) CD8+ CD4+ M1 TAM M2 TAM iDC mDC MDSC Treg Targeting TAM: Targeting Split RTKs:
MRTX-500: Phase 2, Open-Label Study of Sitravatinib + Nivolumab in Patients with Nonsquamous NSCLC with Prior Clinical Benefit from Checkpoint Inhibitor Therapy Key Eligibility Criteria (n=68) Advanced/metastatic nonsquamous NSCLCa No actionable driver mutations Anti–PD-1/L1 must be the most recent line of therapy Prior Clinical Benefit (PCB) to CPI: CR, PR, or SD ≥12 weeks from prior CPI therapy No uncontrolled brain metastases ECOG PS 0-2 Sitravatinib 120 mg QD + nivolumab Data as of 1 June 2021 Primary Endpoint: Objective Response Rateb (ORR), as defined by RECIST 1.1 Presented at the European Society for Medical Oncology (ESMO) Congress, 20 September 2021 Secondary Endpoints: Safety and tolerability DOR CBR PFS OS 1-year survival rate a Additional cohorts included a CPI-experienced cohort that did not receive prior clinical benefit from CPI therapy (radiographic progression of disease ≤12 weeks after initiation of treatment with CPI) and a CPI-naive cohort in patients that were previously treated with platinum-based chemotherapy. bORR based on investigator assessment. Dosing: sitravatinib free base formulation; nivolumab, 240 mg Q2W or 480 mg Q4W. Treatment discontinuation could be due to (but is not limited to) disease progression, global health deterioration, AEs, protocol violation, lost to follow-up, refusal of further treatment, study termination, or death. NSCLC = non-small cell lung cancer; DOR = duration of response; CR = complete response; PR = partial response; SD = stable disease; PFS = progression free survival; OS = overall survival; CPI = checkpoint inhibitor; QD = once a day dosing Sitravatinib + Nivolumab
Overall Survival with Sitravatinib + Nivolumab in Patients with Nonsquamous NSCLC With Prior Clinical Benefit From CPI Therapy Median follow-up in PCB cohort: 33.6 months; Data as of 1 June 2021. * ORR of 18% included 2 complete responses (3%) and 10 partial responses (15%); ORR = overall response rate; OS = overall survival; CPI = checkpoint inhibitor; NSCLC = non-small cell lung cancer Overall Survival in Patients With NSCLC (n=68) Overall Survival, % 100 90 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 42 36 56% 32% 45% Time, months Patients at risk: Sitravatinib + nivolumab 68 52 34 26 16 11 0 4 Sitravatinib + Nivolumab (n=68) Median OS (95% CI) 14.9 (9.3, 21.1) Events/censored, n (%) 46 (68)/22 (32) ORR 18%* Presented at the European Society for Medical Oncology (ESMO) Congress, 20 September 2021 Sitravatinib + Nivolumab
MRTX-500 Phase 2 trial: full Prior Benefit Cohort (PCB) (n=68), data cut-off of June 1, 2021, and presented at European Society for Medical Oncology (ESMO) Congress on September 18, 2021. Patients with PCB on a checkpoint inhibitor as part of their last treatment regimen prior to enrollment. PCB is defined as either complete response, partial response or stable disease for ≥12 weeks. PCB patients who received the combination as either 2nd or 3rd line of therapy after progressing on treatment with a checkpoint inhibitor. a10 (14.7%) patients were not evaluable for ORR: 8 patients without post-baseline scan, 1 patient without measurable disease at baseline, and 1 patient for whom all post-baseline scans were NE. Median follow-up in the PCB cohort was 33.6 months. Data represented are from the CheckMate 057,KEYNOTE 010 and OAK studies and do not reflect results that might have been obtained from head-to-head studies. Results from Mirati’s on-going Phase 3 SAPPHIRE trial comparing sitravatinib + nivolumab to docetaxel may differ materially from prior studies presented. Borghaei H, et al. New England Journal of Medicine 2015;373:1627-1639, Herbst RS, et al. Lancet. 2016;387:1540-1550, Rittmeyer A, et al. Lancet. 2017;389:255-265. OS: overall survival; NSCLC: non-small cell lung cancer; Sitravatinib + Nivolumab Compelling Phase 2 Results Support and Inform SAPPHIRE Phase 3 Trial in 2nd / 3rd Line Non-Squamous NSCLC Sitravatinib + Nivolumab N=266 Docetaxel N=266 Checkpoint Refractory NSCLC 2nd / 3rd Line Patients after Checkpoint Inhibitor Therapy Documented Tumor Progression RANDOMIZATION 1:1 Final OS Analysis Potential for Full Approval Based on Interim OS Analysis (242 events) 2H 2022 N=532 Powered for 3.5-month OS benefit Encouraging Overall Survival (OS) data from Phase 2 trial 1 Median OS of 14.9 months1 in 2nd Line or 3rd Line patients with Prior Clinical Benefit (PCB) on a prior checkpoint inhibitor (CPI) and subsequent disease progression (n=68) 56% and 32% of patients alive at 1- and 2-years, respectively Phase 3 SAPPHIRE clinical trial inclusion criteria in PCB patients who received the combination as either 2nd or 3rd line therapy after progressing on treatment with checkpoint inhibitor Potential to establish sitravatinib + nivolumab as new standard of care after checkpoint inhibitor failure >2nd line NSCLC U.S. & EU Populations (circa 2020): over 100,000 patients with ~70,000 being non-squamous
PRMT5 Inhibitor
1 cBioPortal PRMT5 = Protein Arginine Methyltransferase 5; SAM - S-adenosylmethionine; MTA: methylthioadenosine; MTAP: methylthioadenosine phosphorylase; IND: investigational new drug MRTX1719 PRMT5 Inhibitor Potential First-in-class PRMT5 Inhibitor Selective for MTAP-deleted Cancers MTAP deletions occur in up to 10%1 of all human cancers including pancreatic, lung, and bladder Patients have a poor prognosis, representing a significant unmet medical need Internally discovered PRMT5 inhibitor represent a potential precision medicine for MTAP-deleted cancers Program leverages a synthetic lethal approach and selectively targets the PRMT5/MTA complex in MTAP-deleted cancer cells Designed to spare normal human cells and demonstrates improved therapeutic index in preclinical studies relative to first generation approaches MRTX1719 selected as clinical candidate with IND filing anticipated by year-end 2021
PRMT5 = Protein Arginine Methyltransferase 5; SAM - S-adenosylmethionine; MTA: methylthioadenosine; MTAP: methylthioadenosine phosphorylase
MRTX1719: Potential First-in-class Selective Inhibitor of the PRMT5/MTA Complex MRTX1719 selectively inhibits the PRMT5/MTA complex with a very slow off rate and tight binding leads to prolonged PD effects in preclinical models Greater inhibition of PRMT5 in MTAP-deleted (tumor) cells suggest the potential for an increased therapeutic index with fewer adverse events (e.g., bone marrow suppression) compared to non-PRMT5/MTA selective inhibitors WT = wild type; ADME: absorption, distribution, metabolism, and excretion; PD = pharmacodynamic; SDMA = symmetric dimethylarginine; PRMT5 = Protein Arginine Methyltransferase 5; MTAP: methylthioadenosine phosphorylase Assay Criteria MRTX1719 PRMT5/MTA MTAPDEL SDMA cell activity <15nM <10 nM Selectivity for MTAPWT cells (SDMA) >20-fold >70-fold Drug-drug interaction (CYPs) Low risk ✓ Favorable bioavailability Low risk ADME ✓ MRTX1719 PRMT5 Inhibitor
Financial Update
* This amount is comprised of cash, cash equivalents and short-term investments. ** Shares outstanding as of September 30, 2021, includes 51.8 million shares of common stock outstanding and pre-funded warrants to purchase a total of 7.6 million shares of common stock. The pre-funded warrants have a per share exercise price of $0.001. *** Amount disclosed is calculated as Q3 2021 operating expenses ($151.3M) less Q3 2021 stock-based compensation expense ($26.9M). Select Company Financials NASDAQ MRTX Cash as of September 30, 2021* $1.2B Shares outstanding as of September 30, 2021** 59.4M Q3 2021: Operating Expenses net of stock-based compensation*** $124.4M Q3 2021: Operating Expenses $151.3M
Corporate Overview Presentation November 2021