Revolution Medicines, Inc. · NASDAQ:RVMD

Revolution Medicines — Investor Presentation (June 2020)

40 slides from Revolution Medicines's investor presentation, Jun 22, 2020

  1. Slide 1: Translating Frontier Oncology Targets to Outsmart Cancer

    June 2020 Translating Frontier Oncology Targets to Outsmart Cancer™ Exhibit 99.1

  2. Slide 2: Legal Disclaimer

    Legal Disclaimer This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and fina

  3. Slide 3: Summary

    Summary Clinical-stage precision oncology company with deep focus on RAS cancers; growing clinical momentum Cohesive pipeline of complementary investigational products for targeted mono- and combination treatment Prolific innovation engine, sophisticated preclinical and clinical capabilities, and se

  4. Slide 4: Continued Operational Excellence in COVID-19 Environment

    Continued Operational Excellence in COVID-19 Environment COVID-19 pandemic with profound global impact on health and socioeconomic well-being Operational adjustments implemented by RVMD in mid-March have enabled our team to remain healthy, focused and productive. Currently: Limited impact on preclin

  5. Slide 5: Our Innovation Engine Focused on Genetic Drivers of RAS-Dependent Cancers

    Our Innovation Engine Focused on Genetic Drivers of RAS-Dependent Cancers Deep chemical biology and cancer pharmacology know-how to define critical vulnerabilities of frontier RAS / mTOR pathway targets and signaling circuits Sophisticated structure-based drug discovery capabilities, including prove

  6. Slide 6: Integrated Pipeline Targets Elusive Drivers of RAS Cancers

    Integrated Pipeline Targets Elusive Drivers of RAS Cancers RAS Signaling Cascade Receptor Tyrosine Kinase (RTK) / Growth Factor Receptors mTOR Signaling Cascade Growth, Survival Oncogenes Multiple RAS(ON) SOS1 SHP2 4EBP1/ mTORC1 Cancer

  7. Slide 7: Pipeline Drug Combinations to Overcome Resistance Loops

    Pipeline Drug Combinations to Overcome Resistance Loops that Feed Oncogene Addiction RAS Signaling Cascade Resistance loops Growth, Survival Multiple RAS(ON) SOS1 SHP2 mTOR Signaling Cascade Oncogenes 4EBP1/ mTORC1

  8. Slide 8: Substantial Progress Spanning Clinical and Preclinical Pipeline

    Substantial Progress Spanning Clinical and Preclinical Pipeline RAS Signaling Cascade mTOR Signaling Cascade Growth, Survival Oncogenes Multiple RAS(ON) Lead opt. SOS1 Lead opt. RMC-4630 Phase 1/2 RMC-5552 IND-enabling development Cancer

  9. Slide 9: RMC-4630 SHP2

    RAS Signaling Cascade Growth, Survival SHP2 RMC-4630 Phase 1/2

  10. Slide 10: RMC-4630 Inhibits SHP2, a Shared Node that Regulates RAS Signaling Pathway

    RMC-4630 Inhibits SHP2, a Shared Node that Regulates RAS Signaling Pathway SOS1 NF1 RAS(ON) SHP2 RAF MEK ERK PI3K AKT Growth, Survival GDP RAS(OFF) GTP PTEN ✘ mTORC1 4EBP1 S6K Oncogenes TSC1/2 Multiple Receptor Tyrosine Kinases (RTKs) Oncogenic mutants sensitive to SHP2 inhibitor

  11. Slide 11: RMC-4630 Drives Stasis and Regressions of NSCLC Xenografts

    RMC-4630 Drives Stasis and Regressions of NSCLC Xenografts with Select Pathway Mutations KRASG12C BRAFClass3 NF1LOF LUN092 NCI-H1838 LUN023 EGFRL858R, T790M NCI-H1975 Control RMC-4630 30 mg/kg po qd

  12. Slide 12: RMC-4630-01: Best Change in Tumor Burden in KRAS-mutant NSCLC

    RMC-4630-01: Best Change in Tumor Burden from Baseline in KRASmutant NSCLC Source: EDC as of 5/4/2020 G12C G12D G12V G12A DCR KRASG12C NSCLC = 70% (7/10) DCR RASmutant NSCLC = 59% (17/29) Data presented for efficacy evaluable population (N=29) defined as patients with baseline and at least one post-

  13. Slide 13: RMC-4630-01: Further Insights on Intermittent Dosing Paradigm

    Cytostatic threshold (EC50) Apoptotic threshold (EC75) 60 mg daily (N=11)1 140 mg D1D4 (N=8)2 200 mg D1D2 (N=4)3 RMC-4630-01: Further Insights on Intermittent Dosing Paradigm in the Clinic PK sampled at: 1C1D22 2Post-C1D1 dosing and C1D8 trough (~168 h) 3Post-C1D1 and C1D2 dosing and C1D8 trough (~1

  14. Slide 14: RMC-4630-01: Approaching Dose & Schedule Optimized for Efficacious and Tolerable Exposures

    RMC-4630-01: Approaching Dose & Schedule Optimized for Efficacious and Tolerable Exposures Dose cohort: 60 mg daily N=18^ 140 mg D1D4* N=8 200 mg D1D2* N=4 With related AEs, grade >3: 9/18 (50%)a 4/8 (50%)b 0/4 (0%) With AEs Leading to Discontinuation or Dose Reduction: 4/18 (22.2%) 1/8 (12.5%) 0/4

  15. Slide 15: RMC-4630 Causes Tumor Growth Inhibition and Regressions in NF1LOF Models

    RMC-4630 Causes Tumor Growth Inhibition and Regressions in Diverse Preclinical NF1LOF^ Models LUN #150, NSCLC PDX NCI-H1838, NSCLC CDX ^ NF1LOF (loss-of-function) inferred from deletions, insertions, premature stops and truncations in neurofibromin 1 gene Anti-tumor effects in numerous NF1LOF PDX mo

  16. Slide 16: RMC-4630-01: Best Change in Tumor Burden for NSCLC and Gynecologic Tumors with NF1LOF

    RMC-4630-01: Best Change in Tumor Burden for NSCLC and Gynecologic Tumors with NF1LOF 1 patient (NSCLC) with death due to clinical PD is not represented in this figure NF1LOF (loss-of-function) inferred from deletions, insertions, premature stops and truncations in neurofibromin 1 gene NF1LOF only N

  17. Slide 17: Complete Response in Patient with Uterine Cancer

    Complete Response in Patient with Uterine Cancer 63yr old with stage IVb poorly differentiated uterine carcinosarcoma Diagnosed Oct 2017 – two NF1LOF mutations, POLE (DNA repair) mutation, and ultra-high tumor mutational burden Two treatment regimens prior to starting RMC-4630 Started RMC-4630 200 m

  18. Slide 18: Rational, Mechanism-driven Combinations as Central Clinical Thesis

    Rational, Mechanism-driven Combinations as Central Clinical Thesis SHP2 inhibitor RMC-4630 MEK inhibitors KRASG12C inhibitors Checkpoint inhibitors Monotherapy Dose/regimen optimization Combination therapies Additive anti-tumor effects + combat adaptive resistance RTK inhibitors Select RAS Pathway M

  19. Slide 19: Broad Development Program for RMC-4630 Progressing Well

    Broad Development Program for RMC-4630 Progressing Well 2019 2020 Monotherapy Dose escalation (including expansion cohorts with molecularly-defined tumors) Combination therapy Molecularly-defined solid tumors EGFR Inhibitor (osimertinib) CodeBreaK 101 PD-1 Inhibitor (pembrolizumab) KRASG12C(OFF) AMG

  20. Slide 20: SHP2 Inhibitor Promotes Anti-Tumor Responses via Innate and Adaptive Immunity

    SHP2 Inhibitor Promotes Anti-Tumor Responses via Effects on Innate and Adaptive Immunity Based on Quintana et al. Cancer Research April 2020

  21. Slide 21: Anti-Tumor Responses from SHP2 Inhibitor Monotherapy and Combination with Anti-PD1

    Anti-Tumor Responses from SHP2 Inhibitor Monotherapy and Combination with Anti-PD1 RMC-4550 (SHP2 inh.) Anti-PD1 Control Combination EMT-6 (syngeneic breast cancer, NF1mut;SOS1mut ) 20% CR CR: Complete response, with immunological memory Quintana et al. Cancer Research April 2020

  22. Slide 22: RMC-5552 mTOR Signaling Cascade

    mTOR Signaling Cascade Oncogenes 4EBP1/mTORC1 RMC-5552 IND-enabling development

  23. Slide 23: Hyperactivation of mTOR Signaling Frequently Drives Cancer and/or Drug Resistance

    Hyperactivation of mTOR Signaling Frequently Drives Cancer and/or Drug Resistance RAS Signaling Cascade Resistance loops Growth, Survival Multiple RAS(ON) SOS1 SHP2 mTOR Signaling Cascade Oncogenes 4EBP1/ mTORC1 PI3K PTEN TSC1/2 STK11 mTOR

  24. Slide 24: Attractive Profile of Bi-Steric mTORC1 Inhibitors, including RMC-5552

    Attractive Profile of Bi-Steric mTORC1 Inhibitors, including Development Candidate RMC-5552 Layered structural model mTORC1 FKBP12 Allosteric site Active site RMC-5552 Inhibition of mTORC1: pS6K 0.14 nM Inhibition of mTORC1: p4EBP11 0.48 nM Selectivity over mTORC2: AKT2 40X 1 Rapamycin is not consid

  25. Slide 25: RMC-5552 Monotherapy Drives Regressions in mTORC1-Hyperactivated Tumor Xenografts

    RMC-5552 Monotherapy Drives Regressions in mTORC1-Hyperactivated Tumor Xenografts MCF7 CDX (Breast cancer, PIK3CAmutant; ER+/HER2-) End of study responses

  26. Slide 26: Bi-Steric mTORC1 Inhibitor Exhibits Anti-Tumor Activity in KRASG12C NSCLC Xenograft

    Bi-Steric mTORC1 Inhibitor (RM-006) Exhibits Anti-Tumor Activity in KRASG12C NSCLC Xenograft NCI-H358 CDX (NSCLC, KRASG12C) N = 10/group unless noted All regimens well tolerated Control RM-006 10 mg/kg ip qw (N=8) AMG 510 30 mg/kg po qd Combination RM-006 = mTORC1-selective bi-steric tool compound

  27. Slide 27: Dual Targeted Therapy Delays Acquired Drug Resistance

    Dual Targeted Therapy for RAS/mTOR Pathway Co-Mutations Delays Acquired Drug Resistance NCI-H2030 CDX (NSCLC, KRASG12C;STK11LOF*) n = 10/group unless noted ***p<0.0001, one-way ANOVA *** *** ^ STK11LOF (loss-of-function) inferred from deletions, insertions, premature stops and truncations

  28. Slide 28: Dual Targeted Therapy Overcomes Primary Resistance

    Dual Targeted Therapy for RAS/mTOR Pathway Co-Mutations Overcomes Primary Resistance NCI-H2122 NSCLC CDX (KRASG12C; STK11LOF) *** n = 10/group unless noted ***p<0.0005, one-way ANOVA End of study responses 7 n = number of regressions > 10% from starting volume ^ STK11LOF (loss-of-function) inferred

  29. Slide 29: Multiple RAS(ON)

    Multiple RAS(ON) Lead opt. RAS Signaling Cascade Growth, Survival

  30. Slide 30: Numerous RAS Mutants Commonly Drive Human Cancers and are Important Disease Targets

    Numerous RAS Mutants Commonly Drive Human Cancers and are Important Disease Targets KRAS NRAS HRAS G12 Glycine-12 Q61 Glutamine-61 G13 Glycine-13 C D V S R K E L A P H Isoforms Hotspots Mutations 30% of all cancers (U.S.)

  31. Slide 31: Mutant RAS Tumors are Addicted to High Levels of RAS(ON)

    Mutant RAS Tumors are Addicted to, and Tenaciously Maintain, High Levels of RAS(ON) RAS(ON) Inhibitors RAS(OFF) Inhibitors RAS(ON) RAS(OFF) *Adapted from Patricelli et al., Cancer Discovery 2016 Cancer Mutation* Normal* GDP GTP INACTIVE ACTIVE

  32. Slide 32: Highly Differentiated Inhibitors of Active Form of Oncogenic RAS Proteins

    Highly Differentiated Inhibitors of Active Form of Oncogenic RAS Proteins Tri-Complex Inhibitor Unique target binding mode Active RAS form Near all hotspot mutations Forms tri-complex within cell Directly inhibits oncogenic signaling RASmutant(ON) Chaperone protein

  33. Slide 33: KRASG12C(ON) Inhibitors Drive Tumor Xenograft Regressions in Vivo

    KRASG12C(ON) Inhibitors Drive Tumor Xenograft Regressions in Vivo NSCLC (KRASG12C) PDAC (KRASG12C) Control Inhibitor 30 mg/kg IP qd 10 Control Inhibitor 10 mg/kg IP qd Inhibitor 30 mg/kg IP qd 10 5 End of study responses End of study responses Days Post-Implant Days Post-Implant NCI-H358 MIA PaCa-2

  34. Slide 34: A Potent, Orally Bioavailable KRASG12C(ON) Inhibitor from Lead Optimization Series

    A Potent, Orally Bioavailable KRASG12C(ON) Inhibitor from Lead Optimization Series IC50 Time (hr) Unbound Plasma [RM-017] (nM) Suppression of KRASG12C in Vitro (NCI-H358 cells) PK After Oral Administration in Vivo (mouse)

  35. Slide 35: Oral KRASG12C(ON) Lead Series Compound Drives Regressions in Vivo

    Oral Administration of KRASG12C(ON) Lead Series Compound Drives Regressions in Vivo NCI-H358 CDX (NSCLC, KRASG12C/+) All doses were well tolerated # End of study responses 9 n = number of regressions > 10% from starting volume 8 Control (n=9) AMG 510 100 mg/kg po qd RM-017 100 mg/kg po qd

  36. Slide 36: Summary

    Summary (©2020 Revolution Medicines

  37. Slide 37: 1H-20: Clinical and Preclinical Pipeline Advances Strengthen Therapeutic Strategies

    1H-20: Clinical and Preclinical Pipeline Advances Strengthen Therapeutic Strategies for RAS Tumors RAS Signaling Cascade mTOR Signaling Cascade Growth, Survival Oncogenes Multiple RAS(ON) SOS1 '4630 ‘5552 Clinical activity expanded from KRASG12 mutant NSCLC to second cancer genotype, NF1LOF Orally a

  38. Slide 38: Progress Since IPO and Prospects for 2020

    Progress Since IPO and Prospects for 2020 Program Status RMC-4630 (SHP2) Clinical update Intermittent dosing progressing toward RP2DS for mono- and combination therapy Additional evidence of monotherapy activity in KRASmutant NSCLC Initial monotherapy activity in NF1LOF tumors Begin treating patient

  39. Slide 39: Looking Forward to 2H-2020 Program Milestones

    Looking Forward to 2H-2020 Program Milestones RMC-4630 (SHP2) Additional clinical update Begin treating patients in combination with osimertinib Mutant RAS(ON) Nominate first Development Candidate Lead compound for second target RMC-5552 (mTORC1) IND-ready

  40. Slide 40: Translating Frontier Oncology Targets to Outsmart Cancer

    Translating Frontier Oncology Targets to Outsmart Cancer™

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