Erasca, Inc. · NASDAQ:ERAS
Erasca — Investor Day (September 2022)
62 slides from Erasca's investor day presentation, Sep 7, 2022
Slide 1: Erasca R&D Day September 2022
Erasca R&D Day September 2022 Exhibit 99.1
Slide 2: Forward-looking statements
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 plan
Slide 3: Erasca R&D Day Agenda
Company Overview Erasca pipeline and drug development strategy Key scientific hypotheses and supportive preclinical data Dr. David Hong, MD Anderson Cancer Center Discussant Future directions Key milestones and clinical trial readouts Closing Remarks Q&A Session ERAS-007 / ERAS-601 Preliminary Resul
Slide 4: New cases worldwide by RAS/MAPK alteration: blue and 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 (20
Slide 5: Erasca's tissue specific and tissue agnostic trials target multiple indications
Erasca’s tissue specific and tissue agnostic trials target multiple indications 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
Slide 6: Erasca's clinical development plan generates multiple ways to win for patients
Erasca’s clinical development plan generates multiple ways to win for patients 1 Currently approved standard of care Indication Benchmark1 Regimen tested Erasca trial(s) HERKULES-2 Sub-study 1 EGFRm NSCLC post-osi ERAS-007 + osimertinib ORR 29%, mDOR 4.2 mos. HERKULES-3 Sub-study 1 BRAFm CRC EC-naïv
Slide 7: Key scientific hypotheses and supportive preclinical data
Are there more responsive subsets within the Blue Ocean where promising combination approaches can be particularly effective? ? Key scientific hypotheses and supportive preclinical data
Slide 8: ERAS-007 & ERAS-601 target key downstream and upstream RAS/MAPK nodes
Reminder: ERAS-007 & ERAS-601 target key downstream and upstream RAS/MAPK nodes P P MAPK pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK ERK RAS-GDP EGFR/ FLT3 Other RTKS MYC GEF ERAS-601 ERAS-007 SU2C = Stand Up To Cancer Potent, selective, orally bioavailable SHP2 inhibitor in clinical d
Slide 9: ERK inhibition with CDK4/6 or SHP2 inhibition: two approaches
ERK inhibition with CDK4/6 or SHP2 inhibition offers two compelling approaches to target solid tumors with MAPK pathway alterations P P MAPK pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK ERK RAS-GDP EGFR/ FLT3 Other RTKS MYC GEF Scientific Hypothesis #1: Dual inhibition of RAS/MAPK and t
Slide 10: Dual inhibition of cell cycle and MAPK pathways in PDX models of CRC
Dual inhibition of cell cycle and MAPK pathways enhanced tumor shrinkage in PDX models of KRAS/NRAS mutant CRC Modified from AACR 2021; Courtesy of Scott Kopetz, MD, PhD (MD Anderson Cancer Center) Regimen: Vehicle Palbociclib100 mpk QD Trametinib0.25 mpk QD Combo100/0.25 mpk QD C1047 KRas G12V B809
Slide 11: P-RSK biomarker of ERK and RAS/MAPK pathway activity
ERK directly phosphorylates the p90 ribosomal S6 kinase protein (RSK) so RSK phosphorylation (P-RSK) serves as a biomarker of ERK and ultimately RAS/MAPK pathway activity Source: Unpublished data ATP-competitive ERK inhibitors were more robust in shutting down RAS/MAPK pathway reactivation than allo
Slide 12: ERAS-007 + palbociclib enhanced tumor growth inhibition in KRASm models
ERAS-007 + palbociclib enhanced tumor growth inhibition (TGI) in KRASm CRC and PDAC models Combination was tolerated in mice (e.g., no dose holidays, deaths, or euthanizations) ERAS-007 and palbociclib were dosed orally and continuously TGI in KRAS G13D CRC CDX LoVo TGI in KRAS G12D PDAC PDX PAN026
Slide 13: Scientific Hypothesis #2: MAPKlamp inhibition of upstream and downstream nodes
Scientific Hypothesis #2: “MAPKlamp” inhibition of upstream and downstream RAS/MAPK pathway nodes has potential for deeper, more durable responses P P MAPK pathway RAS-GTP GRB2 SHP2 GAP GDP GTP P1 NF1 SOS1 RAF MEK ERK RAS-GDP EGFR/ FLT3 Other RTKS MYC GEF ERAS-601 ERAS-007 + ERAS-601 “MAPKlamp” Scie
Slide 14: MAPKlamp tumor growth inhibition in KRAS mutant NSCLC CDX models
ERAS-007 + ERAS-601 MAPKlamp showed increased in vivo tumor growth inhibition in two KRAS mutant NSCLC CDX 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
Slide 15: MAPKlamp tumor growth inhibition in KRAS mutant PDAC PDX models
ERAS-007 + ERAS-601 MAPKlamp showed increased in vivo tumor growth inhibition in two KRAS mutant PDAC PDX 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
Slide 16: MAPKlamp combination activity in BRAF class 3 models
ERAS-007 + ERAS-601 MAPKlamp showed consistent combination activity in BRAF class 3 models that had differing sensitivities to single agents MAPKlamp combination showed activity in both models and was tolerated in mice (e.g., no dose holidays, deaths, or euthanizations) ERAS-601 showed regression as
Slide 17: MAPKlamp combination activity in two NF1 loss of function models
ERAS-007 + ERAS-601 MAPKlamp showed promising combination activity in two NF1 loss of function (LoF) 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 i
Slide 18: Preliminary clinical data
Are there more responsive subsets within the Blue Ocean where ERK + cell cycle or ERK + SHP2 inhibition can be particularly effective? ? Preliminary clinical data
Slide 19: Segmentation framework to identify more responsive subsets within the Blue Ocean
CRC Segmentation framework to identify more responsive subsets within the Blue Ocean for prioritized combination development Non-CRC Evaluation of combinations addressing these mechanisms is ongoing in HERKULES-3 (and combination addressing triple wildtype CRC is ongoing in FLAGSHP-1) Phase 1/1b mon
Slide 20: Segmentation framework: targetable, more responsive subset prioritized
CRC Segmentation framework to identify more responsive subsets within the Blue Ocean for prioritized combination development Non-CRC Evaluation of combinations addressing these mechanisms is ongoing in HERKULES-3 (and combination addressing triple wildtype CRC is ongoing in FLAGSHP-1) Targetable, mo
Slide 21: Retrospective Pooled Analysis methodology
Retrospective Pooled Analysis All trials assessing ERAS-007 or ERAS-601 as monotherapies: ASN007-101, HERKULES-1, FLAGSHP-1 Methodology for retrospective pooled efficacy analysis for ERAS-007 and ERAS-601 in solid tumors with RAS/MAPK pathway alterations* * The clinical data presented in the followi
Slide 22: Preliminary responses in solid tumor subsets with RAS/MAPK alterations
CRC Preliminary responses in solid tumor subsets with RAS/MAPK alterations Non-CRC N = 26 Single agent responses to either ERAS-007 or ERAS-601 were observed “Blue Ocean indications” of solid tumors with RAS/MAPK alterations and no approved targeted therapies N = 8 No single agent responses were obs
Slide 23: Preliminary responses: BRAFm subset
CRC Preliminary responses in solid tumor subsets with RAS/MAPK alterations Non-CRC N = 26 Single agent responses to either ERAS-007 or ERAS-601 were observed N = 9 (subset of the N = 26) Higher rate of single agent responses to either agent was observed “Blue Ocean indications” of solid tumors with
Slide 24: Blue Ocean indications with responses by alteration
Alterations GBM HNSCC NSCLC CRC Melanoma PDAC Other solid tumors AML EGFR*/FLT3 125 513 184 338 - - - 61 NF1 25 58 98 35 33 1.9 434 3.2 KRAS G12C - 2.8 240 57 - 5.0 45 0.1 KRAS G12D 0.2 4.7 68 238 0.5 178 200 1.2 Other KRAS 0.4 9.4 183 465 1.2 242 326 3.5 NRAS 0.5 8.4 11.7 72 71 1.0 116 13.8 HRAS 0.
Slide 25: 6 responses in 6 Blue Ocean Indications with monotherapy
Alterations GBM HNSCC NSCLC CRC Melanoma PDAC Other solid tumors AML EGFR*/FLT3 125 513 184 338 - - - 61 NF1 25 58 98 35 33 1.9 434 3.2 KRAS G12C - 2.8 240 57 - 5.0 45 0.1 KRAS G12D 0.2 4.7 68 238 0.5 178 200 1.2 Other KRAS 0.4 9.4 183 465 1.2 242 326 3.5 NRAS 0.5 8.4 11.7 72 71 1.0 116 13.8 HRAS 0.
Slide 26: Best overall response in RAS/MAPK-altered Blue Ocean Indications
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
Slide 27: Duration of treatment in 15 RAS/MAPK-altered Blue Ocean Indications
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
Slide 28: HERKULES-1 Case Study: Single agent ERAS-007 response
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); gemcita
Slide 29: Targetable, more responsive subset: BRAFm
CRC Targetable, more responsive subset of patients with RAS/MAPK alterations Non-CRC N = 9 (subset of the N = 26) Higher rate of single agent responses to either agent was observed “Blue Ocean indications” of solid tumors with RAS/MAPK alterations and no approved targeted therapies BRAFm
Slide 30: Best overall response in BRAF-driven Blue Ocean Indications
* 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 12
Slide 31: Duration of treatment in BRAF-driven Blue Ocean Indications
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 m
Slide 32: FLAGSHP-1 Case Study: Single agent ERAS-601 response
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
Slide 33: Single agent activity indicates responsiveness in certain tumor types
Are there more responsive subsets within the Blue Ocean where ERK + cell cycle or ERK + SHP2 inhibition can be particularly effective? Single agent activity of ERAS-007 and ERAS-601 indicates responsiveness in certain tumor types and molecular alterations Combination approaches have potential to dee
Slide 34: Unmet needs in Blue Ocean Indications: ~half a million patients per year
Unmet needs in the 6 Blue Ocean Indications where single agent responses were observed comprise ~half a million patients worldwide per year 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 35 33 1.
Slide 35: Preliminary data support combination trials to address unmet needs
Preliminary data support existing and new combination trials to help address majority of unmet needs in these Blue Ocean Indications 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 35 33 1.9 434 3
Slide 36: Combinations of ERK inhibition with CDK4/6 or SHP2 inhibition: opportunities and challenges
Combinations of ERK inhibition with CDK4/6 or SHP2 inhibition offer two compelling approaches to targeting solid tumors with MAPK pathway alterations Opportunities Challenges Target alterations with no available direct inhibitors Achieve deeper pathway suppression than either agent alone May overcom
Slide 37: Can ERAS-007 be combined safely with palbociclib or ERAS-601?
Can ERAS-007 be combined safely with palbociclib or ERAS-601 in patients? ?
Slide 38: Expected TRAEs associated with ERK and CDK4/6 inhibitors
Expected TRAEs associated with ERK and CDK4/6 inhibitors have been limited Common ERKi TRAEs Common CDK4/6i TRAEs TRAE: treatment‐related adverse event Skin Gastrointestinal Eye General (fatigue) Hematologic Gastrointestinal Infections General (fatigue)
Slide 39: ERAS-007 + palbociclib enrolling at biologically relevant dose level
ERAS-007 combination with palbociclib is enrolling and is currently at a biologically relevant dose level BID-QW: twice a day on a single day each week. QD: once daily. HERKULES-3 GI Cancer Regimen ERAS-007 + palbociclib Indication Status KRAS- or NRAS-mutant CRC; KRAS-mutant PDAC Dose escalation on
Slide 40: Expected TRAEs associated with SHP2 and ERK inhibitors
Expected TRAEs associated with SHP2 and ERK inhibitors have been limited TRAE: treatment‐related adverse event Common ERKi TRAEs Skin Gastrointestinal Eye General (fatigue) Common SHP2i TRAEs Gastrointestinal General (peripheral edema) Hematologic Cardiovascular Hepatic
Slide 41: Treatment-related AEs for ERAS-601 and ERAS-007
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 Hypertensio
Slide 42: Likely recommended dose of ERAS-007 for combinations was well tolerated
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, an
Slide 43: Will ERAS-601 and ERAS-007 provide adequate target inhibition?
Will ERAS-601 and ERAS-007 provide adequate target inhibition at the combination dose and schedule? ?
Slide 44: HERKULES-1: ERAS-007 PK aligned with model prediction
HERKULES-1: Preliminary observed PK characteristics of ERAS-007 have been generally aligned with model prediction IC90* IC50* Model-Based Simulated PK Profile Observed PK Profile In general, ERAS-007 PK exposure at 100mg and 125mg BID-QW had comparable IC90 coverage compared to that of 250mg QW, but
Slide 45: FLAGSHP-1: ERAS-601 well behaved PK characteristics
FLAGSHP-1: ERAS-601 showed well behaved PK characteristics Source: FLAGSHP-1 trial Rapid absorption (median Tmax < 4h post dose) Estimated terminal half-life: ~15-22h PK exposure increased in a dose-dependent manner At 40mg BID, steady-state mean exposure exceeded pERK IC50 (NCI-H358) throughout the
Slide 46: Different target coverage strategies for ERAS-007 and ERAS-601
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 to
Slide 47: Proposed MAPKlamp dose escalation in HERKULES-1
Proposed MAPKlamp dose escalation in HERKULES-1 is designed to maximize target inhibition and optimize risk/benefit for patients BID (3/1): twice a day, three weeks on, one week off BID-QW: twice a day on a single day each week ERAS-007 100mg, BID-QW ERAS-601 40mg BID (3/1) ERAS-007 50mg, BID-QW
Slide 48: Pooled analysis sharpened focus of MAPKlamp trial on BRAF-driven solid tumors
Erasca’s tissue specific and tissue agnostic trials target multiple indications Pooled analysis has sharpened the focus of MAPKlamp trial on BRAF-driven solid tumors Alterations GBM HNSCC NSCLC CRC Melanoma PDAC Other solid tumors AML EGFR*/FLT3 125 513 184 338 - - - 61 NF1 25 58 98 35 33 1.9 434 3.
Slide 49: Discussant: Dr. David Hong
Discussant: Dr. David Hong Deputy Chair in the Department of Investigational Cancer Therapeutics MD Anderson Cancer Center
Slide 50: David Hong, MD
David Hong, MD Professor, Deputy Chair Department of Investigational Cancer Therapeutics
Slide 51: Best overall response in RAS/MAPK-altered Blue Ocean Indications
Best overall response with ERAS-007 or ERAS-601 in 15 RAS/MAPK-altered Blue Ocean Indications across lines of therapy Kopetz et al NEJM ‘19 * Unconfirmed partial responses indicated with an asterisk. NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/
Slide 52: Duration of treatment in 15 RAS/MAPK-altered Blue Ocean Indications
Duration of treatment observed with ERAS-007 or ERAS-601 in 15 RAS/MAPK-altered Blue Ocean Indications across lines of therapy Kopetz et al NEJM ‘19 NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/MAPK alterations where no targeted therapies are ap
Slide 53: Best overall response in BRAF-driven Blue Ocean Indications
Best Overall Response Observed with ERAS-007 or ERAS-601 in BRAF-driven Blue Ocean Indications across lines of therapy Kopetz et al NEJM ‘19 * Unconfirmed partial responses indicated with an asterisk NOTE: Blue Ocean Indications defined as populations of unmet need with relevant tumor types and RAS/
Slide 54: Duration of treatment in BRAF-driven Blue Ocean Indications
Duration of Treatment Observed with ERAS-007 or ERAS-601 in BRAF-driven Blue Ocean Indications Kopetz et al NEJM ‘19 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 do
Slide 55: At MD Anderson, ~20% of BRAF patients have Class II and III mutations
At MD Anderson, ~20% of BRAF patients have Class II and III mutations Kopetz et al NEJM ‘19 Source: MD Anderson Institute for Personal Cancer Therapy database, 2019-2022 Other BRAF includes Class I and unannotated mutations Most common tumor types include: Genitourinary Lung Head and neck BRAF Class
Slide 56: Conclusions
Conclusions Kopetz et al NEJM ‘19 While Erasca data set is small, encouraging monotherapy activity has been observed with both ERAS-007 and ERAS-601 in patients with tumors driven by an activated RAS/MAPK pathway. 6 of 26 patients with RAS/MAPK alterations experienced a confirmed or unconfirmed PR i
Slide 57: Future Directions and Key Milestones
Future Directions and Key Milestones
Slide 58: Future directions
Future directions ERAS-007 and ERAS-601 are being developed as foundational combination agents for targeting solid tumors with RAS/MAPK alterations. These agents are currently being explored: In combination with multiple other agents, including inhibitors of BRAF (e.g., encorafenib), EGFR (e.g., cet
Slide 59: Anticipated key milestones and clinical trial readouts
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 Data to include preliminary monotherapy safety and pharmacokinetics to su
Slide 60: Q&A
ERASCA- Q&A
Slide 61: Breakdown of tumor types and molecular drivers by trial
Breakdown of tumor types and molecular drivers by trial 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 ASN007-101 trial1: ~93% of patients had non-CRC
Slide 62: Other solid tumors: tumor type and alteration in Blue Ocean Indication
Other solid tumors Other solid tumor type and alteration Blue Ocean Indication Small bowel adenocarcinoma, BRAF Class 2 14 Prostate cancer, BRAF Class 2 14 Thyroid cancer, NRAS Q61 11 Squamous cell carcinoma, BRAF rearrangement 14 Thyroid cancer, BRAF V600E 13 Medullary thyroid carcinoma, HRAS Q61 1