Erasca, Inc 8-K, filed Dec 9, 2022
Erasca, Inc. (ERAS)
About this 8-K
Erasca, Inc filed this 8-K on December 9, 2022.
Items reported
- Item 1.01: Entered into a material agreement
- Item 3.02: Unregistered sale of equity
- Item 8.01: Other events
- Item 9.01: Financial statements and exhibits
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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Item 1.01 Entry into a Material Definitive Agreement.
On December 9, 2022, Erasca, Inc. (the Company) entered into an exclusive license agreement (the License Agreement) with Novartis Pharma AG (Novartis) under which the Company was granted an exclusive, worldwide, royalty-bearing license to certain patent and other intellectual property rights owned or controlled by Novartis to develop, manufacture, use, and commercialize naporafenib in all fields of use. The Company has the right to sublicense (through multiple tiers) its rights under the License Agreement, subject to certain limitations and conditions, and is required to use commercially reasonable efforts to commercialize licensed products in certain geographical markets.
The license granted under the License Agreement is subject to Novartis’ reserved right to: (i) develop, manufacture, use, and commercialize compounds unrelated to naporafenib under the licensed patent rights and know-how, (ii) use the licensed patent rights and know-how for non-clinical research purposes, and (iii) use the licensed patent rights and know-how to the extent necessary to perform ongoing clinical trials and its obligations under existing contracts and under the License Agreement.
Under the License Agreement, the Company will make an upfront cash payment to Novartis of $20 million, and issued to Novartis shares of common stock of the Company having an aggregate value of approximately $80 million (the Shares). The Shares were issued in a private placement in reliance on Section 4(a)(2) of the Securities Act of 1933, as amended, for transactions by an issuer not involving any public offering. The Company relied upon this exemption from registration based in part on representations made by Novartis in a stock issuance agreement entered into between the Company and Novartis, dated December 9, 2022. During the six-month period following the date of the stock issuance agreement, Novartis agreed not to sell or otherwise transfer, subject to certain exceptions, the Shares, and for the period until one year following the date of issuance, to certain volume restriction on any sales of Shares.
The Company is obligated to make future regulatory milestone payments of up to $80 million and sales milestone payments of up to $200 million. The Company is also obligated to pay royalties on net sales of all licensed products, in the low-single digit percentages, subject to certain reductions.
The License Agreement will expire upon the last to expire royalty term, which is determined on a licensed product-by-licensed product and country-by-country basis, and is the later of: (i) ten years from the date of first commercial sale for the licensed product in such country, (ii) the last to expire valid claim within the licensed patent rights covering such licensed product, or (iii) the expiration of all regulatory exclusivity for the licensed product in such country. Upon expiration of the License Agreement, on a licensed product-by-licensed product and country-by-country basis, the Company will have a fully paid-up, perpetual, and irrevocable license to develop, manufacture, use, and commercialize the licensed products.
The License Agreement may be terminated in its entirety by either party in the event of an uncured material breach by the other party. Novartis may terminate the License Agreement upon written notice in the event the Company becomes subject to specified bankruptcy, insolvency, or similar circumstances. The Company may terminate the License Agreement in its entirety at any time upon the provision of prior written notice to Novartis.
Upon termination of the License Agreement for any reason, all rights and licenses granted to the Company will terminate. In addition, upon termination of the License Agreement for any reason other than its natural expiration, Novartis has an option to negotiate a license under any patent rights, know-how, or other intellectual property rights relating to the licensed products that are owned or controlled by the Company for the purpose of developing, manufacturing and commercializing the licensed products on terms to be negotiated between the parties.
The foregoing description of the License Agreement is not complete and is qualified in its entirety by reference to the full text of the License Agreement, a copy of which will be filed as an exhibit to the Company’s Annual Report on Form 10-K to be filed with respect to the fiscal year ending December 31, 2022.
Item 3.02 Unregistered Sales of Equity Securities.
The disclosure set forth in Item 1.01 above with respect to the issuance of the Shares is incorporated in this Item 3.02 by reference.
Item 8.01 Other Events.
An updated Company presentation, including an overview of naporafenib, is attached as Exhibit 99.1 to this report and is incorporated herein by reference.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
| Exhibit No. | Description | |
| 99.1 | Erasca, Inc. Corporate Presentation, dated December 2022 | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.
| Erasca, Inc. | ||||||
| Date: December 9, 2022 | By: | /s/ Ebun Garner | ||||
| Ebun Garner, General Counsel | ||||||
Exhibit 99.1 On a Journey to Erase Cancer Erasca Corporate Presentation December 2022
Disclaimer: Forward Looking Statements & Market Data We caution you that this presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation, including statements regarding the anticipated naporafenib licensing transaction and when and whether such transaction will close, our future results of operations and financial position, business strategy, research and development plans, the anticipated timing, costs, design and conduct of our ongoing and planned preclinical studies and clinical trials for our product candidates, the potential benefits from our current or future arrangements with third parties, including without limitation the anticipated naporafenib license agreement, the timing and likelihood of success of our plans and objectives, and future results of anticipated product development efforts, are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negative of these terms or other similar expressions. The inclusion of forward-looking statements should not be regarded as a representation by us that any of our plans will be achieved. Actual results may differ from those set forth in this presentation due to the risks and uncertainties inherent in our business, including, without limitation: our approach to the discovery and development of product candidates based on our singular focus on shutting down the RAS/MAPK pathway, a novel and unproven approach; we are early in our development efforts and have only three product candidates in early clinical development and all of our other development efforts are in the preclinical or development stage; the retrospective analysis of pooled clinical data for ERAS-007 and ERAS-601 covers multiple clinical trials with different designs, inclusion criteria, and dosing regimens, which cannot be directly compared, and therefore may not be a reliable indicator of efficacy and safety data; interim results of clinical trials are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and more patient data become available; potential delays in the commencement, enrollment, and completion of clinical trials and preclinical studies; our dependence on third parties in connection with manufacturing, research, and preclinical and clinical testing; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization, or may result in recalls or product liability claims; unfavorable results from preclinical studies or clinical trials; results from preclinical studies or early clinical trials not necessarily being predictive of future results; the inability to realize any benefits from our current licenses and acquisitions and any future licenses, acquisitions, or collaborations, and our ability to fulfill our obligations under such arrangements; regulatory developments in the United States and foreign countries; our ability to obtain and maintain intellectual property protection for our product candidates; our ability to fund our operating plans with our current cash, cash equivalents, and investments; our ability to maintain undisrupted business operations due to the COVID- 19 pandemic, including delaying or disrupting our clinical trials, manufacturing, and supply chain; unstable market and economic conditions having serious adverse consequences on our business, financial condition and stock price; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in our annual report on Form 10-K for the year ended December 31, 2021, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. This data involves a number of assumptions, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions, and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. These and other factors could cause results to differ materially from those expressed in the estimates made by the independent parties and by us. 2
Erasca is accelerating its leadership in the RAS/MAPK pathway through 1 in-licensing of exclusive worldwide rights to naporafenib (LXH254; pan-RAFi) • Naporafenib is a Phase 2, pivotal-ready pan-RAF inhibitor with a potential first-in-class and Bolsters best-in-class profile in NRASm melanoma & other RAS/MAPK-driven tumors pipeline with late- • 500+ patients treated with naporafenib establishing safety, tolerability and preliminary POC in stage asset both monotherapy and combinations • Broad development strategy for naporafenib could address up to ~3.5m patients WW, significantly Expands expanding Erasca’s total addressable patient population addressable • Opportunities for multiple combination approaches (esp. with MEKi or ERKi) in many tumor types patients and populations with poor prognosis and high unmet medical need (e.g., NRASm melanoma) • Naporafenib targets BRAF and CRAF node critical to driving downstream RAS/MAPK pathway signaling in a broad range of RAS mutant cancers Complements Erasca’s portfolio • Synergistic with Erasca’s industry leading portfolio shutting down every node of the RAS/MAPK pathway • Erasca’s planned SEACRAFT trials are enabled by naporafenib’s broad development opportunities in combination with other targeted therapies Accelerates path • Prioritizing rapid development for naporafenib + trametinib in RAS Q61X tissue agnostic tumors to market (Phase 2 SEACRAFT-1) and NRASm melanoma (Phase 3 SEACRAFT-2) • Commercial process and formulation have been developed and successfully manufactured at scale 1 For commercial and portfolio prioritization reasons, Novartis is out-licensing this program and ran a competitive process with multiple bidders for a worldwide license 3
Pro forma with naporafenib Our name is our mission: to erase cancer 1 Vision to one day erase cancer in at least 100,000 patients annually as a leading global oncology company Experienced leadership team and SAB with track record of serial successes • Founded by Jonathan Lim, MD & Kevan Shokat, PhD around disruptive idea to target RAS • World class scientific advisory board of leading pioneers in RAS/MAPK pathway • Team with deep experience in efficient planning and execution of global clinical trials Industry leading portfolio focused on shutting down the RAS/MAPK pathway • Naporafenib pan-RAFi with first-in-class potential for NRASm & other MAPK tumors • ERAS-007 ERKi & ERAS-601 SHP2i with best-in-class potential for MAPK tumors • ERAS-3490, CNS-penetrant KRAS G12Ci with best-in-class potential in NSCLC • ERAS-801, CNS-penetrant EGFRi with first-in-class potential for EGFR-driven rGBM Strong financial position with high quality investor base and industry visibility 2 • ~$365M in cash, cash equivalents, and short-term marketable securities • One of Fierce Biotech’s 2021 “Fierce 15” most promising biotechnology companies CNS = central nervous system 1 Number of patients alive and free of cancer or free from cancer progression 2-yrs after starting an Erasca regimen, as measured by disease-free survival (adjuvant setting) and progression-free survival (metastatic setting) 2 Unaudited, as of September 30, 2022 4
Relevant RASm’s recut for naporafenib ~5.5m lives at stake annually worldwide with RAS/MAPK pathway alterations Naporafenib’s broad development strategy significantly expands our addressable patient populations New cases estimated worldwide per annum (thousands; numbers may not add up due to rounding) Other solid Alterations GBM HNSCC NSCLC CRC Melanoma PDAC AML US EU ROW Global tumors EGFR*/FLT3 125 513 184 338 - - - 61 82 222 917 1,220 NF1 25 58 98 34 33 1.9 434 3.2 75 159 453 687 KRAS G12C - 2.8 240 57 - 5.1 45 0.1 36 82 232 350 KRAS G12D 0.2 4.7 68 238 0.5 178 201 1.3 65 171 456 692 N/H/KRAS Q61X 0.4 23 35 80 69 32 155 4.1 51 106 242 399 H/N/KRAS G13R - 9.4 5.9 5.5 2.1 - 14 0.5 3.6 8.1 26 37 Other K/N/HRAS 0.6 31 162 452 4.4 211 331 13 112 291 800 1,203 BRAF V600E/K 2.0 1.9 23 180 93 1.4 158 0.4 63 127 271 461 BRAF Class 2 0.4 3.8 18 6.9 5.3 0.5 57 - 11 23 58 92 BRAF Class 3 0.1 0.9 12 17 2.5 - 29 0.2 6.1 15 40 61 Other BRAF - - 3.9 - 1.9 0.3 0.5 - 0.7 1.0 4.9 6.6 MEK 0.2 1.9 12 8.8 4.6 0.2 22 - 5.2 11 33 50 Co-occurring activating MAPK 1.4 10 62 59 37 7.1 84 3.0 33 69 162 264 pathway alterations** US 12 29 93 114 77 51 153 11 542 EU 34 76 194 398 116 124 324 18 1,285 Rest of World 109 555 635 964 60 264 1,053 57 3,696 Global 155 660 923 1,476 253 438 1,530 86 5,522 Blue ocean opportunities Red ocean opportunities * Post-Osimertinib resistant population shown for EGFRm NSCLC except for SCLC transformation ** Co-occurring activating MAPK pathway alterations exclude EGFR overexpression Source: SEER database (2020), ECIS database (2020), GLOBOCAN database (2020), The AACR Project GENIE Consortium version 8.1 (2020), TCGA Research Network: https://www.cancer.gov/tcga, Tyner JW et al. (2018) PMID: 30333627, Brenner CW et al (2013) PMID: 24120142, Chen J et al. (2020) PMID: 32015526, and Ostrom QT, et al. (2020) PMID: 33123732 5
Erasca’s SEACRAFT trials to address naporafenib’s Blue Ocean opportunities In any nautical journey, seacraft are needed to traverse the vast blue ocean not just in their capacity as seagoing ships, but also for their important second meaning: skill in navigation. Erasca is navigating the ”blue ocean” of unmet medical needs using next generation sequencing and other techniques to identify RAS/MAPK pathway-altered tumors that can be treated with naporafenib, a potent, selective, orally bioavailable pan-RAF inhibitor, in combination with other targeted therapies. 1. SEACRAFT-1 2. SEACRAFT-2 3. SEACRAFT-3 Strategy: Signal-seeking trial designed to Strategy: Pivotal study to support global Strategy: Expand development of generate data in the near term to inform approval in the lead indication, NRASm naporafenib with other RAS/MAPK targeting development, including potential tissue melanoma agents agnostic indication Design: Expected to be a randomized phase 3 Design: Expected to be a Phase 1/2 in Design: Expected to be a single-arm phase 2 pivotal trial assessing naporafenib + trametinib patients with solid tumors driven by NF1 LOF, trial assessing naporafenib + trametinib for the for the treatment of NRASm melanoma pan-RAS G13R, KRAS G12C, and BRAF treatment of pan-RAS Q61X tissue agnostic Class 2 and 3 alterations solid tumors 6
Pro forma with naporafenib Our singular focus is on the RAS/MAPK pathway Naporafenib targets BRAF/CRAF node critical to driving signaling in a broad range of RASm cancers EGFR/ FLT3 Other RTKs Our Strategy RAS-GDP 2 GEF Comprehensively shut down GRB2 GDP the RAS/MAPK pathway GAP P GTP 1 Target RAS directly SOS1 2 NF1 with single agents and SHP2 combinations with upstream, RAS-GTP Autophagy 2 downstream, and escape route MAPK PI3K targeted therapies pathway pathway 1 RAF PI3K P P 1 AKT MEK Target escape routes 3 Target upstream and P enabled by other proteins or ERK mTOR ULK downstream RAS/MAPK nodes pathways to further disrupt with single agents and clamp RAS/MAPK pathway signaling oncogenic drivers (MAPKlamp) with MYC 3 combinations Nodes targeted by Erasca 7
Pro forma with naporafenib Naporafenib complements and significantly advances Erasca’s deep modality-agnostic RAS/MAPK pathway-focused pipeline Program/ Erase Cancer Worldwide Target Modality Indication Discovery IND-enabling Phase 1 Phase 2 Phase 3 Company Strategy Rights Pan-RAS Q61X tissue agnostic SEACRAFT-1 (planned) ❶ NRASm melanoma ❶ SEACRAFT-2 (planned) Naporafenib BRAF/CRAF NF1 LOF, pan-RAS G13R, KRAS G12C, SEACRAFT-3 (planned) ❶ BRAF Class 2/3 solid tumors RAS/MAPK altered tissue agnostic, NSCLC HERKULES-1 / -2 / -3 ǂ ERAS-007* ERK1/2 ❶ and GI Tumors FLAGSHP-1 ERAS-601* SHP2 RAS/MAPK altered tumors ❶ THUNDERBBOLT-1 ERAS-801 EGFR EGFR altered GBM ❶ AURORAS-1 ERAS-3490 KRAS G12C KRAS G12C solid tumors ❷ ERAS-2/3 RAS-GTP RASm solid tumors ❷ ERAS-4 KRAS G12D KRAS G12D solid tumors ❷ ERAS-5 ULK RASm solid tumors ❸ ERAS-9 SOS1 RAS/MAPK altered solid tumors ❶ ERAS-10 RAS/MAPK RAS/MAPK altered cancers ❶❷❸ ERAS-11 MYC MYC & RAS/MAPK altered solid tumors ❸ ERAS-12 EGFR D2/D3 EGFR & RAS/MAPK altered solid tumors ❶ Affini-T KRAS G12V/D KRASm solid tumors ❷ * Together, ERAS-007 and ERAS-601 comprise our first innovative MAPKlamp investment ǂ small molecule protein degrader large molecule TCR T cell therapy Also being evaluated in combo w/ G12Ci in KRAS G12C NSCLC and GI Tumors under Stand Up to Cancer grant 8
Pro forma with naporafenib Naporafenib is synergistic with Erasca’s industry-leading pipeline shutting down every node of the RAS/MAPK pathway ERAS-801 EGFR/ FLT3 ERAS-12 Other RTKs RAS-GDP ERAS-3490 GEF GRB2 GDP GAP P GTP 1 SOS1 ERAS-9 NF1 SHP2 RAS-GTP ERAS-2/3/4 ERAS-601 MAPK PI3K ERAS-10 pathway pathway RAF PI3K naporafenib P P MEK AKT P ERAS-007 ERK mTOR ULK ERAS-5 MYC ERAS-11 9
Pro forma with naporafenib Naporafenib milestones and clinical trial readouts complement 4 Erasca’s existing portfolio and potentially accelerate path to market Program Trial Name 2022 2023 2024 Mechanism Indication SEACRAFT-1 H2 2023 H2 2024 – H1 2025 3 Ph 2 FPD Ph 2 combo data RAS Q61 Solid Tumors Naporafenib Pan-RAF inhibitor SEACRAFT-2 H1 2024 3 Ph 3 pivotal FPD NRASm Melanoma HERKULES-1 H2 2022 H1 2023 ERAS-007 and/or 3 MAPKlamp Ph 1b FPD Ph 1b data (achieved) Advanced Solid Tumors ERAS-601 1 HERKULES-2 2023 (MAPKlamp ) Ph 1b combo data Lung Cancers ERK1/2 inhibitor and/or HERKULES-3 H1 2023 SHP2 inhibitor Ph 1b combo data GI Cancers FLAGSHP-1 H2 2022 Advanced Solid Tumors Ph 1 data (achieved) ERAS-601 SHP2 inhibitor FLAGSHP-1 H1 2023 2 Triple WT CRC Ph 1b combo data ERAS-3490 AURORAS-1 H2 2022 CNS-penetrant KRAS G12Cm NSCLC File IND KRAS G12C inhibitor ERAS-801 THUNDERBBOLT-1 H1 2022 CNS-penetrant 3 FPD (achieved) Glioblastoma Multiforme EGFR inhibitor 1 ERAS-007 (oral ERK1/2 inhibitor) and ERAS-601 (oral SHP2 inhibitor) together comprise our first innovative MAPKlamp 2 Triple wildtype CRC is KRASwt, NRASwt, and BRAFwt 3 FPD = first patient dosed 4 Guidance on milestones and clinical trial readouts for rest of pipeline to be provided in 2023 10
SAB includes world’s leading experts in the RAS/MAPK pathway Erasca co-founder. World expert in RAS who pioneered development of approaches to inhibit KRAS G12C (RAS-GDP) and active states of RAS (RAS-GTP) Kevan Shokat, PhD World expert in RAS/MAPK pathway with World expert in ERK, having studied World expert in SHP2 who helped nearly every ERK inhibitor that has focus on the SHOC2 phosphatase complex as a unique regulatory node pioneer development of the first SHP2 been or is being developed, as well as required for efficient pathway activation targeted therapies directed against inhibitor with Novartis in the context of diseases such as KRAS, BRAF, and MEK mutations cancer and RASopathies Stephen Blacklow Ryan Corcoran, Pablo Rodriguez- MD, PhD MD, PhD Viciana, PhD World expert in targeted oncology World expert in structure-based drug design; World expert in RAS/MAPK pathway therapies who pioneered the development former head of research at Agouron and signaling and identifying novel combination ® of Gleevec , which helped launched the former head of Genentech’s Research and therapies to shut it down precision oncology revolution Early Development (gRED) George Michael Karen Demetri, MD Cichowski, PhD Varney, PhD 11
Leadership team has global experience and drive to make a difference Jonathan Lim, MD Mike Varney, PhD David Chacko, MD Ebun Garner, JD Wei Lin, MD Lisa Tesvich- Chairman, CEO, Chairman of R&D, SAB Member, Chief Financial Officer General Counsel Chief Medical Officer Bonora, PhD and Co-Founder and Board Director Chief People Officer Amy Grekowicz Parker, Tim Grammer, PhD Brian Baker, CPA Les Brail, PhD Rachel Cervantes, PhD Nik Chetwyn, PhD Chandra Lovejoy, MS VP of Portfolio, Program SVP of Finance VP of Clinical VP of Business SVP of Operations MPH SVP of Regulatory Affairs & Alliance Management Development Development VP Clinical Operations Robert Shoemaker, PhD Jean-Michel Vernier, PhD Minli Xie, PhD Dawei Xuan, PhD Jing Yi, PhD Shannon Morris, MD SVP of Research VP of Chemistry VP of CMC VP of Clinical Pharmacology VP of Data Science PhD SVP of Clinical Development 12
Product Development Team leadership with deep collective experience and track record of successfully obtaining approvals Complex / Novel HA Negotiations, Global Marketing Commercialization, CDP and Study Implementation, Application ROW Submissions, Study Designs Overall Development Content & Strategy Payer Plans ü Successful study designs forü Successful health authorityü Successful Marketing Application ü Successful Global Marketing Phase 2 approvals, use of novel negotiations: US/ EU/ Japan/ China Development: Strategies to support Application Submissions: endpoints, and companion AA/CMA and Full Approval US/EU/China/Japan ü Complex trial implementation diagnostics across multiple geographiesü ROW Strategy & Planning ü Life Cycle Management planning ü Master protocol experience: (label expansion) ü Successful overall developmentü Successful regulatory inspections designing and implementing complex plans to include Pediatric Strategies, (US/EU): establishing quality systems ü HTA/Payer Experience to support trials Rare Diseases and Biomarkers; for rapid Phase 2 initial approvals reimbursement and price negotiation ü Creativity and Drive: Success in ü Continued process verification and short timelines and in small companies product serialization to support global demands ü Regulatory Designations: BTD, PRIME, Sakigake, Orphan, EU SME Examples from previous companies where drive and creativity led to efficient and novel initial global approvals Tumor agnostic and Novel indication Novel drug/Dx on Ph 2 Early CDP/BLA Novel ROW Filing Fast Filing Initiative CDx approval on Ph 2 Data Data on Ph 2 Data Ignyta/Roche G1 Therapeutics Roche/Genentech MedImmune Roche/Genentech Roche/Genentech CDP: clinical development plan 13
Key license terms for naporafenib (LXH254) pan-RAFi: Potential first-to-market molecule for melanoma, tissue agnostic, and more Expected financial terms Amount ($M unless otherwise indicated) • License scope: Exclusive license to patent Total upfront $100 rights, know-how, and regulatory – Cash $20 1 – Equity $80 documentation covering naporafenib and all backups Total development milestones – cash $0 Up to $80 • Field: All fields of use 2 Total regulatory milestones – cash nd (incl. up to $30 for 2 indication) • Territory: Worldwide Total commercial milestones – cash Up to $200 – First commercial sale – $0 • Drug supply: Novartis will transfer existing – Sales-based milestones – Up to $200 inventory of naporafenib and provide access Total deal value before royalties to trametinib Up to $300 (excluding equity) Royalties Low single digit percentage 3 Erasca and Novartis are currently negotiating the definitive agreement and are targeting deal signing and announcement during the week of December 5, 2022 1 Equity to be issued at an agreed upon price 2 Covers two indications in US, EU, and JP 3 Deal terms subject to change until the definitive agreement is executed 14
Naporafenib Overview
BRAF/CRAF is a critical node of the RAS/MAPK pathway EGFR/ FLT3 Other RTKs RAS-GDP GEF • BRAF and CRAF drive downstream RAS/MAPK GRB2 GDP pathway signaling in RAS mutant cancers GAP P GTP 1 SOS1 NF1 SHP2 • NRASm melanoma and RAS Q61X solid tumors RAS-GTP Autophagy are exquisitely dependent on BRAF and CRAF MAPK PI3K pathway pathway • RAF kinases are activated through dimerization BRAF CRAF RAF PI3K with the same or other members of the RAF family P P MEK AKT • Opportunities exist for multiple combination P approaches, especially with inhibitors of ERK mTOR ULK downstream nodes, MEK and/or ERK MYC 16
Naporafenib is a potent and selective inhibitor of BRAF and CRAF with sub- nanomolar IC50 potency and most advanced pan-RAFi in development Biochemical activity of naporafenib against RAF kinase family Biochemical kinome profiling of LXH254 in HCT116 cell lysates Assay Value (nM) Biochemical CRAF IC50 (IC ) 0.1 50 Biochemical BRAF IC50 (IC ) 0.2 50 Biochemical ARAF Inhibition (IC ) 6.4 50 Kinases inhibited >80% by naporafenib at 1 µM out of 456 kinases, per KINOMEscan (kinases are WT unless marked otherwise) Biochemical activity of naporafenib across 456 kinases (KINOMEscan) Kinase % Inhibition at 1 µM PDGFRB 99.9% DDR1 99.7% BRAF V600E 99.7% BRAF 99.6% CRAF 98.8% DDR2 84.0% Source: Monaco K-A, Delach S, et al. LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors. 2021. PMID: 33355204; Ramurthy S, Taft BR, et al. Design and Discovery of N-(3-(2-(2- 17 Hydroxyethoxy)-6-Morpholinopyridin-4-Yl)-4-Methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic. 2020. PMID: 31059256
Naporafenib clinical development to date in more than 500 patients Wealth of early phase data has established safety, tolerability and preliminary POC EGFR Other RTKs • Trial LXH254X2101 (n=142): naporafenib FIH dose escalation study RAS-GDP GEF conducted in patients with RAS/MAPK-driven solid tumors GRB2 GDP GAP P GTP 1 SOS1 • Trial LXH254X2102 (n=241): dose finding study of naporafenib NF1 combinations (+rineterkib [ERKi] [n=101], trametinib [MEKi] [n=115], or SHP2 ribociclib [CDK4/6i] [n=25]) in patients with NRASm melanoma, RAS-GTP KRASm or BRAFm NSCLC MAPK PI3K pathway pathway • Trial LXH254C12201 (n=134): Phase 2 study of naporafenib combinations (+rineterkib [n=59], trametinib [n=53], or ribociclib RAF PI3K naporafenib [n=22]) in patients with NRASm or BRAF V600X melanoma P P MEK AKT trametinib • Trial ADPT01C12101 (n=7): platform study exploring the triplet combination of naporafenib + dabrafenib + rineterkib (n=7) in BRAF P V600X CRC ERK mTOR ULK rineterkib • Total size of safety database > 500 patients (includes CDK4/6 monotherapy and combinations) MYC ribociclib Source: Novartis Non-Confidential Materials 18
Erasca is well positioned to advance naporafenib through a focused development plan that leverages RAS/MAPK pipeline synergies Top priority to address unmet needs in ~395,000 patients WW Focus on securing regulatory approval for naporafenib + trametinib in RAS Q61X tissue agnostic solid tumors (SEACRAFT-1) and/or NRASm melanoma (SEACRAFT-2) as soon as possible Top Exploratory combos to address unmet needs in ~1.2m patients WW Priority Explore novel doublet, and possibly triplet, combination(s) in NF1 LOF, RAS Exploratory G13R, KRAS G12C, and BRAF Class 2 and 3 altered solid tumors (SEACRAFT-3) Combinations Potential RASm Potential RASm opportunities to address unmet needs for ~1.9m patients WW Opportunities Ungate potential opportunities in other RASm indications if well tolerated combinations are identified above and/or supported by evolving data 19
~5.5m lives at stake annually worldwide with RAS/MAPK pathway alterations Prioritized development plan for naporafenib potentially addresses ~3.5m (over 63%) of these New cases estimated worldwide per annum (thousands; numbers may not add up due to rounding) Other solid Alterations GBM HNSCC NSCLC CRC Melanoma PDAC AML US EU ROW Global tumors EGFR*/FLT3 125 513 184 338 - - - 61 82 222 917 1,220 NF1 25 58 98 34 33 1.9 434 3.2 75 159 453 687 KRAS G12C - 2.8 240 57 - 5.1 45 0.1 36 82 232 350 KRAS G12D 0.2 4.7 68 238 0.5 178 201 1.3 65 171 456 692 N/H/KRAS Q61X 0.4 23 35 80 69 32 155 4.1 51 106 242 399 H/N/KRAS G13R - 9.4 5.9 5.5 2.1 - 14 0.5 3.6 8.1 26 37 Other K/N/HRAS 0.6 31 162 452 4.4 211 331 13 112 291 800 1,203 BRAF V600E/K 2.0 1.9 23 180 93 1.4 158 0.4 63 127 271 461 BRAF Class 2 0.4 3.8 18 6.9 5.3 0.5 57 - 11 23 58 92 BRAF Class 3 0.1 0.9 12 17 2.5 - 29 0.2 6.1 15 40 61 Other BRAF - - 3.9 - 1.9 0.3 0.5 - 0.7 1.0 4.9 6.6 MEK 0.2 1.9 12 8.8 4.6 0.2 22 - 5.2 11 33 50 Co-occurring activating MAPK 1.4 10 62 59 37 7.1 84 3.0 33 69 162 264 pathway alterations** US 12 29 93 114 77 51 153 11 542 Top priority addresses ~395,000 patients worldwide EU 34 76 194 398 116 124 324 18 1,285 Exploratory combos address ~1.2m patients worldwide Rest of World 109 555 635 964 60 264 1,053 57 3,696 Potential RASm opportunities address ~1.9m patients worldwide Global 155 660 923 1,476 253 438 1,530 86 5,522 Blue ocean opportunities Red ocean opportunities * Post-Osimertinib resistant population shown for EGFRm NSCLC except for SCLC transformation ** Co-occurring activating MAPK pathway alterations exclude EGFR overexpression Source: SEER database (2020), ECIS database (2020), GLOBOCAN database (2020), The AACR Project GENIE Consortium version 8.1 (2020), TCGA Research Network: https://www.cancer.gov/tcga, Tyner JW et al. (2018) PMID: 30333627, Brenner CW et al (2013) PMID: 24120142, Chen J et al. (2020) PMID: 32015526, and Ostrom QT, et al. (2020) PMID: 33123732 20
Focused development plan in Q61X tissue agnostic solid tumors (SEACRAFT-1) Focus on securing regulatory approval for naporafenib + trametinib in RAS Q61X tissue agnostic solid tumors (SEACRAFT-1) and/or NRASm melanoma (SEACRAFT-2) as soon as possible Top Priority 21
Structural and cell line screening data suggest that differences exist across different RAS mutants in vitro; e.g., Q61X mutant tumors likely to be CRAF addicted Cellular activity of naporafenib across 265 cell lines, separated by RAS mutation type 22 Source: Monaco K-A, Delach S, et al. LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors. 2021. PMID: 33355204
Strong activity of naporafenib + trametinib observed in NRASm melanoma in LXH254X2102 Phase 1 may also be driven by natural enrichment of Q61X mutations • Strong antitumor activity observed, with ORR = 44% • 15 out of 16 patients had confirmed codon Q61X melanoma (1 patient had no data) Source: Novartis Non-Confidential Materials 23
Strong activity of naporafenib + trametinib also observed in KRASm NSCLC (N=49) in LXH254X2102 Phase 1, showing 34x higher ORR in Q61X/G13R mutated group • ORR in mutated group is 34x more than the ORR in the non-mutated group - ORR in mutated group (n=4): 75% (95% CI: 19.4% - 99.4%) (variability is high and sample size is low in the mutated group) - ORR in non-mutated group (n=45): 2.2% (95% CI: 0.1% - 11.8%) - Confirmed/unconfirmed RECIST responses shown Source: Novartis Non-Confidential Materials 24
Naporafenib + trametinib combination has a compelling opportunity to address unmet needs in the Q61X tissue agnostic solid tumor indication • The targeted patient population has exhausted all treatment options • In these types of advanced patients without any SOC options, preventing Clinical progression is important since progression frequently leads to mortality; i.e., there Unmet Need are not any approved therapies they can receive once they progress • Strong scientific rationale for targeting RAS Q61X mutations with naporafenib; trametinib adds synergistic activity Naporafenib • Clinical POC for Q61X already achieved for melanoma and NSCLC and • Trametinib is already an established SOC component which is predicted to facilitate trametinib physician comfort with this combination SOC = standard of care 25
Focused development plan in NRASm melanoma (SEACRAFT-2) Focus on securing regulatory approval for naporafenib + trametinib in RAS Q61X tissue agnostic solid tumors (SEACRAFT-1) and/or NRASm melanoma (SEACRAFT-2) as soon as possible Top Priority 26
NRAS mutant in vivo models exhibited sensitivity to naporafenib both as a single agent and in anchored combinations NRASm model treated with NRASm melanoma PDX models treated with LXH254 single agent LXH254 anchored combinations Note: LEE011 or Rib. (ribociclib) is a CDK4/6 inhibitor; Tram (trametinib) is a MEK inhibitor; and LTT (LTT462) is an ERK inhibitor Source: Novartis Non-Confidential Materials 27
Current Standard of Care for metastatic melanoma with NRAS mutation Poor SOC in post-IO setting highlights a high unmet need indication Frontline therapy is IO mono Post-IO therapy is predominantly chemo or combo Immunotherapy Chemotherapy MEKi (not approved) Nivolumab Dacarbazine Binimetinib Pembrolizumab Temozolomide (recommended by US Nivolumab + Ipilimumab Paclitaxel NCCN but not by EU Nivolumab + Relatlimab Nab-paclitaxel guidelines) Carboplatin + paclitaxel Cisplatin + vinblastine + dacarbazine SOC * ORR DCR PFS OS Dacarbazine 7% 24% 1.5m 10.1m Binimetinib 15% 56% 2.8m 11.0m Improvement in ORR and DCR of binimetinib vs. dacarbazine translated to improvement in PFS * NEMO trial (Lancet Oncol (2017) 18: 435-445.) 28
The observed clinical activity of naporafenib + trametinib in NRASm melanoma was reproducible across Phase 1 and Phase 2 studies at two RDEs LXH254 (200 mg BID) + LXH254 (400 mg BID) + trametinib (1.0 mg QD) trametinib (0.5 mg QD) Data Study/Indication Cutoff ORR DCR DOR ORR DCR DOR Source LXH254X2102* 9 Dec 7/15 12/15 2/15 10/15 3.75 mo 3.75 mo AACR 2022 NRASm melanoma 2021 (46.7%) (80.0%) (13.3%) (66.7%) # LXH254C12201 4 July 6/24 17/24 5/17 12/17 NA NA ESMO 2022 NRASm melanoma 2022 (25%) (70.8%) (29%) (70.6%) Total of 13/39 responses Total of 7/32 responses 33.3% ORR 21.9% ORR RDE = recommended dose expansion *De Braud et al AACR 2022 # Lebbe et al ESMO 2022 29
Naporafenib + trametinib exhibited anti-tumor activity in NRASm melanoma Addition of naporafenib to MEKi improves the historical MEKi mono activity ORR 47% (21%-73%)* ORR 13% (1.7%-41%)* DCR 80% (n=15) DCR 67% (n=15) Regimen (n) Median Prior Therapy ^ ORR * DCR Napo + Trame (30 combined in both RDEs) 2 (1-7) 30% (15-49) 73% Dacarbazine (133) 1 7% (3-13) 25% Binimetinib (269) 1 15% (11-20) 58% De Braud et al AACR 2022 (Trial LXH254X2102, NCT02974725). ^ NEMO trial initially limited to 1 prior therapy later amended to allow more than 1 line. Range not available. * 95% confidence interval. ORR: objective response rate. DCR: disease control rate (ORR + stable disease). 30
Naporafenib + trametinib exhibited durable responses in NRASm melanoma Duration of Exposure • Responses observed in patients with normal or high LDH • Median DOR was 3.75 months for both doses • Median PFS was 5.03 months (95% CI: 3.42–5.62)* BID, twice daily; CR, complete response; PD, progressive disease; PR, partial response; De Braud et al AACR 2022 (Trial LXH254X2102, NCT02974725) * For both doses combined. QD, once daily; SD, stable disease; UNK, unknown. 31
Dual MAPK blockade with naporafenib regimens was effective in NRASm melanoma LXH254C12201 Ph 2 trial confirms encouraging activity of panRAFi + MEKi/ERKi combinations Best Overall Responses in NRASm Melanoma (n=70) Treatment Duration in NRASm Tumors + ERKi + MEKi + MEKi + CDK4/6i + ERKi ORR = 21% ORR = 25% ORR = 29% ORR = 7% + MEKi + MEKi + CDK4/6i Responses were ongoing in 14 patients Naporafenib combination activity in NRASm melanoma was consistent across two nodes (MEK, ERK) and two doses (200mg, 400mg) Source: Lebbe et al, ESMO 2022 32
Case Study: Partial response with naporafenib 200 mg BID + trametinib 1 mg QD in a patient with NRASm melanoma Source: Novartis Non-Confidential Materials 33
Naporafenib + trametinib has a favorable safety and manageable AE profile De Braud et al AACR 2022 34
Naporafenib demonstrates combinability with inhibitors of MAPK and other pathways No apparent drug-drug interactions noted Treatment-related AEs (in ≥5% of patients) 35 CONFIDENTIAL Source: Lebbe et al, ESMO 2022
Skin toxicities are the most common AEs in naporafenib combinations AEs are manageable and expected to improve with prophylactic skin care Treatment-related Skin AEs (in ≥5% of patients) Source: Lebbe et al, ESMO 2022 36 CONFIDENTIAL
Naporafenib + trametinib combination has a compelling opportunity to address unmet needs in NRASm melanoma • For patients with NRASm melanoma, the SOC therapies in the post-IO space are minimally active ⎼ Median PFS on chemotherapy is only 1.5 months Clinical ⎼ Median OS on chemotherapy is only 10.1 months Unmet Need • In these types of advanced patients without good SOC options, preventing progression is important since progression frequently leads to mortality; i.e., there aren’t any therapies they can receive once they progress • Higher ORR and DCR than comparators (chemo or MEKi) coupled with encouraging duration of treatment in Ph 1 and Ph 2 studies are predicted to translate into prolonged PFS and/or OS compared to SOC Naporafenib • Naporafenib + trametinib predicted to be more efficacious than MEKi monotherapy and • Trametinib is the established SOC in BRAF V600 melanoma and considered to be the best-in-class MEKi, trametinib which is predicted to facilitate adoption of naporafenib + trametinib combo in NRASm melanoma • Enthusiastic KOL support SOC = standard of care 37
Preliminary plan subject to global Proposed pivotal & Phase 2 trial designs: Creative CDP strategy includes high health authority PTS randomized NRASm melanoma trial and potential for tissue agnostic indication feedback Initiate single-arm and randomized trials in quick succession. NRASm melanoma is the lead indication. Tissue agnostic registration will be supported by melanoma and other solid tumor data, based on regulatory feedback. Single-Arm Phase 2 Trial (SEACRAFT-1) Solid Tumors (Age 12+) Study Endpoints Post-available therapy naporafenib + trametinib RAS Q61X ORR, DOR (NRAS, HRAS, KRAS) N~30 - 100 Randomized Phase 3 Trial (SEACRAFT-2) Metastatic Melanoma Study Endpoints naporafenib + trametinib Post-IO R PFS, OS (dual primary) NRASm ORR, DOR (secondary) 1:1 TBD (e.g., dacarbazine, physician’s choice) (Q61X and non-Q61X) N~350 - 400 * Assumptions: CoC for naporafenib monotherapy in melanoma from FIH trial. CoC in solid tumors is not needed. AA: accelerated/conditional approval. RA: regular approval. 38
Analysis of pts with NRASm melanoma in Ph 2 who remain on treatment show potential for napo + tram to potentially demonstrate PFS benefit in SEACRAFT-2 Duration of Exposure (months) for naporafenib 200 mg BID + trametinib 1 mg QD SD >6 PR >5 SD >5 PR <6 PR >5 PR >5 SD >4 SD >4 PR >4 SD <4 SD <4 SD <4 SD <4 PR >5 SD <4 SD <4 PD <2 PD <2 uPR <4 PD <2 Note: Patients who remain on PD <2 NE treatment shown in teal NE NE 0 2 4 6 8 9/24 patients remain on treatment as of data cutoff • 1 of these has already delayed progression by >6 months • 8 other patients have possibility of continuing on treatment for >6 months (5 are at >5 mos., 3 are at >4 mos.; 5 of them have PRs, 3 of them have SDs) and could extend PFS Source: annotated LXH254C12201 Ph 2 trial data from Lebbe et al, ESMO 2022 39
Ph 2 patients continuing on treatment on naporafenib + trametinib = potential for confirmation of Ph 1 DOR and potential PFS advantage in SEACRAFT-2 Naporafenib 200mg BID + trametinib 1mg QD 24 enrolled 15 off treatment 9 on treatment n=1 PR progression delayed < 6mo n=1 uPR progression delayed < 4mo n=6 SD progression delayed < 4mo n=4 PD progression delayed < 2mo 4 SDs 5 PRs n=3 NE n=1 progression delayed > 6mo n=4 progression delayed > 5mo n=1 progression delayed > 5mo n=1 progression delayed > 4mo n=2 progression delayed > 4mo Patients with SD at, or on track, for delayed progression > 4 months could contribute to PFS benefit vs. SOC *includes unconfirmed responses Source: annotated LXH254C12201 Ph 2 trial data from Lebbe et al, ESMO 2022 40
Naporafenib’s addition to Erasca’s pipeline can broaden our exploration into other well-defined indications Explore novel doublet, and possibly triplet, combination(s) in NF1 LOF, RAS G13R, KRAS G12C, and BRAF Class 2 and 3 altered solid tumors (SEACRAFT-3) Exploratory Combinations • These biomarker defined tumors have shown biologically a strong addiction to the RAS/MAPK pathway and are selected as the next indications to explore. • Combinations of naporafenib with Erasca’s RAS/MAPK pathway focused pipeline may demonstrate efficacy by effecting a more complete shutdown of the pathway. 41
Pro forma with naporafenib Our pipeline supports multiple pairwise combinations to expand the potential of naporafenib to patients with other RAS/MAPK-driven tumors and unmet clinical needs EGFR/ FLT3 Other RTKs RAS-GDP ERAS-3490 GEF GRB2 GDP GAP Potential Naporafenib combos with Erasca Pipeline P GTP 1 SOS1 • naporafenib + ERAS-007 NF1 SHP2 ERAS-601 • naporafenib + ERAS-601 RAS-GTP • naporafenib + ERAS-007 + ERAS-601 • naporafenib + ERAS-3490 MAPK PI3K pathway pathway RAF PI3K naporafenib P P Target Tumor Types AKT MEK trametinib NF1 LOF Tissue Agnostic P RAS G13R Tissue Agnostic ERAS-007 ERK mTOR ULK KRAS G12C NSCLC BRAF Class 2 Tissue Agnostic MYC BRAF Class 3 Tissue Agnostic 42
BRAF Class 2 and Class 3 mutations represent an unmet need Naporafenib provides us with an additional agent to target these Potential combinations within Erasca Pipeline that could target BRAF Class 2 and 3 mutations • naporafenib + ERAS-007 • naporafenib + ERAS-601 • ERAS-007 + ERAS-601 • ERAS-007 + ERAS-601 + naporafenib 43
Erasca’s pipeline can expand naporafenib into other RAS-driven tumors that lack direct targeted inhibitors • Confirmation of proof-of-concept in NRASm melanoma and RAS Q61X solid tumors, together with signals from exploration into RAS G13R, KRAS G12C, NF1 LOF, and BRAF Class 2 and 3 mutations, will help to better define the tumor types, mutations, and combinations for the potential upside opportunities such as other RASm settings. • Erasca’s deep pipeline in the RAS/MAPK pathway can maximize the central role naporafenib may play in improving the standard of care in RAS-driven tumors. Potential RASm Ungate potential opportunities in other RASm indications if well tolerated Opportunities combinations are identified above and/or supported by evolving data 44
Pro forma with naporafenib Erasca’s clinical development plan generates multiple ways to win for patients RAS/MAPK EGFRm NRASm KRASwt/ RAS Q61X melanoma altered solid NSCLC KRAS G12C BRAFm CRC BRAFm CRC KRASm/ NRASwt/ HPV-negative EGFR altered Indication tumors post-osi NSCLC EC-naïve EC-treated NRASm CRC BRAFwt CRC HNSCC rGBM solid tumors post-IO SOC is ORR 7%, SOC is ORR 29%, ORR 36%, ORR 20%, ORR ~2%, ORR ~2%, ORR 20%, ORR 13%, ORR 26%, largely chemo mDOR 4.2 mDOR 10 mDOR 6.1 mDOR NA mDOR NA mDOR 5.4 mDOR 5.8 mDOR 4.2 largely chemo mDOR 4.1 Benchmark mos. mos. mos. mos. mos. mos. mos. naporafenib naporafenib ERAS-007 ERAS-007 ERAS-007 ERAS-007 ERAS-007 ERAS-007 ERAS-601 ERAS-601 ERAS-801 + + or + + + + + monotherapy + + trametinib trametinib ERAS-601 osimertinib ERAS-601 encorafenib encorafenib palbociclib cetuximab cetuximab (our first + + + MAPKlamp) sotorasib cetuximab cetuximab Regimen tested ERAS-007 ERAS-3490 (alternative schedules) ERAS-601 (alternative schedules) HERKULES-1 HERKULES-2 HERKULES-2 HERKULES-3 HERKULES-3 HERKULES-3 FLAGSHP-1 FLAGSHP-1 THUND- SEACRAFT-1 SEACRAFT-2 Sub-study 1 Sub-study 2 Sub-study 1 Sub-study 1 Sub-study 2 ERBBOLT-1 Erasca trial(s) FLAGSHP-1 AURORAS-1 (planned) 100% of CRC 45
Pro forma with naporafenib Compelling investment thesis EXPERIENCED TEAM WITH TRACK RECORD OF SERIAL SUCCESSES Seasoned drug developers who have advanced multiple programs from discovery to IND to global approvals WORLD-CLASS SCIENTIFIC ADVISORY BOARD Leading pioneers in KRAS (Shokat, UCSF), SHP2 (Blacklow, HMS), ERK (Corcoran, MGH), RAS/MAPK pathway (Rodriguez-Viciana, UCL; Cichowski, HMS), precision oncology (Demetri, DFCI), and biopharma (Varney, Genentech) BROAD PORTFOLIO TO ERASE CANCER We believe we have built the deepest pipeline in the industry to comprehensively shut down RAS/MAPK pathway, with the potential to address unmet needs in over 5 million patients globally FOUR CLINICAL STAGE COMPOUNDS Differentiated profiles including naporafenib, a phase 2, pivotal-ready pan-RAF inhibitor for NRASm melanoma and Q61X tissue agnostic solid tumors MULTIPLE POTENTIAL NEAR-TERM AND LONG-TERM VALUE DRIVERS Five compounds anticipated to be in the clinic in 2023; addl. IND filings anticipated every 12-18 mos. through 2026 46
Thank You!
Naporafenib (LXH254): a Phase 2, pivotal-ready pan-RAF inhibitor with potential first-in-class and best-in-class profile in RAS/MAPK-altered tumors Naporafenib • Potent (sub-nanomolar IC50 against BRAF and CRAF), • 500+ patients treated with naporafenib selective, orally bioavailable pan-RAF inhibitor as a single agent or in combination • Type 2, ATP-competitive inhibitor of RAF by maintaining the • Clinical POC or responses have been kinase in an inactive c-���� in/DFG -out conformation achieved in pan-RAS Q61X solid tumors (melanoma, NSCLC), NRASm ⎼ Generates minimal paradoxical activation (as observed with V600X targeting RAFi’s) melanoma, and KRAS G13R NSCLC ⎼ Inhibits both monomeric (V600E) and dimerized RAF • Key toxicities are generally consistent with on-target effects observed with ⎼ Enables suppression of RAS/MAPK pathway signaling, other RAF inhibitors (e.g., skin, GI, including RAS-activated wild-type RAF and activated mutant fatigue) RAF 48
Naporafenib inhibits RAS/MAPK pathway signaling in RAS mutant cells pMEK MEK Cellular Assay IC50 (nM) pERK pMEK (Calu-6, KRAS Q61K) 14 ERK Cellular proliferation 470 BRAF inhibition (Calu-6) CRAF GAPDH HCT116 MEL-JUSO MIA PaCa-2 KRAS G13D KRAS Q61L KRAS G12C NRAS G13D Source: Monaco K-A, Delach S, et al. LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors. 2021. PMID: 33355204; Ramurthy S, Taft BR, et al. Design and Discovery of N-(3-(2-(2- 49 Hydroxyethoxy)-6-Morpholinopyridin-4-Yl)-4-Methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic. 2020. PMID: 31059256 DMSO LY3009120 Naporafenib DMSO LY3009120 Naporafenib DMSO LY3009120 Naporafenib
As the terminal node of the RAS/MAPK pathway, ERK is a critical target EGFR/ FLT3 Other RTKs RAS-GDP GEF GRB2 GDP GAP P GTP 1 SOS1 • ERK is less susceptible to pathway reactivation NF1 SHP2 compared to MEK RAS-GTP Autophagy MAPK PI3K • ERK is implicated in acquired resistance to pathway pathway RAFi/MEKi’s and other targeted therapies RAF PI3K P P • Opportunities exist for multiple combination MEK AKT approaches P ERK mTOR ULK ERK MYC 50
We believe ERAS-007 is the most potent ERK inhibitor in development Assay Type Assay ERAS-007 IC50 (nM) ERAS-007 ERK1 2 Biochemical designed to be a potent, selective, ERK2 2 reversible, oral inhibitor of ERK1/2 Cell-based mechanistic (HT-29) pRSK 7 ERAS-007 exhibited potent anti-proliferative activity in cell lines with mutations in the RAS/MAPK pathway compared to other ERKi’s 10 000 1 000 Compound ERAS-007 100 Rav oxertinib Ulixertinib 10 1 BRAF HRAS KRAS NRAS wildtype RAS and wildtype RAF 51 IC50 (nM) HT-29 A375 Colo 205 T24 NCI-H2122 LoVo PANC-1 HCT116 Calu-6 A549 NCI-H460 CFPAC-1 SK-MEL-2 Hep G2 A2780 LNCaP PC-3 U-87 MG MCF7 T-47D BT-474 786-O
ERAS-007’s uniquely long target residence time may enable dosing flexibility In multiple assays, ERAS-007 had longer target residence time vs. other ERKi’s, which may allow for longer intervals between doses in patients -1 Compound k (s ) Residence Time (min) off -4 ERAS-007 0.30 x 10 550 -4 Ulixertinib 10.1 x 10 16 -4 Ravoxertinib 13.9 x 10 12 52
HERKULES and SU2C clinical trial series – ERAS-007 master protocols HERKULES-1 HERKULES-2 HERKULES-3 Stand Up To Cancer Tissue Agnostic Lung Cancer GI Cancer Lung and GI Cancer Agent(s) Indication Regimen Indication Regimen Indication Regimen Indication Regimen Indication Exploring safety ERAS-007 + BRAF V600E- & PK of various ERAS-007 + encorafenib KRAS G12C- EGFR-mutant mutant CRC ERAS-007 + ® 1,4 ERAS-007 intermittent osimertinib (Braftovi ) and mutant NSCLC NSCLC (EC naïve and adagrasib ® dosing schedules (Tagrisso ) cetuximab and CRC treated) ® 2 for combinations (Erbitux ) ERAS-007 + RAS/MAPK- ERAS-007 or KRAS- or NRAS- ERAS-007 + ERAS-601 altered Solid ERAS-601 + KRAS G12C- mutant CRC; 3 palbociclib (our first Tumors (potential sotorasib mutant NSCLC KRAS-mutant ® (Ibrance ) TM MAPKlamp) tissue agnostic) (Lumakras ) PDAC 1 Sep. 2021: Announced CTCSA with Pfizer ® for encorafenib (Braftovi ) ERAS-007 in Mutational ERAS-007 in Mutational 2 Mar. 2022: Announced CTCSA with Lilly for ® cetuximab (Erbitux ) combination with subtypes of combination with subtypes of GI 3 Oct. 2022: Announced CTCSA with Pfizer other agents NSCLC other agents cancers ® for palbociclib (Ibrance ) Ongoing sub-study 4 Nov. 2022: Announced CTCSA with Pierre ® Future sub-study Fabre for encorafenib (Braftovi ) Note: CTCSA = clinical trial collaboration and supply agreement 53
ERAS-007 showed strong in vivo combination activity in BRAF V600E CRC TGI in RKO (BRAF V600E CRC) TGI in WiDr (BRAF V600E CRC) EC-resistant CDX Model EC-sensitive CDX Model Treatment group Treatment group ERAS-007 30 mpk BID ERAS-007 30 mpk BID 1,500 2,000 Cetux. 30 mpk Q3D Cetux. 30 mpk Q3D Encor. 90 mpk QD Encor. 90 mpk QD ERAS-007 30 mpk BID + Encor. 90 mpk QD ERAS-007 30 mpk BID + Encor. 90 mpk QD Encor. 90 mpk QD + Cetux. 30 mpk Q3D Encor. 90 mpk QD + Cetux. 30 mpk Q3D ERAS-007 30 mpk BID + Encor. 90 mpk QD + ERAS-007 30 mpk BID + Encor. 90 mpk QD + 1,500 Cetux. 30 mpk Q3D Cetux. 30 mpk Q3D 1,000 Vehicle Vehicle control 1,000 500 500 * 0 0 5 10 15 20 0 10 20 Treatment day Treatment day • ERAS-007 60 mpk QD dose showed similar activity to 30 mpk BID, either as a mono or combo Tx with encor. +/- cetux. • ERAS-007 combinations were generally well tolerated across the tested models as demonstrated by the minimal percentage body weight changes observed. *p-value < 0.01 Note: Cetux. = cetuximab; encor. = encorafenib; EC = encorafenib plus cetuximab (BEACON regimen) 54 Mean tumor volume (mm3) +/- SEM Mean tumor volume (mm3) +/- SEM
ERAS-007 + palbociclib enhanced tumor growth inhibition (TGI) in KRASm CRC and PDAC models TGI in KRAS G13D CRC CDX LoVo TGI in KRAS G12D PDAC PDX PAN026 • Combination was tolerated in mice (e.g., no dose holidays, deaths, or euthanizations) • ERAS-007 and palbociclib were dosed orally and continuously 55
ERAS-007 + ERAS-601 MAPKlamp showed consistent combination activity in BRAF class 3 and NF1 loss of function (LoF) models TGI in NF1 LoF NSCLC NCI-H1838 TGI in BRAF Class 3 NSCLC PDX LUN023 • MAPKlamp combination showed activity in both models and was tolerated in mice (e.g., no dose holidays, deaths, or euthanizations) • ERAS-007 and ERAS-601 were dosed orally and continuously 56
SHP2 is a critical “on/off switch” that activates GTP-bound KRAS signaling EGFR/ FLT3 Other RTKs • SHP2 is a convergent node for upstream RAS-GDP GEF RTK signaling GRB2 GDP GAP P GTP 1 SOS1 NF1 SHP2 • A SHP2i can block dephosphorylation to SHP2 RAS-GTP Autophagy maintain GTP-bound KRAS in a “dark MAPK PI3K pathway pathway state” and thereby reduce RAS signaling RAF PI3K • SHP2 inhibition is emerging as a P P MEK AKT backbone of combination therapy P ERK mTOR ULK MYC 57
ERAS-601 demonstrates high potency and selectivity against SHP2 IC (nM) 50 Cell Line Cancer Type Biochemical SHP2 1 Compound ERAS-601 RMC-4550 inhibition IC50 (nM) HCC44 NSCLC 48 95 ERAS-601 4.6 MIA PaCa-2 Pancreatic 6 17 NCI-H1373 NSCLC 64 474 NCI-H1792 NSCLC 40 27 KRAS G12C NCI-H2122 NSCLC 259 1,876 ERAS-601 NCI-H358 NSCLC 12 49 demonstrated no off-target activity in 300 kinase (<30% inhibition @ 1μM) and 12 phosphatase SW1573 NSCLC 104 298 panels (IC50 >10μM) NCI-H1666 NSCLC 19 51 BRAF class III NCI-H508 CRC 95 208 NF1 LoF MeWo Melanoma 56 241 wtEGFR amplification KYSE-520 Esophageal 119 440 1 RMC-4550 is Revolution Medicine’s SHP2i tool compound and is believed to behave similarly to their clinical compound, RMC-4630 (per company disclosure); LoF = loss of function; wtEGFR = wildtype EGFR 58
ERAS-601: favorable physicochemical, ADME, and PK properties well suited for combination therapy ERAS-601 PK Route of Assay ERAS-601 Parameter Mouse Rat Dog Administration (Unit) (CD-1) (SD) (Beagle) cLogP/PSA <1/<130 Cl IV 13 9.9 9.8 (mL/min/kg) MW <600 PO %F 63 48-83 75-107 PBS solubility (µM) >300 Caco2 permeability at 10 μM, 2.57/27.5 -6 Papp (AB/BA) (10 , cm/s) Key takeaways: 26/11/35/33 Plasma protein binding, Free fraction % M/R/D/H • Low DDI risk and no CYP flags make ERAS- 601 well suited for combination therapy Stability in liver microsomes, M/R/D/H Low Clearance • Low in vivo Cl and high bioavailability in Inhibition of CYP 3A4, 2C9, 2D6, IC50 (µM) >100 multiple species suggest favorable human CYP3A4 TDI No flag PK profile hERG Q-patch IC50 (µM) >30 GLP hERG IC50 (µM) 12 59
ERAS-601 in FLAGSHP-1 clinical trial and HERKULES master protocol HERKULES-2 FLAGSHP-1 Sub-Study B Part A, B, and C Part D ERAS-601 + sotorasib combination in Monotherapy ERAS-601 + NSCLC Dose Escalation 1 cetuximab Combination Dose Escalation Dose Expansion QD Dose Dose Escalation Cohorts Cohorts Cohorts Ongoing Pending Completed BID Dose Cohorts Additional sub-studies are dedicated to other indications and combinations. Completed Intermittent Combo Dose Dose Cohorts Cohorts Ongoing Ongoing 1 Jul 2022: Clinical trial collaboration and supply agreement with ® Lilly for cetuximab (Erbitux ) executed 60
ERAS-601 + cetuximab demonstrated significantly greater tumor inhibition vs. cetuximab alone in triple wildtype CRC and HPV-negative HNSCC models TGI in Triple WT CRC PDX model CRC1021 TGI in HPV-negative HNSCC PDX HN3411 700 Vehicle 1,000 Vehicle Cetuximab 20 mg/kg BIW Cetuximab 30 mg/kg Q3D ERAS-601 10 mg/kg/dose BID ERAS-601 30 mg/kg QD 600 ERAS-601 30 mg/kg QD ERAS-601 30 mg/kg QD + Cetuximab 30 mg/kg Q3D 800 ERAS-601 10 mg/kg/dose BID + Cetuximab 20 mg/kg BIW ERAS-601 30 mg/kg QD + Cetuximab 20 mg/kg BIW 500 400 600 300 400 200 200 100 0 0 0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 28 Treatment period (days) Treatment period (days) • Combination was tolerated in mice (e.g., no dose holidays, deaths, or euthanizations) • ERAS-007 and palbociclib were dosed orally and continuously 61 3 Tumor volume (mm ) Tumor volume (mm3) Mean ± SEM
SHP2 and ERK are critical nodes of the RAS/MAPK pathway EGFR/ FLT3 • As the terminal node, ERK is Other • SHP2 is a convergent RTKs less susceptible to node for upstream RTK RAS-GDP GEF pathway reactivation signaling GRB2 GDP compared to MEK GAP P GTP 1 SOS1 • A SHP2i can block NF1 SHP2 SHP2 • ERK is implicated in dephosphorylation to RAS-GTP Autophagy acquired resistance to maintain GTP-bound KRAS RAFi/MEKi’s and other MAPK PI3K in a “dark state” and thereby pathway pathway targeted therapies reduce RAS signaling RAF PI3K • Opportunities exist for • SHP2 inhibition is emerging P P MEK AKT multiple combination as a backbone of approaches combination therapy P ERK mTOR ULK ERK MYC 62
ERAS-601 and ERAS-007 target SHP2 and ERK, respectively EGFR/ FLT3 Other RTKS Potent, RAS-GDP GEF selective, orally GRB2 GDP bioavailable GAP P GTP 1 SOS1 SHP2 inhibitor NF1 SHP2 ERAS-601 in clinical SHP2 RAS-GTP Autophagy development in FLAGSHP-1 MAPK PI3K pathway pathway and HERKULES-2 RAF PI3K Potent, P P selective, orally MEK AKT bioavailable P ERK inhibitor in ERK mTOR ULK ERAS-007 ERK clinical development in HERKULES-1, - MYC 2, -3 and SU2C 63
Sept. 2022 R&D Day and ENA 2022 highlights • ERAS-007 and ERAS-601 are active drugs – monotherapy responses • ERAS-007: uPR in KRAS G12V PDAC on new BID-QW dosing • ERAS-601: cPR in BRAF Class III endometrial cancer—only second company to show Efficacy monotherapy response with SHP2 inhibitor Future Directions: • Validated hypotheses for combo of upstream + downstream RAS/MAPK pathway inhibition (MAPKlamp) and combo of RAS/MAPK + cell cycle inhibition • Erasca identified a meaningful and targetable population—specifically BRAF Class II and III— • Both compounds appear safe and tolerable, with limited overlapping tox (diarrhea) that could benefit from Safety • Diarrhea can be managed with prophylaxis or supportive care MAPKlamp (ERAS-007 + ERAS-601) • This patient population currently has no approved • ERAS-007: data from PK modeling is nearly superimposable with observed data targeted therapy • ERAS-007: good exposure above IC90 for tumor cell killing and below IC50 for normal PK cell recovery enables “hit and run” profile • ERAS-601: good exposure above IC50 for sustained target coverage Note: PK = pharmacokinetics; u/cPR = unconfirmed/confirmed partial response; PDAC = pancreatic ductal adenocarcinoma; BID-QW = two doses on one day each week 64
Segmentation framework to identify more responsive subsets within the Blue Ocean for prioritized combination development “Blue Ocean indications” of solid tumors with RAS/MAPK alterations and no approved targeted therapies Less sensitive to Phase 1/1b monotherapy monotherapy inhibition due responses used to inform CRC Non-CRC to more RAS/MAPK prioritized combination reactivation and bypass development pathway activation Evaluation of combinations addressing these mechanisms is ongoing in HERKULES-3 (and combination addressing triple wildtype CRC is ongoing in FLAGSHP-1) Targetable, more responsive subset of patients prioritized for combination development 65
Methodology for retrospective pooled efficacy analysis for ERAS-007 and ERAS-601 in solid tumors with RAS/MAPK pathway alterations* All trials assessing ERAS-007 or ERAS-601 as monotherapies: Retrospective Pooled Analysis ASN007-101, HERKULES-1, FLAGSHP-1 Biologically relevant regimens above the efficacious dose and at or below the maximum tolerated dose (MTD) for ERAS-007 and at or below the maximum administered dose (MAD) for ERAS-601 Dosing Regimens ERAS-007: weekly dose intensity between 120mg and 250mg, ERAS-601: daily dose intensity of 40mg CRC: Less sensitive to monotherapy inhibition due to more RAS/MAPK reactivation and bypass RAS/MAPK Alterations pathway activation in Solid Tumors Non-CRC: Less RAS/MAPK reactivation and no targeted therapies with full approval Evaluable tumor assessment at baseline and at least one post dose tumor assessment Efficacy Evaluable Evaluated as per RECIST v1.1 by investigator Patients * The clinical data presented in the following slides are based on a retrospective analysis of pooled data across multiple clinical trials with different designs, inclusion criteria, and dosing regimens. Results across such clinical trials cannot be directly compared. 66
Best overall response with ERAS-007 or ERAS-601 in 15 RAS/MAPK-altered Blue Ocean Indications across lines of therapy 23% (6 out of 26) of patients responded (confirmed and unconfirmed PR) to single agent ERAS-007 or ERAS-601 * * * * * Unconfirmed partial responses indicated with an asterisk. NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/MAPK alterations where no targeted therapies are approved; Biologically relevant dose defined as weekly monotherapy dose intensity between 120mg and 250mg for ERAS-007 and daily monotherapy dose intensity of 40mg (40mg QD or 20mg BID) for ERAS-601; data extraction date: 6NOV2020 for ASN007-101, 11JUL2022 for ERAS-601-01, 16May2022 for ERAS-007-01. One patient without measurable disease at baseline and at least one post baseline target lesion measurement was excluded from the waterfall plot 67
Duration of treatment observed with ERAS-007 or ERAS-601 in 15 RAS/MAPK-altered Blue Ocean Indications across lines of therapy Thyroid, BRAF V600E Ovarian, KRAS G12C Saliv. Gland, HRAS Q61 Endometrial, BRAF D594G Pancreatic, KRAS G12V Melanoma, BRAF rearr. Ampullary, KRAS G12V NSCLC, BRAF K601E Pleom. Parotid, HRAS G13R, BRAF V600L Pancreatic, KRAS G12V Pancreatic, KRAS G12D Melanoma, NRAS Q61 Squamous cell, BRAF rearr. Medull. Thyroid, HRAS Q61 Thyroid, NRAS Q61 Melanoma, NRAS Q61 Esophageal, NF1 LOF Pancreatic, KRAS G12D Cervical, KRAS G13D Pancreatic, KRAS G12D Ovarian, KRAS G12A Small bowel, BRAF K601E Lung, BRAF fusion Pancreatic, KRAS G12D Melanoma, BRAF N581F Prostate, BRAF K601E NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/MAPK alterations where no targeted therapies are approved; Biologically relevant dose defined as weekly monotherapy dose intensity between 120mg and 250mg for ERAS-007 and daily monotherapy dose intensity of 40mg (40mg QD or 20mg BID) for ERAS-601; data extraction date: 6NOV2020 for ASN007-101, 11JUL2022 for ERAS-601-01, 16May2022 for ERAS-007-01. 68 Efficacy-Evaluable Patients
HERKULES-1 Case Study: Single agent ERAS-007 response 70-year-old female (Patient 0033) with KRAS G12V metastatic pancreatic cancer Diagnosis Stage II pancreatic cancer, metastatic disease, KRAS G12V, initially diagnosed in January 2018 Sites of Metastases Lung, lymph nodes Surgery, adjuvant radiation, gemcitabine/ capecitabine (#1); 5FU/oxaliplatin/irinotecan (#2); gemcitabine/abraxane Prior Therapy (#3); 5FU/liposomal irinotecan (#4); alomfilimab (ICOS-targeted antibody)/atezolizumab (#5); MVT-5873 (anti-CA 19-9 antibody) (#6) Dosing ERAS-007 125 mg BID-QW Baseline 31% reduction in tumor size 16 Weeks Patient progressed with new lesion at subsequent assessment Per RECIST 1.1: ≥30% = objective response 69
Targetable, more responsive subset of patients with RAS/MAPK alterations “Blue Ocean indications” of solid tumors with RAS/MAPK alterations and no approved targeted therapies CRC Non-CRC BRAFm • N = 9 (subset of the N = 26) • Higher rate of single agent responses to either agent was observed 70
Best Overall Response Observed with ERAS-007 or ERAS-601 in BRAF-driven Blue Ocean Indications across lines of therapy 44% (4 out of 9) of patients responded (confirmed and unconfirmed PR) to single agent ERAS-007 or ERAS-601 * * * * Unconfirmed partial responses indicated with an asterisk NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/MAPK alterations where no targeted therapies are approved; Biologically relevant dose defined as weekly monotherapy dose intensity between 120mg and 250mg for ERAS-007 and daily monotherapy dose intensity of 40mg (40mg QD or 20mg BID) for ERAS-601; data extraction date: 6NOV2020 for ASN007-101, 11JUL2022 for ERAS-601-01, 16May2022 for ERAS-007-01. 71
Duration of Treatment Observed with ERAS-007 or ERAS-601 in BRAF-driven Blue Ocean Indications Thyroid, BRAF V600E (Class 1) Endometrial, BRAF D594G (Class 3) Melanoma, BRAF rearr. (Class 2) NSCLC, BRAF K601E (Class 2) Squamous cell, BRAF rearr. (Class 2) Small bowel, BRAF K601E (Class 2) Lung, BRAF fusion (Class 2) Melanoma, BRAF N581F (Class 3) Prostate, BRAF K601E (Class 2) NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/MAPK alterations where no targeted therapies are approved; Biologically relevant dose defined as weekly monotherapy dose intensity between 120mg and 250mg for ERAS-007 and daily monotherapy dose intensity of 40mg (40mg QD or 20mg BID) for ERAS-601; data extraction date: 6NOV2020 for ASN007-101, 11JUL2022 for ERAS-601-01, 16May2022 for ERAS-007-01. 72 Efficacy-Evaluable Patients
FLAGSHP-1 Case Study: Single agent ERAS-601 response 63-year-old female (Patient 0009) with BRAF Class 3 metastatic endometrial cancer Diagnosis Stage III/IV endometrial cancer, metastatic disease, BRAF Class 3, initially diagnosed in September 2018 Sites of Metastases Lung, lymph nodes Prior Therapy Surgery, chemotherapy, pembrolizumab Dosing ERAS-601 20 mg BID 24 Weeks Baseline 32 Weeks 32% decrease 50% decrease Tumor assessment (5) (Jan 4, 2022): patient had radiologic progressive disease (PD) due to a new lesion Per RECIST 1.1: ≥30% = objective response Peri-Esophageal lesion, shrinkage in non-target lesions also noted (not shown) 73
Breakdown of tumor types and molecular drivers by trial Number of patients in ERAS-007 and ERAS-601 trials CRC Non-CRC, Non-BRAF-driven 1 ASN007-101 trial : Non-CRC, BRAF-driven 34 ‒ ~93% of patients had non-CRC tumors 1 ‒ Of these, ~62% were 5 BRAF-driven 8 ASN007-101 14 1 HERKULES-1 trial : 0 ‒ ~63% of patients had 6 non-CRC tumors ‒ Of these, none were 10 2 solely BRAF-driven HERKULES-1 16 1 FLAGSHP-1 trial : 1 1 ‒ 75% of patients had non- CRC t umors FLAGSHP-1 4 ‒ Of these, ~33% were 2 Patients with BRAF-driven RAS/MAPK Alterations 1 ASN007-101 trial was sponsored by Asana BioSciences; HERKULES-1 and FLAGSHP-1 trials are sponsored by Erasca 2 One patient had HRAS G13R and BRAF V600L, so BRAF was not the sole oncogene driver 74
TRAEs of ERAS-601 and ERAS-007 have been largely non-overlapping ERAS-601 and ERAS-007 by common SHP2i TRAEs ERAS-601 and ERAS-007 by common ERKi TRAEs ERAS-601 ERAS-007 ERAS-601 ERAS-007 50-125mg BID-QW 50-125mg BID-QW Treatment-related AEs in 20 and 40 mg BID Treatment-related AEs in 20 and 40 mg BID (N=23) (N=23) Preferred Terms (N=13) Preferred Terms (N=13) All Grade Gr ≥ 3 All Grade Gr ≥ 3 All Grade Gr ≥ 3 All Grade Gr ≥ 3 HEMATOLOGIC SKIN Thrombocytopenia* 3 (23.1%) 2 (15.4%) 0 0 Maculopapular rash 0 0 2 (8.7%) 0 Anemia 3 (23.1%) 1 (7.7%) 1 (4.3%) 1 (4.3%) Dermatitis acneiform 2 (15.4%) 0 8 (34.8%) 0 CARDIOVASCULAR EYE DISORDERS Hypertension 3 (23.1%) 1 (7.7%) 0 0 Blurred vision 2 (15.4%) 0 5 (21.7%) 1 (4.3%) Hypertensive Retinopathy 0 0 6 (26.1%) 0 1 (7.7%) 1 (7.7%) 0 0 encephalopathy Retinal Detachment 0 0 1 (4.3%) 1 (4.3%) HEPATIC Vision Impairment 0 0 1 (4.3%) 1 (4.3%) AST increase 2 (15.4%) 1 (7.7%) 0 0 GASTROINTESTINAL ALT increase 2 (15.4%) 0 0 0 Nausea 0 0 12 (52.2%) 0 Blood bilirubin 0 0 1 (4.3%) 1 (4.3%) Vomiting 0 0 7 (30.4%) 0 increased Potential overlapping Diarrhea 5 (38.5%) 1 (7.7%) 5 (21.7%) 0 tox; can be managed GENERAL proactively Constipation 0 0 2 (8.7%) 0 Peripheral edema 4 (30.8%) 0 1 (4.3%) 0 Dyspepsia 2 (8.7%) 0 Gr 4 AEs: GENERAL ERAS-601: anemia, hypertensive encephalopathy ERAS-007: none Fatigue 1 (7.7%) 0 9 (39.1%) 2 (8.7%) • Data cut off for FLAGSHP-1: 11JUL2022 & for HERKULES-1: 23May2022 • In this table is reported the number of patients who experienced the reported AE at the highest grade. Dehydration 0 0 4 (17.4%) 0 • TRAEs included in this table met at least one of the following criteria: (1) experienced by ≥ 2 patients in either the 20 and 40 mg BID treatment group for ERAS-601 OR the 50-125 mg BID-QW column for ERAS- Dizziness 0 0 2 (8.7%) 0 007; (2) experienced by at least 1 patient and Grade ≥3. • *includes platelets count decrease 75
Likely recommended dose of ERAS-007 for combinations was well tolerated Treatment-related Adverse Events Occurring in ≥ 20% and ≥ 2 Patients at Any Dose (arranged by descending frequency in the 250mg QW any grade column) 50 mg BID-QW (n=4) 100 mg BID-QW (n=11) 125 mg BID-QW (n=8) 250 mg QW (n=29) System Organ Class/ Preferred Term Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade At least one TRAE 4 (100.0%) 1 (25.0%) 9 (81.8%) 2 (18.2%) 8 (100.0%) 3 (37.5%) 27 (93.1%) 10 (34.5%) Eye Disorders* 1 (25.0%) 0 6 (54.5%) 1 (9.1%) 5 (62.5%) 2 (25.0%) 16 (55.2%) 5 (17.2%) Diarrhea 0 0 2 (18.2%) 0 3 (37.5%) 0 16 (55.2%) 1 (3.4%) Nausea 2 (50.0%) 0 5 (45.5%) 0 5 (62.5%) 0 14 (48.3%) 0 1 (25.0%) 0 3 (27.3%) 0 3 (37.5%) 0 9 (31.0%) 2 (6.9%) Vomiting 1 (25.0%) 0 4 (36.4%) 0 3 (37.5%) 0 6 (20.7%) 0 Dermatitis acneiform Rash maculopapular 0 0 1 (9.1%) 0 1 (12.5%) 0 6 (20.7%) 1 (3.4%) Dehydration 2 (50.0%) 0 1 (9.1%) 0 1 (12.5%) 0 4 (13.8%) 0 1 (25.0%) 1 (25.0%) 4 (36.4%) 0 4 (50.0%) 1 (12.5%) 5 (17.2%) 1 (3.4%) Fatigue Likely recommended dose between 50 – 100mg BID-QW for combinations was well tolerated *includes uniocular blindness (one patient in 250mg QW cohort), chorioretinopathy, papilloedema, retinal detachment, retinal oedema, retinopathy, serous retinal detachment, subretinal fluid, vision blurred, visual impairment, and vitreous floaters. Data extraction for ASN-007-101 was on 6 Nov. 2020; data cutoff for HERKULES-1 was 23 May 2022 76
ERAS-007 and ERAS-601 use different target coverage strategies that seek to achieve optimal efficacy and safety ERAS-007 Mean Cycle 1 PK Profile ERAS-601 Mean Steady State PK Profile * IC * 50 IC 90 * IC 50 ERAS-007: 50-125mg BID-QW dosing provided high target coverage ERAS-601: 40mg BID dosing provided sustained target coverage (C>IC ) for maximum activity, followed by lower PK coverage (C<IC ) (C>IC ) throughout the dosing interval 90 50 50 for MAPK pathway recovery to alleviate target driven toxicity *HCT 116 anti-proliferation assay for ERAS-007; pERK in NCI-358 for ERAS-601 77
Dr. Kevan Shokat at UCSF turned KRAS from undruggable to druggable EGFR/ FLT3 Other RTKS RAS-GDP RAS-GDP GEF GRB2 GDP GAP P • Shokat identified a G12C-specific inhibitor that locks GTP 1 SOS1 NF1 KRAS in inactive state, spurring multiple companies SHP2 RAS-GTP Autophagy to develop KRAS G12C inhibitors MAPK PI3K pathway pathway • High unmet need remains for patients with NSCLC (CNS metastases occur in up to 40% of patients) RAF PI3K P P MEK AKT • Focus of our discovery efforts has been on developing KRAS G12C inhibitors with high CNS P ERK mTOR ULK penetration MYC Source: Ostrem J., et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013. PMID: 24256730 78
We have discovered promising CNS-penetrant KRAS G12Ci pre-candidates Reference 1 Parameter 3490 3691 3599 3537 3788 2 compounds Mouse AUC /D po (hr*kg*ng/mL/mg) 693 597 1,333 535 326 102 - 637 Rat brain / plasma (%) total total 52% 13% 66% 68% 11% 1 - 6% Rat brain concentration (ng / g) 156 32 176 290 91 6 - 36 3 P-gp substrate ratio 4 1.5 4.1 2.7 8.3 4.0 30.9 Human LM metabolic stability (CL normalized to hepatic blood flow) 0.7 0.5 0.6 0.4 0.5 0.7 - 0.8 Mouse LM metabolic stability (CL normalized to hepatic blood flow) 0.8 0.6 0.7 0.7 0.4 0.4 - 0.9 In vitro potency (4 hr pERK IC50, nM / RAS Initiative KRAS G12C 3D 5-day viability IC50, nM) 13 / 4 58 / 9 37 / 15 21 / 9 12 / 2 17 - 31 / 1 - 4 1 ERAS-3490 has been selected as the KRAS G12C inhibitor development candidate 2 The reference compounds are sotorasib and adagrasib 3 P-gp substrate ratios were characterized in a P-gp expressing MDCK cell line. Per compound, a P-gp substrate ratio was calculated by dividing its efflux ratio in absence of a P-gp inhibitor by its efflux ratio in presence of a P-gp inhibitor. Compounds with lower P-gp substrate ratios are less likely to be P-gp substrates 4 The P-gp substrate ratio was characterized for a single reference compound. 79
Beyond G12C: Targeting KRAS G12D and other RAS-GTP mutations EGFR/ FLT3 Other RAS-GDP State RTKS RAS-GDP 2 GEF GRB2 GDP GAP P GTP 1 SOS1 NF1 SHP2 RAS-GTP Autophagy 2 RAS-GTP MAPK PI3K pathway pathway • Targeting KRAS G12D and other RAS-GTP mutations is more challenging, as they are more commonly found in the active GTP state RAF PI3K RAS-GTP State • ERAS-4 KRAS G12D program leverages expertise from ERAS-3490 and ERAS-2/3 discovery; P P molecules in lead op have demonstrated low nM IC50 potency in RAS-RAF binding assay MEK AKT • ERAS-2/3 RAS-GTP inhibitor program based on Kevan Shokat’s identification of a new binding P site called S-IIG that is pres ERK ent in both mTO RA RS-GTP and ULK RAS-GDP states ⎼ Discovery opens possibility to selectively target other RAS mutations in active state ⎼ Erasca has exclusive WW license from UCSF related to work performed by Shokat MYC in this field Source: Gentile DR, et al., Cell Chem Biol. 2017 Dec 21;24(12):1455-1466.e14 80
Our EGFR franchise programs are highly differentiated ERAS-12: ERAS-801: EGFR CNS- D2/D3 penetrant bispecific for EGFRvIII/wt CRC and inhibitor other tumors • High BBB penetration and good oral bioavailability • Next generation EGFR bispecific antibody discovered by Drs. Dev Sidhu, Sekar Seshagiri & Jagath Reddy Junutula; former Genentech • Oral inhibitor with high CNS exposure (3.7:1 brain:plasma) 1 • Approved EGFR mAbs target D3, not D2 • K over 4x higher than approved EGFRi’s p,uu • EGFR D2 targeting antibodies expected to be more effective when EGF is • Potently/selectively inhibited EGFR alteration s overexpressed (like pertuzumab blocking receptor dimerization in HER2) (e.g., vIII, amps., polysomy) • High unmet monotherapy opportunity in recurrent GBM 1 K is a measure of the ratio of unbound brain concentration to unbound plasma concentration p,uu 81