UNITED STATES
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WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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Item 7.01 Regulation FD Disclosure.
On January 9, 2023, representatives of Erasca, Inc. (the Company) will be presenting at the J.P. Morgan Healthcare Conference and will be attending meetings with investors and analysts during the week in connection with the conference. During the presentation and the meetings, the Company will present the corporate presentation attached as Exhibit 99.1 to this report, which is incorporated herein by reference.
The Company’s updated corporate presentation will be posted to the Company’s website, www.erasca.com. The Company plans to use its website to disseminate future updates to its corporate presentation and does not intend to file or furnish a Form 8-K alerting investors each time the presentation is updated.
The information set forth in this Item 7.01 is being furnished pursuant to Item 7.01 and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the Exchange Act), or otherwise subject to the liabilities of that section, and it shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or under the Exchange Act, whether made before or after the date hereof, except as expressly provided by specific reference in such a filing.
By filing this report and furnishing the information in this Item 7.01, the Company makes no admission as to the materiality of Item 7.01 in this report or the presentation available on the Company’s website. The information contained in the presentation is summary information that is intended to be considered in the context of the Company’s filings with the Securities and Exchange Commission (the SEC) and other public announcements that the Company makes, by press release or otherwise, from time to time. The Company undertakes no duty or obligation to publicly update or revise the information contained in this report, although it may do so from time to time as its management believes is appropriate or as required by applicable law. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases, by updating the Company’s website or through other public disclosure.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
| Exhibit No. | Description | |
| 99.1 | Erasca, Inc. Corporate Presentation, dated January 2023 | |
| 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: January 9, 2023 | By: | /s/ Ebun Garner | ||||
| Ebun Garner, General Counsel | ||||||
On a Journey to Erase Cancer Erasca Corporate Presentation January 2023 Exhibit 99.1
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 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, 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 five product candidates in 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. Disclaimer: Forward Looking Statements & Market Data
Our name is our mission: to erase cancer 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 Vision to one day erase cancer1 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-801, CNS-penetrant EGFRi with first-in-class potential for EGFR-driven rGBM ERAS-3490, CNS-penetrant KRAS G12Ci with best-in-class potential in NSCLC Strong financial position with high quality investor base and industry visibility ~$365M in cash, cash equivalents, and short-term marketable securities2; plus $100M equity financing announced on 12/9/2022 One of Fierce Biotech’s 2021 “Fierce 15” most promising biotechnology companies
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) World expert in ERK, having studied nearly every ERK inhibitor that has been or is being developed, as well as targeted therapies directed against KRAS, BRAF, and MEK mutations World expert in targeted oncology therapies who pioneered the development of Gleevec®, which helped launched the precision oncology revolution World expert in structure-based drug design; former head of research at Agouron and former head of Genentech’s Research and Early Development (gRED) World expert in RAS/MAPK pathway signaling and identifying novel combination therapies to shut it down Karen Cichowski, PhD George Demetri, MD Michael Varney, PhD Stephen Blacklow MD, PhD World expert in SHP2 who helped pioneer development of the first SHP2 inhibitor with Novartis Ryan Corcoran, MD, PhD World expert in RAS/MAPK pathway with focus on the SHOC2 phosphatase complex as a unique regulatory node required for efficient pathway activation in the context of diseases such as cancer and RASopathies Pablo Rodriguez-Viciana, PhD Kevan Shokat, PhD
* 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 New cases estimated worldwide per annum (thousands; numbers may not add up due to rounding) Blue ocean opportunities Red ocean opportunities Alterations GBM HNSCC NSCLC CRC Melanoma PDAC Other solid tumors AML US EU ROW Global 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 RAS Q61X 0.4 23 35 80 69 32 155 4.1 51 106 242 399 RAS G13R - 9.4 5.9 5.5 2.1 - 14 0.5 3.6 8.1 26 37 Other RAS 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 pathway alterations** 1.4 10 62 59 37 7.1 84 3.0 33 69 162 264 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 ~5.5m lives at stake annually worldwide with RAS/MAPK pathway alterations; 70+% of unmet needs are “blue oceans” with no approved targeted therapies
Our singular focus is on the RAS/MAPK pathway P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR/ FLT3 Other RTKs MYC GEF Nodes targeted by Erasca Target upstream and downstream RAS/MAPK nodes with single agents and clamp oncogenic drivers (MAPKlamp) with combinations 1 1 Target RAS directly with single agents and combinations with upstream, downstream, and escape route targeted therapies 2 2 2 Target escape routes enabled by other proteins or pathways to further disrupt RAS/MAPK pathway signaling 3 3 Our Strategy Comprehensively shut down the RAS/MAPK pathway
Program/ Company Target Modality Indication Discovery IND-enabling Phase 1 Phase 2 Phase 3 Erase Cancer Strategy Worldwide Rights Naporafenib BRAF/CRAF Pan-RAS Q61X tissue agnostic ❶ NRASm melanoma ❶ NF1 LOF, pan-RAS G13R, KRAS G12C, BRAF Class 2/3 solid tumors ❶ ERAS-007*ǂ ERK1/2 RAS/MAPK altered tissue agnostic, NSCLC and GI Tumors ❶ ERAS-601* SHP2 RAS/MAPK altered tumors ❶ ERAS-801 EGFR EGFR altered GBM ❶ 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 ǂ Also being evaluated in combo w/ G12Ci in KRAS G12C NSCLC and GI Tumors under Stand Up to Cancer grant large molecule protein degrader small molecule TCR T cell therapy investment SEACRAFT-2 (planned) HERKULES-1 / -2 / -3 SEACRAFT-1 (planned) THUNDERBBOLT-1 AURORAS-1 FLAGSHP-1 Erasca’s deep modality-agnostic RAS/MAPK pathway-focused pipeline SEACRAFT-3 (planned)
Our pipeline targets every node of the RAS/MAPK pathway Note: MAPKlamp = ERAS-007 in combination with ERAS-601 and/or other agents P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR Other RTKS MYC GEF ERAS-9 ERAS-601 naporafenib ERAS-007 ERAS-10 ERAS-5 ERAS-11 ERAS-3490 ERAS-801 ERAS-12 ERAS-2/3/4
Erasca’s clinical development plan generates multiple ways to win for patients Indication Benchmark Regimen tested Erasca trial(s) HERKULES-2 Sub-study 11 EGFRm NSCLC post-osi ERAS-007 + osimertinib ORR 29%, mDOR 4.2 mos. HERKULES-3 Sub-study 13 BRAFm CRC EC-naïve ERAS-007 + encorafenib + cetuximab ORR 20%, mDOR 6.1 mos. HERKULES-3 Sub-study 13 BRAFm CRC EC-treated ERAS-007 + encorafenib + cetuximab ORR ~2%, mDOR NA HERKULES-3 Sub-study 24 RASm CRC + KRASm PDAC ERAS-007 + palbociclib ORR ~2%, mDOR NA FLAGSHP-15 KRASwt/ NRASwt/ BRAFwt CRC ERAS-601 + cetuximab ORR 20%, mDOR 5.4 mos. THUND- ERBBOLT-1 EGFR altered rGBM ERAS-801 monotherapy ORR 7-8% mDOR 3.9 mos. HERKULES-2 Sub-study 22 KRAS G12C NSCLC ERAS-601 + sotorasib ORR 36%, mDOR 10 mos. ERAS-3490 AURORAS-1 HERKULES-1 RAS/MAPK altered solid tumors ERAS-007 + ERAS-601 (our first MAPKlamp) SOC is largely chemo 100% of CRC FLAGSHP-15 HPV-negative HNSCC ERAS-601 + cetuximab ORR 13%, mDOR 5.8 mos. SEACRAFT-1 RAS Q61X solid tumors naporafenib + trametinib SOC is largely chemo SEACRAFT-2 NRASm melanoma post-IO naporafenib + trametinib ORR 7%, mDOR 4.1 mos. 1 Completed enrollment; data in H1 2023 2 Closed from further enrollment due to prioritization of other opportunities Focus of presentation 3 Sep. 2021: Announced CTCSA with Pfizer for encorafenib (Braftovi®) Mar. 2022: Announced CTCSA with Lilly for cetuximab (Erbitux®) Nov. 2022: Announced CTCSA with Pierre Fabre for encorafenib (Braftovi®) 4 Oct. 2022: Announced CTCSA with Pfizer for palbociclib (Ibrance®) 5Jul. 2022: Announced CTCSA with Lilly for cetuximab (Erbitux®) BRAFm CRC EC-naïve BRAFm CRC EC-treated KRASwt/ NRASwt/ BRAFwt CRC EGFR altered rGBM RAS/MAPK altered solid tumors HPV-negative HNSCC RAS Q61X solid tumors NRASm melanoma post-IO
Erasca’s clinical-stage programs could address unmet needs in up to 1.7 million patients annually in the US and Europe SEACRAFT-3/HERKULES-1: BRAF Class 2/3 * Addressable patient population, US and Europe (’000s; numbers may not add up due to rounding) ERAS-801 Naporafenib Napo + ERAS-007 or ERAS-601, ERAS-007 + ERAS-601, or Napo + ERAS-007 + ERAS-601 Erasca pipeline agents ERAS-007 ERAS-601 483 1,221 Source: * Post-Osimertinib resistant population shown for EGFRm NSCLC except for SCLC transformation Source: SEER database (2020), ECIS 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 466 ERAS-3490
P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR RAS-GDP EGFR/ FLT3 Other RTKs MYC GEF Erasca’s naporafenib pan-RAFi could address unmet needs in approximately 500k patients in the US and Europe ERK BRAF CRAF naporafenib Addressable Patient Pop. Tumor Type RAS Q61X Solid Tumors 157,000 NF1 Loss-of-Function 234,000 BRAF Class II/III Solid 55,000 TOTAL 500,000 NRASm Melanoma 54,000 tissue agnostic indication Note: Addressable patient population rounded to nearest thousand
Naporafenib is a potent and selective inhibitor of BRAF and CRAF with sub-nanomolar IC50 potency and most advanced pan-RAFi in development 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-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 Assay Value (nM) Biochemical CRAF IC50 (IC50) 0.1 Biochemical BRAF IC50 (IC50) 0.2 Biochemical ARAF Inhibition (IC50) 6.4 Biochemical activity of naporafenib against RAF kinase family Biochemical activity of naporafenib across 456 kinases (KINOMEscan)
Naporafenib has been dosed in more than 500 patients to date, establishing its safety, tolerability, and preliminary PoC in multiple indications Source: Novartis Non-Confidential Materials; PoC = proof-of concept P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR Other RTKs MYC GEF CDK4/6 Study (Trial #) Description N Ph 1 FIH study (LXH254X2101) Naporafenib dose escalation in patients with RAS/MAPK-driven solid tumors 142 Ph 1b combo dose finding (LXH254X2102) Dose-finding study (+ rineterkib, trametinib, or ribociclib) in patients with NRASm melanoma, KRASm or BRAFm NSCLC 241 Ph 2 combo study (LXH254C12201) Evaluating efficacy (+ rineterkib, trametinib or ribociclib) in patients with NRASm or BRAF V600X melanoma 134 Platform study (ADPT01C12101) Exploring triplet combination of naporafenib + dabrafenib + rineterkib in BRAF V600X CRC 7 Total size of safety database > 500 patients (includes monotherapy and combinations) trametinib naporafenib rineterkib ribociclib
Preliminary clinical PoC in NRAS Q61X melanoma and KRAS Q61X NSCLC supports development in RAS Q61X tissue agnostic solid tumors (SEACRAFT-1) Strong antitumor activity, with confirmed ORR = 44% 15 out of 16 patients had confirmed codon Q61X melanoma (1 patient had no data) Source: LXH254X2102 Ph 1b combination data from Novartis Non-Confidential Materials; PoC = proof-of-concept KRASm NSCLC NRASm Melanoma ORR in Q61/G13R mutated group (n=4) = 75% Confirmed/unconfirmed RECIST responses shown
Current standard of care post-IO for NRASm metastatic melanoma is chemotherapy with 7% ORR and 1.5m PFS 1 NEMO trial (Lancet Oncol (2017) 18: 435-445.); IO = immuno-oncology Front line Second line plus IO mono or combo Ex: nivolumab, pembrolizumab, nivolumab + ipilimumab Post-IO therapy is predominantly chemo Binimetinib (MEKi) is not approved; recommended by US NCCN but not by EU guidelines Improvement in ORR and DCR of binimetinib vs. dacarbazine translated to improvement in PFS SOC1 ORR DCR PFS OS Dacarbazine 7% 24% 1.5m 10.1m Binimetinib 15% 56% 2.8m 11.0m
Phase 1 in NRASm melanoma: naporafenib 200mg BID + trametinib 1mg QD showed strong anti-tumor activity 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). ORR 47% (21%-73%)* DCR 80% (n=15) Regimen (n) Median Prior Therapy ^ ORR * DCR Dacarbazine (133) 1 7% (3-13) 25% Binimetinib (269) 1 15% (11-20) 58% Napo 200mg BID + Trame 1mg QD (15) 2 (1-7) 47% (21-73) 80%
Case Study: Partial response with naporafenib 200mg BID + trametinib 1mg QD in a patient with NRASm melanoma Source: Novartis Non-Confidential Materials On treatment Pre-treatment
Phase 1 in NRASm melanoma: naporafenib and trametinib exhibited durable time on treatment De Braud et al AACR 2022 (Trial LXH254X2102, NCT02974725) * Median PFS was calculated based on two RDEs: napo 200mg BID + trame 1.0mg QD and napo 400mg BID + trame 0.5mg QD Responses observed in patients with normal or high LDH Median DOR was 3.75 months Median PFS was 5.03 months (95% CI: 3.42–5.62)* Duration of Exposure DOR, duration of response; BID, twice daily; CR, complete response; PD, progressive disease; PR, partial response; QD, once daily; SD, stable disease; UNK, unknown. Patient
Clinical activity of naporafenib + trametinib in NRASm melanoma at the likely Recommended Dose was reproducible across Phase 1 and Phase 2 studies *De Braud et al AACR 2022 # Lebbe et al ESMO 2022 Total of 13/39 responses 33.3% ORR Study/Indication Data Cutoff Naporafenib (200 mg BID) + trametinib (1.0 mg QD) Source ORR DCR DOR Phase 1 (LXH254X2102*) 9 Dec 2021 7/15 (46.7%) 12/15 (80.0%) 3.75 mo AACR 2022 Phase 2 (LXH254C12201#) 4 July 2022 6/24 (25.0%) 17/24 (70.8%) NA ESMO 2022
Phase 2 in NRASm melanoma: Analysis of pts who remain on treatment show potential for naporafenib + trametinib to demonstrate PFS benefit Duration of Exposure (months) for naporafenib 200 mg BID + trametinib 1 mg QD 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 PR <6 SD >6 PR >5 SD >5 PR >5 PR >5 SD >4 SD >4 PR >4 SD <4 SD <4 SD <4 SD <4 SD <4 SD <4 PD <2 PR >5 PD <2 PD <2 PD <2 NE NE uPR <4 NE Note: Patients who remain on treatment shown in teal 0 2 4 6 8 Source: annotated LXH254C12201 Ph 2 trial data from Lebbe et al, ESMO 2022
Patients with SD at, or on track, for delayed progression > 4 months could contribute to PFS benefit vs. SOC Ph 2 patients continuing on treatment on naporafenib + trametinib = potential for confirmation of Ph 1 DOR and PFS advantage in SEACRAFT-2 *includes unconfirmed responses 24 enrolled 15 off 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 n=3 NE 9 on treatment 4 SDs n=1 progression delayed > 6mo n=1 progression delayed > 5mo n=2 progression delayed > 4mo 5 PRs n=4 progression delayed > 5mo n=1 progression delayed > 4mo Naporafenib 200mg BID + trametinib 1mg QD Source: annotated LXH254C12201 Ph 2 trial data from Lebbe et al, ESMO 2022
Naporafenib + trametinib demonstrated a favorable and manageable safety profile Phase 1 data in NRASm melanoma from De Braud et al AACR 2022
Single-Arm Phase 2 Trial (SEACRAFT-1) Randomized Phase 3 Trial (SEACRAFT-2) naporafenib + trametinib TBD (e.g., dacarbazine, physician’s choice) Metastatic Melanoma Post-IO NRASm (Q61X and non-Q61X) R Study Endpoints PFS, OS (dual primary) ORR, DOR (secondary) 1:1 Solid Tumors (Age 12+) Post-available therapy RAS Q61X (NRAS, HRAS, KRAS) 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. Study Endpoints ORR, DOR Proposed pivotal & Phase 2 trial designs: Creative CDP strategy includes high PTS randomized NRASm melanoma trial and tissue agnostic indication Note: Preliminary plan subject to global health authority feedback. Assumes CoC for naporafenib monotherapy in melanoma from FIH trial; CoC in solid tumors is not needed. N~30 - 100 N~350 - 400 naporafenib + trametinib
SEACRAFT-3: Naporafenib could combine synergistically with the rest of our pipeline P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR/ FLT3 Other RTKs MYC GEF trametinib Target Tumor Types NF1 LOF Tissue Agnostic RAS G13R Tissue Agnostic KRAS G12C NSCLC BRAF Class 2 Tissue Agnostic BRAF Class 3 Tissue Agnostic Potential Naporafenib combos with Erasca Pipeline naporafenib + ERAS-007 naporafenib + ERAS-601 naporafenib + ERAS-007 + ERAS-601 naporafenib + ERAS-3490 ERAS-601 Naporafenib ERAS-007 ERAS-3490
ERAS-007 ERKi and ERAS-601 SHP2i could address unmet needs in over 1.1 million patients in the US and Europe P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR Other RTKS MYC GEF ERAS-601 ERAS-007 BRAF Class II/III Solid 55,000 TOTAL tissue agnostic indication EGFRm NSCLC 55,000 BRAF V600m CRC 45,000 KRASm/NRASm CRC 289,000 KRASm PDAC 169,000 Triple WT CRC 334,000 HPV-neg HNSCC 176,000 1,123,000 Focus of this section Addressable Patient Pop. Tumor Type Note: Addressable patient population rounded to nearest thousand
We believe ERAS-007 is the most potent ERK inhibitor in development, with a uniquely longer target residence time Assay Type Assay ERAS-007 IC50 (nM) Biochemical ERK1 2 ERK2 2 Cell-based mechanistic (HT-29) pRSK 7 ERAS-007 was designed to be a potent, selective, reversible, oral inhibitor of ERK1/2 Compound koff (s-1) Residence Time (min) ERAS-007 0.30 x 10-4 550 Ulixertinib 10.1 x 10-4 16 Ravoxertinib 13.9 x 10-4 12 ERAS-007 had longer target residence time vs. other ERKi’s, which may allow for longer intervals between doses in patients
We believe ERAS-601 is a potential best-in-class SHP2 inhibitor that demonstrates high potency and selectivity against SHP2 Compound Biochemical SHP2 inhibition IC50 (nM) ERAS-601 4.6 Cell Line Cancer Type IC50 (nM) ERAS-601 RMC-45501 HCC44 NSCLC 48 95 MIA PaCa-2 Pancreatic 6 17 NCI-H1373 NSCLC 64 474 NCI-H1792 NSCLC 40 27 NCI-H2122 NSCLC 259 1,876 NCI-H358 NSCLC 12 49 SW1573 NSCLC 104 298 NCI-H1666 NSCLC 19 51 NCI-H508 CRC 95 208 MeWo Melanoma 56 241 KYSE-520 Esophageal 119 440 KRAS G12C BRAF class III NF1 LoF wtEGFR amplification 1RMC-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 ERAS-601 demonstrated no off-target activity in 300 kinase (<30% inhibition @ 1μM) and 12 phosphatase panels (IC50 >10μM)
ERAS-007 + EC in BRAFm CRC: ERAS-007 showed strong in vivo combination activity in BRAF V600E CRC 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. TGI in RKO (BRAF V600E CRC) EC-resistant CDX Model TGI in WiDr (BRAF V600E CRC) EC-sensitive CDX Model * *p-value < 0.01 Note: Cetux. = cetuximab; encor. = encorafenib; EC = encorafenib plus cetuximab (BEACON regimen)
ERAS-601 + cetuximab in triple wildtype CRC and HPV-negative HNSCC: Combo demonstrated significantly greater tumor inhibition vs. cetuximab alone in both models Combination was tolerated in mice (e.g., no dose holidays, deaths, or euthanizations) ERAS-601 was dosed orally and cetuximab was dosed intraperitoneally TGI in Triple WT CRC PDX model CRC1021 TGI in HPV-negative HNSCC PDX HN3411
ERAS-007 + ERAS-601 MAPKlamp in BRAF Class 3 and NF1 loss of function: Combination showed consistent activity in both models 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 TGI in BRAF Class 3 NSCLC PDX LUN023 TGI in NF1 LoF NSCLC NCI-H1838 Note: LoF. = loss of function
* 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. * * * 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
Duration of Treatment Observed with ERAS-007 or ERAS-601 in BRAF-driven Blue Ocean Indications 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. Efficacy-Evaluable Patients 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)
Per RECIST 1.1: ≥30% = objective response Tumor assessment (5) (Jan 4, 2022): patient had radiologic progressive disease (PD) due to a new lesion Peri-Esophageal lesion, shrinkage in non-target lesions also noted (not shown) 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 50% decrease 32% decrease Baseline 24 Weeks 32 Weeks FLAGSHP-1 Case Study: Single agent ERAS-601 response 63-year-old female (Patient 0009) with BRAF Class 3 metastatic endometrial cancer
Likely recommended dose of ERAS-007 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 System Organ Class/ Preferred Term 50 mg BID-QW (n=4) 100 mg BID-QW (n=11) 125 mg BID-QW (n=8) 250 mg QW (n=29) Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 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 Vomiting 1 (25.0%) 0 3 (27.3%) 0 3 (37.5%) 0 9 (31.0%) 2 (6.9%) Dermatitis acneiform 1 (25.0%) 0 4 (36.4%) 0 3 (37.5%) 0 6 (20.7%) 0 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 Fatigue 1 (25.0%) 1 (25.0%) 4 (36.4%) 0 4 (50.0%) 1 (12.5%) 5 (17.2%) 1 (3.4%) Treatment-related Adverse Events Occurring in ≥ 20% and ≥ 2 Patients at Any Dose (arranged by descending frequency in the 250mg QW any grade column) Likely recommended dose between 50 – 100mg BID-QW for combinations was well tolerated
ERAS-601 QD and BID regimens were well tolerated with acceptable safety profile * Includes thrombocytopenia and platelet count decrease Source: ENA 2022 System Organ Class/ Preferred Term QD (20-80 mg) N=15 QD MTD (40 mg) N=3 BID (20 and 40 mg) N=13 BID MTD (40 mg) N=9 QD + BID N=28 ALL Gr ≥ 3 ALL Gr ≥ 3 ALL Gr ≥ 3 ALL Gr ≥ 3 ALL Gr ≥ 3 At least one TRAE 14 (93.3) 6 (40) 3 (100) 2 (66.7) 13 (100) 6 (46.2) 9 (100) 4 (44.4) 27 (96.4) 12 (42.9) Thrombocytopenia* 7 (46.7) 2 (13.3) 2 (66.7) 1 (33.3) 3 (23.1) 2 (15.4) 2 (22.2) 2 (22.2) 10 (35.7) 4 (14.3) AST increased 6 (40.0) 2 (13.3) 1 (33.3) 0 2 (15.4) 1 (7.7) 2 (22.2) 1 (11.1) 8 (28.6) 3 (10.7) ALT increased 6 (40.0) 1 (6.7) 1 (33.3) 0 2 (15.4) 0 2 (22.2) 0 8 (28.6) 1 (3.6) Diarrhea 4 (26.7) 0 1 (33.3) 0 4 (30.8) 1 (7.7) 2 (22.2) 0 8 (28.6) 1 (3.6) Oedema peripheral 3 (20.0) 0 2 (66.7) 0 4 (30.8) 0 2 (22.2) 0 7 (25.0) 0 Treatment-related Adverse Events occurring in ≥ 20% of patients in QD and BID cohorts
ERAS-801 EGFRi could address high unmet need in 37k patients in US and EU P P P MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR ERK RAS-GDP EGFR Other RTKS MYC GEF ERAS-801 Glioblastoma multiforme 37,000 TOTAL 37,000 Addressable Patient Pop. Tumor Type Note: Addressable patient population rounded to nearest thousand
Poor activity of legacy EGFRi in GBM due to minimal activity against GBM-specific EGFR alterations and poor CNS penetration TCGA Cell, 2013 Therapy (brain penetration %) Clinical Trial Results: NSCLC/BrCa Clinical Trial Results: GBM Erlotinib (8%) Recurrent NSCLC: Improved PFS and OS vs. chemo (Ph 3) Failed (Ph 2) Lapatinib (0.1%) Recurrent HER2 BrCa: Improved PFS vs. chemo (Ph 3) Failed (Ph 2) Gefitinib (1.1%) 1L NSCLC: Improved PFS and OS vs. chemo (Ph 3) Failed (Ph 2) Afatinib (0.7%) 1L NSCLC: Improved PFS vs. chemo (Ph 3) Failed (Ph 2)
ERAS-801, a potent EGFRvIII/wt inhibitor with a Kp,uu over 4-fold higher than approved EGFR inhibitors, was specifically designed to inhibit EGFR in GBM 1 Kp,uu is a measure of the ratio of unbound brain concentration to unbound plasma concentration Kim M, et al. Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice. Drug Metab. Dispos., 2019. PMID: 30705084 Compound (Brand Name) Company Kp, brain (mouse) Kp,uu, brain (mouse)1 ERAS-801 Erasca 3.7 1.2 osimertinib AstraZeneca 0.99 0.29 afatinib Boehringer Ingelheim 0.25 0.05 erlotinib Genentech 0.06 0.13 gefitinib AstraZeneca 0.36 0.10 dacomitinib Pfizer 0.61 0.49 erlotinib lapatinib osimertinib ERAS-801
ERAS-801 shows significant survival benefit in multiple glioma PDX models harboring a variety of EGFR alterations
ERAS-801 improves outcomes of >90% of EGFR mutant and/or amplified GBM PDXs across a diverse range tested EGFR mut and/or amplified EGFR All models Significant survival benefit
All of Erasca’s 2022 milestones were achieved on or ahead of schedule 1 ERAS-007 (oral ERK1/2 inhibitor) and ERAS-601 (oral SHP2 inhibitor) together comprise our first innovative MAPKlamp Program Mechanism Trial Name Indication 2022 milestone guidance Status ERAS-007 and/or ERAS-601 (MAPKlamp1) ERK1/2 inhibitor and/or SHP2 inhibitor HERKULES-1 Advanced Solid Tumors Achieved Sept. 2022 Achieved Dec. 2022 – one half early ERAS-601 SHP2 inhibitor FLAGSHP-1 Advanced Solid Tumors Achieved Sept. 2022 ERAS-801 CNS-penetrant EGFR inhibitor THUNDERBBOLT-1 Glioblastoma Multiforme Achieved Feb. 2022 ERAS-3490 CNS-penetrant KRAS G12C inhibitor AURORAS-1 KRAS G12Cm NSCLC Achieved Nov. 2022 Q1 2022 FPD (achieved) H2 2022 File IND (achieved) H2 2022 Ph 1b data (achieved) H2 2022 Ph 1 data (achieved) H1 2023 MAPKlamp FPD (achieved)
Anticipated key milestones and clinical trial readouts 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 dose 4 Data to include preliminary combination safety and pharmacokinetics to support combination dose expansion Program Mechanism Trial Name Indication 2023 2024 Naporafenib Pan-RAF inhibitor SEACRAFT-1 RAS Q61X Solid Tumors SEACRAFT-2 NRASm Melanoma ERAS-007 and/or ERAS-601 (MAPKlamp1) ERK1/2 inhibitor and/or SHP2 inhibitor HERKULES-1 Advanced Solid Tumors HERKULES-2 Lung Cancers HERKULES-3 BRAFm CRC and RASm GI Cancers ERAS-601 SHP2 inhibitor FLAGSHP-1 Triple WT CRC2 and HPV-neg HNSCC ERAS-801 CNS-penetrant EGFR inhibitor THUNDERBBOLT-1 Glioblastoma Multiforme ERAS-3490 CNS-penetrant KRAS G12C inhibitor AURORAS-1 KRAS G12Cm NSCLC H2 2023 Ph 1 data in rGBM H1 2023 Ph 1b combo data H1 2023 Ph 1b combo data H1 2023 Ph 1b dose escalation (incl. MTD) data H1 2024 Ph 1b combo data4 H2 2024 – H1 2025 Ph 2 combo data H1 2024 Ph 3 pivotal FPD3 H2 2023 Ph 2 FPD3 H2 2023 – H1 2024 Ph 1b combo data in BRAFm CRC and/or RASm GI cancers 2024 Ph 1b combo data in triple WT CRC and/or HPV-neg HNSCC 2024 Ph 1 data
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 FIVE clinical-stage compounds Differentiated profiles including naporafenib, a phase 2, pivotal-ready pan-RAF inhibitor for NRASm melanoma and Q61X tissue agnostic solid tumors and our first, innovative MAPKlamp comprising compelling ERK and SHP2 inhibitors Multiple potential near-term and long-term value drivers Robust clinical development plan with multiple combination and monotherapy readouts in 2023 and beyond and a strong Research engine to drive novel compounds into the clinic
Thank You!
Naporafenib: Potential first-in-class pan-RAF inhibitor Company Program Stage naporafenib Ph 2 tovarafenib Ph 2 Lead indication in pediatric low-grade glioma; novel-novel belvarafenib Ph 1b FORE-8394 Ph 1 lifirafenib Ph 1 BGB-3245 Ph 1 Combo w/ mirdametinib starting 2023 KIN-2787 Ph 1 Unclear whether non-clinical parameters will translate in clinic JZP815 Ph 1 Ph 1 FPD Nov 2022 BDTX-4933 Preclinical CUL-BRAF Preclinical Most advanced pan-RAF inhibitor Dosed in the most patients (500+) of any pan-RAF inhibitor in development Potential to be first-to-market and raise SoC in prioritized indications PoC established Evaluating naporafenib in indications where it has already shown promising PoC – namely, NRASm melanoma and RAS Q61X tissue agnostic solid tumors Strong complementarity with Erasca pipeline Highly complementary, if not synergistic, with the rest of Erasca’s RAS/MAPK pathway-targeting pipeline
Erasca is well positioned to advance naporafenib through a focused development plan that leverages RAS/MAPK pipeline synergies Top Priority Potential RASm opportunities to address unmet needs for ~1.9m patients WW Ungate potential opportunities in other RASm indications if well tolerated combinations are identified above and/or supported by evolving data Exploratory combos to address unmet needs in ~1.2m patients WW Explore novel combination(s) in NF1 LOF, RAS G13R, KRAS G12C, and BRAF Class 2 and 3 altered solid tumors (SEACRAFT-3); combos include naporafenib with ERAS-007, ERAS-601, ERAS-007 + ERAS-601, or ERAS-3490 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 Potential RASm Opportunities Exploratory Combinations
ERAS-007: Potential best-in-class ERK1/2 inhibitor in a field marked by attrition Company Program Stage ulixertinib Ph 2 (combo w/ HCQ, palbo) Safety concerns (disfiguring rash); CoM patent through 2025 ERAS-007 Ph 2 (multiple combos) ASTX029 Ph 2 (combo w/ internal SHP2) temuterkib Ph 1 Reported monotherapy ORR1 of 0% rineterkib Ph 1 (combo w/ napo, TNO155) Reported monotherapy ORR of 2% JSI-1187 Ph 1 (combo w/ dabrafenib) ATG-017 Ph 1 (combo w/ nivolumab) MK-8353 Ph 1 (combo w/ pembro) GDC-0994 Terminated Significant tolerability issues KO-947 Terminated Placed on partial clinical hold; IV administered CC-90003 Terminated MTD “did not offer sufficiently encouraging profile to proceed” Hit-and-run profile optimizing efficacy, tolerability Highest potency and longest target residence time of known ERKi enable ERAS-007 to be dosed intermittently instead of daily like other clinical ERKi Safety and tolerability established Comparable if not better tolerability than other clinical ERKi’s particularly as it relates to rash Intermittent dosing regimen has the potential to further optimize clinical utility Encouraging signs of efficacy Monotherapy responses observed in FIH and HERKULES-1 studies indicating areas of focus for combination development 1 ORR = objective response rate
P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR RAS-GDP EGFR/ FLT3 Other RTKS MYC GEF ERK Scientific rationale: Triple blockade of BRAF, EGFR and ERK in BRAFm CRC SHP2 ERK inhibition may overcome treatment-induced resistance to BRAF/EGFR inhibition by adding ERAS-007 to encorafenib + cetuximab (EC) Combined blockade of ERK plus BRAF/EGFR could more effectively inhibit the RAS/MAPK pathway, as well as prevent MAPK feedback reactivation in BRAFm CRC, representing approximately 10% of patients with CRC ERAS-007 Cetuximab Encorafenib
BRAF V600E CRC Cell Lines MEKi combination ERKi combinations Binimetinib 1 µM + Encorafenib 0.1 µM ERAS-007 0.1 µM + Encorafenib 0.1 µM LY3214996 1 µM + Encorafenib 0.1 µM Ravoxertinib 1 µM + Encorafenib 0.1 µM RKO HT29 MAPK Feedback Reactivation No Reactivation Reactivation Reactivation Source: Unpublished data P-RSK P-ERK GAPDH P-RSK P-ERK GAPDH P-RSK GAPDH P-RSK P-ERK GAPDH 0 4 24 48 72h 0 4 24 48 72h ERAS-007 blocked the MAPK feedback reactivation observed with MEK or other ERK plus BRAF inhibitor combinations
HERKULES and SU2C clinical trial series – ERAS-007 master protocols Indication Agent(s) Tissue Agnostic Regimen ERAS-007 Indication Exploring safety & PK of various intermittent dosing schedules for combinations Regimen Indication Lung Cancer EGFR-mutant NSCLC KRAS G12C-mutant NSCLC ERAS-007 + osimertinib (Tagrisso®) ERAS-007 or ERAS-601 + sotorasib (LumakrasTM) Regimen Indication GI Cancer Lung and GI Cancer ERAS-007 + encorafenib (Braftovi®)1,4 and cetuximab (Erbitux®)2 ERAS-007 + palbociclib3 (Ibrance®) ERAS-007 in combination with other agents BRAF V600E-mutant CRC (EC naïve and treated) KRAS- or NRAS-mutant CRC; KRAS-mutant PDAC Mutational subtypes of GI cancers Regimen Indication ERAS-007 + adagrasib KRAS G12C-mutant NSCLC and CRC HERKULES-1 HERKULES-2 HERKULES-3 Stand Up To Cancer Mutational subtypes of NSCLC ERAS-007 in combination with other agents ERAS-007 + ERAS-601 (our first MAPKlamp) RAS/MAPK-altered Solid Tumors (potential tissue agnostic) Ongoing sub-study Future sub-study Note: CTCSA = clinical trial collaboration and supply agreement 1 Sep. 2021: Announced CTCSA with Pfizer for encorafenib (Braftovi®) 2 Mar. 2022: Announced CTCSA with Lilly for cetuximab (Erbitux®) 3Oct. 2022: Announced CTCSA with Pfizer for palbociclib (Ibrance®) 4 Nov. 2022: Announced CTCSA with Pierre Fabre for encorafenib (Braftovi®)
Four responses seen in patients with: BRAF V600E thyroid CA (180mg) BRAF K601E NSCLC (120mg) HRAS salivary gland CA (250mg) BRAF rearranged melanoma (250mg) ERAS-007 Phase 1: Responses observed in patients with RAS and RAF alterations in diverse tumor types with single agent QW schedule Source: ASN007-101 study; as of the November 6, 2020, data extraction Note: Best percent change from baseline in tumor lesions is defined as the maximum reduction in post-baseline tumor lesion diameter compared to baseline tumor lesion diameter. Prior treatments in patients with objective responses: HRAS salivary gland – radiation; BRAF rearranged melanoma – nivolumab/ipilimumab, radiation; BRAF V600E thyroid – radiation; BRAF K601E NSCLC – carbo/pemetrexed, carbo-paclitaxel + durvalumab Waterfall Plot of Tumor Response by Patient for Once Weekly Schedule Efficacy-Evaluable Analysis Set
ERAS-007 swimmer plot demonstrated encouraging duration of treatment Melanoma BRAF (mutation not available) 7110-011 Prostate Ca BRAF K601E 7110-013 Melanoma NRAS Q61 any 7106-004 Prostate Ca BRAF 7104-007 Oropharynx ACC BRAF D594N 7110-012 NSCLC BRAF 6466V 7104-006 CRC KRAS G13 any 7101-007 Salivary Gland Ca HRAS 7106-002 Melanoma BRAF V600E 7104-010 Melanoma BRAF rearrangement 7106-006 Thyroid Ca NRAS Q61 any 7104-008 Melanoma, ocular GNA11 Q209L 7106-005 Thyroid cancer (MTC) HRAS Q61R 7110-014 Skin SCC BRAF – SGCE Translocation 7106-010 Prostate Ca MAP3K1 7104-003 Small Bowel Ca BRAF K601E 7104-004 Melanoma GNA11 Q209L 7106-009 Melanoma BRAF N581F 7106-007 Prostate Ca BRAF 601E 7104-005 Melanoma (mutation not available) 7110-015 Thyroid Ca BRAF V600E 7109-013 Melanoma NRAS Q61 any 7101-006 Melanoma NRAS Q61 any 7110-008 NSCLC BRAF fusion 7104-001 Ovarian Ca KRAS (mutation not available) 7110-006 NSCLC BRAF (K601E) 7106-008 Colorectal Ca NRAS G12 any; KRAS G12 any 7110-005 Ovarian Ca BRAF; PIK3CA 7101-005 Colorectal Ca BRAF V600E 7102-006 Melanoma NRAS Q61 any 7102-005 Bile Duct KRAS G12 any 7109-011 Ovarian Ca RAS/RAF wt 7109-010 One patient with BRAF V600E melanoma (7104-010) received ERAS-007 for a total of 71 weeks before experiencing disease progression Source: ASN007-101 study; as of the November 6, 2020, data extraction
Sept. 2022 R&D Day highlights*: MAPKlamp has potential to meaningfully impact BRAF Class II and III patients ERAS-007 and ERAS-601 are active drugs – monotherapy responses 23% (6/26) of patients with RAS/MAPK-altered non-CRC solid tumors and 44% (4/9) with BRAF-driven non-CRC solid tumors responded (confirmed and unconfirmed PR) to single agent ERAS-007 or ERAS-601 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 monotherapy response with SHP2 inhibitor Validated hypotheses for combo of upstream + downstream RAS/MAPK pathway inhibition (MAPKlamp) and combo of RAS/MAPK + cell cycle inhibition Well behaved PK characteristics for both drugs ERAS-007: data from PK modeling is nearly superimposable with observed data ERAS-007: good exposure above IC90 for tumor cell killing and below IC50 for normal cell recovery enables “hit and run” profile ERAS-601: good exposure above IC50 for sustained target coverage Both compounds appear safe and tolerable, with limited overlapping tox (diarrhea) Diarrhea should be able to be managed with prophylaxis or supportive care Efficacy PK Safety Note: PK = pharmacokinetics; u/cPR = unconfirmed/confirmed partial response; PDAC = pancreatic ductal adenocarcinoma; BID-QW = two doses on one day each week * 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. Erasca identified a meaningful and targetable population—specifically BRAF Class II and III—that could benefit from MAPKlamp (ERAS-007 + ERAS-601) This patient population currently has no approved targeted therapy Future directions:
Best overall response with ERAS-007 or ERAS-601 in 15 RAS/MAPK-altered Blue Ocean Indications across lines of therapy * 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 23% (6 out of 26) of patients responded (confirmed and unconfirmed PR) to single agent ERAS-007 or ERAS-601 * * * *
Duration of treatment observed with ERAS-007 or ERAS-601 in 15 RAS/MAPK-altered Blue Ocean Indications across lines of therapy Efficacy-Evaluable Patients 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.
Per RECIST 1.1: ≥30% = objective response Diagnosis Stage II pancreatic cancer, metastatic disease, KRAS G12V, initially diagnosed in January 2018 Sites of Metastases Lung, lymph nodes Prior Therapy Surgery, adjuvant radiation, gemcitabine/ capecitabine (#1); 5FU/oxaliplatin/irinotecan (#2); gemcitabine/abraxane (#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 Patient progressed with new lesion at subsequent assessment Baseline 16 Weeks 31% reduction in tumor size HERKULES-1 Case Study: Single agent ERAS-007 response 70-year-old female (Patient 0033) with KRAS G12V metastatic pancreatic cancer
Goal is to maximize the time above IC90 to improve cancer cell killing, while maintaining Cmin near or below IC50 to give normal cells a treatment break (i.e., extend time below IC50) Dosing Regimen Cmax, ng/mL Cmin, ng/mL T>IC90 T<IC50 250 mg QW 425 3 ~2/7 ~1/7 50 mg BID-QW 103 3 ~2/7 ~1/7 80 mg BID-QW 165 5 ~3/7 ~0.5/7 100 mg D1D2 BIW 186 5 ~2/7 ~0.5/7 100 mg D1D4 BIW 183 11 ~2/7 0 Phase 1 PK data showed QW is preferable to QD dosing; Simulations suggest BID-QW dosing may improve PK/PD profiles and combinability even more
ERAS-601: Potential best-in-class SHP2i, favorable profile for combination Company Program Stage TNO155 Ph 3 Observed LVEF decrease may pose combo challenges RMC-4630 Ph 2 Observed anemia does not improve with intermittent dosing JAB-3312 Ph 2 ERAS-601 Ph 1b RG6433 Ph 1 In-licensed from Relay Therapeutics BBP398 Ph 1 In-licensed from BridgeBio PF-07284892 Ph 1 TAS-ASTC Ph 1 Strong potency, favorable ADME/PK Strong in vivo potency relative to other SHP2i’s in development Good exposure above IC50 for sustained target coverage Safety and tolerability profile Clinical data to-date suggests ERAS-601 is generally safe and tolerable with reversible AEs Favorable for combinations Encouraging signs of efficacy Although SHP2i expected to have its greatest impact in combination, ERAS-601 achieved monotherapy cPR (BRAF Class III endometrial)
P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR RAS-GDP EGFR/ FLT3 Other RTKS MYC GEF ERK Scientific rationale: Dual inhibition of EGFR and SHP2 in triple wildtype CRC and HPV-negative head and neck squamous cell carcinoma (HNSCC) SHP2 EGFR-driven CRC and HPV-negative HNSCC are highly dependent on RAS/MAPK pathway signaling Dual blockade of EGFR and SHP2 could potentially broaden and deepen responses compared to EGFR inhibition alone, including in: Triple wildtype (KRASwt, NRASwt, BRAFwt) CRC, representing nearly 50% of all patients with CRC HPV-negative HNSCC, representing 70-75% of all patients with HNSCC ERAS-601 Cetuximab
ERAS-007 and ERAS-601 use different target coverage strategies that seek to achieve optimal efficacy and safety ERAS-007: 50-125mg BID-QW dosing provided high target coverage (C>IC90) for maximum activity, followed by lower PK coverage (C<IC50) for MAPK pathway recovery to alleviate target driven toxicity ERAS-601: 40mg BID dosing provided sustained target coverage (C>IC50) throughout the dosing interval ERAS-007 Mean Cycle 1 PK Profile ERAS-601 Mean Steady State PK Profile *HCT 116 anti-proliferation assay for ERAS-007; pERK in NCI-358 for ERAS-601 IC90* IC50* IC50*
ERAS-601 ERAS-007 Treatment-related AEs in Preferred Terms 20 and 40 mg BID (N=13) 50-125mg BID-QW (N=23) System Organ Class / Preferred Term All Grade Gr ≥ 3 All Grade Gr ≥ 3 Hematologic Thrombocytopenia* 3 (23.1%) 2 (15.4%) 0 0 Anemia 3 (23.1%) 1 (7.7%) 1 (4.3%) 1 (4.3%) Cardiovascular Hypertension 3 (23.1%) 1 (7.7%) 0 0 Hypertensive encephalopathy 1 (7.7%) 1 (7.7%) 0 0 Hepatic AST increase 2 (15.4%) 1 (7.7%) 0 0 ALT increase 2 (15.4%) 0 0 0 Blood bilirubin increased 0 0 1 (4.3%) 1 (4.3%) General Peripheral edema 4 (30.8%) 0 1 (4.3%) 0 TRAEs of ERAS-601 and ERAS-007 have been largely non-overlapping 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. 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-007; (2) experienced by at least 1 patient and Grade ≥3. *includes platelets count decrease ERAS-601 ERAS-007 Treatment-related AEs in Preferred Terms 20 and 40 mg BID (N=13) 50-125mg BID-QW (N=23) System Organ Class / Preferred Term All Grade Gr ≥ 3 All Grade Gr ≥ 3 Skin Maculopapular rash 0 0 2 (8.7%) 0 Dermatitis acneiform 2 (15.4%) 0 8 (34.8%) 0 EYE DISORDERS Blurred vision 2 (15.4%) 0 5 (21.7%) 1 (4.3%) Retinopathy 0 0 6 (26.1%) 0 Retinal Detachment 0 0 1 (4.3%) 1 (4.3%) Vision Impairment 0 0 1 (4.3%) 1 (4.3%) Gastrointestinal Nausea 0 0 12 (52.2%) 0 Vomiting 0 0 7 (30.4%) 0 Diarrhea 5 (38.5%) 1 (7.7%) 5 (21.7%) 0 Constipation 0 0 2 (8.7%) 0 Dyspepsia 2 (8.7%) 0 General Fatigue 1 (7.7%) 0 9 (39.1%) 2 (8.7%) Dehydration 0 0 4 (17.4%) 0 Dizziness 0 0 2 (8.7%) 0 ERAS-601 and ERAS-007 by common SHP2i TRAEs ERAS-601 and ERAS-007 by common ERKi TRAEs Potential overlapping tox; can be managed proactively Gr 4 AEs: ERAS-601: anemia, hypertensive encephalopathy ERAS-007: none
P P P Autophagy MAPK pathway ULK PI3K pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK PI3K AKT mTOR EGFR/ FLT3 Other RTKS MYC GEF ERK Dr. Kevan Shokat at UCSF turned KRAS from undruggable to druggable RAS-GDP RAS-GDP Source: Ostrem J., et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013. PMID: 24256730 Shokat identified a G12C-specific inhibitor that locks KRAS in inactive state, spurring multiple companies to develop KRAS G12C inhibitors High unmet need remains for patients with NSCLC (CNS metastases occur in up to 40% of patients) Focus of our discovery efforts has been on developing KRAS G12C inhibitors with high CNS penetration
Parameter 34901 3691 3599 3537 3788 Reference compounds2 Mouse AUCpo/D (hr*kg*ng/mL/mg) 693 597 1,333 535 326 102 - 637 Rat braintotal / plasmatotal (%) 52% 13% 66% 68% 11% 1 - 6% Rat brain concentration (ng / g) 156 32 176 290 91 6 - 36 P-gp substrate ratio3 1.5 4.1 2.7 8.3 4.0 30.94 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 We have discovered promising CNS-penetrant KRAS G12Ci pre-candidates 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.