Revolution Medicines, Inc. · NASDAQ:RVMD
Revolution Medicines — Investor Presentation (October 2023)
48 slides from Revolution Medicines's investor presentation, Oct 23, 2023
Slide 1: On Target to Outsmart Cancer
Exhibit 99.1 On Target to Outsmart Cancer October 22, 2023 © 2023 Revolution Medicines
Slide 2: Legal Disclaimer
2 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 fi
Slide 3: Mission: to revolutionize treatment for patients with RAS-addicted cancers
3 Mission: to revolutionize treatment for patients with RAS-addicted cancers through the discovery, development and delivery of innovative, targeted medicines. • Pioneering class of drug candidates designed to serve RAS-addicted cancer patients by targeting oncogenic RAS(ON) drivers of common, life-
Slide 4: Excessive RAS(ON) Signaling Drives 30% of Human Cancers
4 Excessive RAS(ON) Signaling Drives 30% of Human Cancers, Targeted by Our RAS(ON) Inhibitors RAS-Mutant Cancers = RAS(OFF) (1) Normal New patients per year (U.S.) RAS Cancer Mutations = RAS(ON) >200,000 including Cell 60,000 Membrane Lung cancer (29% of NSCLC) Excessive Tightly regulated RAS(ON) si
Slide 5: Pioneering Tri-complex RAS(ON) Inhibitors
5 Pioneering Tri-complex RAS(ON) Inhibitors Designed to Deliver Robust and Durable Anti-Tumor Activity • Direct inhibition of RAS(ON) Oncogenic RAS(ON) Inhibited RAS(ON) cancer drivers RAS(ON) Inhibitor • Deep and durable suppression of GTP RAS cancer signaling designed to defy common drug resistanc
Slide 6: Development-Stage RAS(ON) Inhibitor Portfolio
6 Development-Stage RAS(ON) Inhibitor Portfolio Designed to Treat Nearly All Patients with RAS-Addicted Cancers >200,000 new patients (1) RAS Selectivity MULTI per year (U.S.) multiple mutations RMC-6236 G12C clinical (initial focus on G12X) and WT Mutant-Selective G12D RMC-6291 clinical G12C G12X R
Slide 7: Complementary RAS(ON) Inhibitors for Monotherapy and Combination Strategies
7 Complementary RAS(ON) Inhibitors Designed for Monotherapy and Combination Strategies Against RAS-Addicted Cancers MULTI RAS RAS Mutant-Selective • Monotherapy with broad • Alternative monotherapy potential for RAS-addicted approaches cancers MULTI • Complementary to RAS • Backbone of RAS(ON) Inhib
Slide 8: RMC-6236: First-in-Class RAS(ON) Inhibitor
8 MULTI RMC-6236: First-in-Class, RAS (ON) Inhibitor with Broad Potential Against RAS-Addicted Cancers • Highly selective for RAS(ON) proteins with broad and deep anti-tumor activity in preclinical models • Orally bioavailable and generally well-tolerated in patients at active doses 166,000 • Unprec
Slide 9: RMC-6236: Dose-Dependent Anti-Tumor Activity in NSCLC Model
9 RMC-6236: Dose-Dependent Anti-Tumor Activity at Low Doses in RAS-Addicted NSCLC Model End of Study Responses Control RMC-6236 1 mg/kg 3000 RMC-6236 10 mg/kg 500 Control RMC-6236 25 mg/kg RMC-6236 1 mg/kg 400 RMC-6236 10 mg/kg RMC-6236 25 mg/kg 2000 300 200 1000 Dosing 100 start 8/10 R 10/10 CR 0 0
Slide 10: RMC-6236: Highly Active with Durable Responses Across Models
10 RMC-6236: Highly Active with Durable Responses Across Models G12X of Major Human Cancers with RAS Drivers NSCLC PDAC CRC PFS 53% ORR (8/15) 61% ORR (11/18) 44% ORR (8/18) RMC-6236 – Median not reached 100% DCR (15/15) 89% DCR (16/18) 56% DCR (10/18) Control – Median 9 days 300 300 300 100 200 200
Slide 11: RMC-6236-001 Phase 1 Study Design
11 RMC-6236-001 Phase 1 Study Design Key Eligibility Criteria Dose Escalation RMC-6236 administered orally QD • Advanced solid tumors (1) G12X with KRAS mutations 500 mg (currently excluding G12C 400 mg KRAS ) • Received prior standard 300 mg Dose Expansion / therapy appropriate for (2) 220 mg Optim
Slide 12: RMC-6236: Patient Demographics and Baseline Characteristics
12 RMC-6236: Patient Demographics and Baseline Characteristics Total Tumor KRAS Genotypes, n (%) n=131 Age, median (range), years 64 (30–86) Male, n (%) 69 (53) Tumor type, n (%) G12V PDAC 69 (53) 37 (28) G12D NSCLC 47 (36) 67 (51) CRC 10 (7) Other* 5 (4) G12R 14 (11) ECOG PS, n (%) 0 40 (31) 1 91 (
Slide 13: RMC-6236: Dose-Dependent Increases in Exposure
13 RMC-6236: Dose-Dependent Increases in Exposure Mean Steady-State Blood PK Individual Steady-State Blood AUC Profiles 400 mg Exposure in mice at 25 300 mg mg/kg* 200/220 mg Exposure in mice at 10 160 mg mg/kg* 120 mg 80 mg 40 mg 20 mg 10 mg Time (Hours) Dose Level • Dose-dependent increases in exp
Slide 14: RMC-6236: Summary of Treatment-Related Adverse Events
14 RMC-6236: Summary of Treatment-Related Adverse Events Total (n=131) Maximum severity of TRAEs Grade 1 Grade 2 Grade 3 Grade 4 Any Grade TRAEs occurring in ≥10% of patients, n (%) * Rash 57 (44) 29 (22) 6 (5) 0 92 (70) Nausea 41 (31) 14 (11) 0 0 55 (42) Diarrhea 32 (24) 9 (7) 1 (1) 0 42 (32) Vomit
Slide 15: G12X KRAS NSCLC: Best Overall Response to RMC-6236
15 G12X KRAS NSCLC: Best Overall Response to RMC-6236 (a) Evaluable for Efficacy (n = 40) Tumor Response (per RECIST 1.1) Best overall response, n (%) Complete response 1 (3) Partial response 14 (35) Stable disease 19 (48) Progressive disease 5 (13) (b) Not evaluable 1 (3) ORR, n (%) 15 (38) Confirm
Slide 16: G12X KRAS NSCLC: Duration of Treatment and Responses
16 G12X KRAS NSCLC: Duration of Treatment and Responses to RMC-6236 (a) Evaluable for Efficacy (n = 40) Median time to response: 1.4 months (range, 1.2–2.7 months) Median time on treatment: 3.1 months (range, 0.5–10.9 months) * Duration of Treatment (Weeks) (a) Patients who received first dose of RM
Slide 17: Case Report: Patient with KRAS G12V NSCLC on RMC-6236
17 G12V Case Report: Patient with KRAS NSCLC on RMC-6236 On Treatment Baseline RMC-6236, Demographics and Baseline Week 6 Characteristics • 83-year-old woman • Former smoker (~60 pack years) • Diagnosed with NSCLC in 2021 Treatment History • Prior therapies: • Ipilimumab/nivolumab • Paclitaxel Targe
Slide 18: G12X KRAS PDAC: Best Overall Response to RMC-6236
18 G12X KRAS PDAC: Best Overall Response to RMC-6236 (a) Evaluable for Efficacy (n = 46) Tumor Response (per RECIST 1.1) Best overall response, n (%) Partial response 9 (20) Stable disease 31 (67) Progressive disease 3 (7) (b) Not evaluable 3 (7) ORR, n (%) 9 (20) Confirmed, n 5 DCR (CR+PR+SD), n (%
Slide 19: G12X KRAS PDAC: Duration of Treatment and Responses
19 G12X KRAS PDAC: Duration of Treatment and Responses to RMC-6236 (a) Evaluable for Efficacy (n = 46) Median time to response: 1.4 months (range, 1.2–4.1 months) Median time on treatment: 3.3 months (range, 0.2–10.9 months) * Duration of Treatment (Weeks) (a) Patients who received first dose of RMC
Slide 20: KRAS Variant Allele Frequency in ctDNA and Clinical Response
20 KRAS Variant Allele Frequency in ctDNA Across Tumor Types and Correlation with Clinical Response NSCLC PDAC • Patients with NSCLC or PDAC were dosed at 80–300 mg • Overall, 23/50 patients (46%) were evaluable for change in mutant KRAS VAF (a) while on-treatment • In total, 8/10 (80%) patients wit
Slide 21: RMC-6291: Mutant-Selective, Covalent RAS(ON) G12C Inhibitor
21 RMC-6291: Mutant-Selective, Covalent RAS(ON) Inhibitor with G12C Differentiated Clinical Profile for KRAS Cancers G12C • Highly selective for KRAS (ON) with potent CRC activity across a range of preclinical models 17% • Orally bioavailable and generally well-tolerated in PDAC patients at active d
Slide 22: RMC-6291 Drives Tumor Regressions at Low Doses in G12C NSCLC Models
22 RMC-6291 Drives Tumor Regressions at Low Doses in Preclinical G12C Models of KRAS NSCLC Control End of Study Responses RMC-6291 3 mg/kg 2500 300 RMC-6291 10 mg/kg RMC-6291 25 mg/kg 2000 RMC-6291 100 mg/kg 200 1500 100 4/8 R 1/8 R 1000 1/8 CR 6/8 CR 8/8 CR 8/8 CR Dosing start 0 500 -100 0 10 20 30
Slide 23: RMC-6291 in Models of G12C KRAS(OFF) Inhibitor Resistance
23 RMC-6291 Drives Tumor Regressions in Preclinical Models of G12C KRAS (OFF) Inhibitor Clinical Resistance Mechanisms (1) KRAS Amplification (2) KRAS and RTK Amplification 3000 Control 1500 Control Sotorasib Adagrasib RMC-6291 RMC-6291 2000 1000 Dosing start 1000 500 0 0 0 10 20 30 40 50 60 70 80 9
Slide 24: RMC-6236 + RMC-6291 Doublet Overcomes Resistance
24 RMC-6236 + RMC-6291 Doublet Overcomes Resistance and G12C Prolongs Durability in KRAS NSCLC Models 100 75 Control RMC-6291 50 RMC-6236 RMC-6291 + RMC-6236 25 0 0 20 40 60 80 100 Days on Treatment • RAS(ON) Inhibitor doublet evaluated across seven models, including five identified as resistant to
Slide 25: RMC-6291-001 Phase 1 Study Design
25 RMC-6291-001 Phase 1 Study Design Key Eligibility Criteria Dose Escalation RMC-6291 administered orally QD or BID • Advanced solid tumors G12C with KRAS mutations 400 mg BID • Received prior standard therapy including treatment 300 mg BID G12C with KRAS (OFF) 200 mg BID Dose Expansion / inhibitor
Slide 26: RMC-6291: Patient Demographics and Baseline Characteristics
26 RMC-6291: Patient Demographics and Baseline Characteristics NSCLC CRC Other All Histologies n=23 n=33 n=7 n=63 Age, median (range), years 65 (45–85) 54 (26–84) 66 (52–78) 64 (26–85) Male, n (%) 13 (57) 21 (64) 2 (29) 36 (57) ECOG PS, n (%) 0 8 (35) 13 (39) 3 (43) 24 (38) 1 15 (65) 20 (61) 4 (57)
Slide 27: RMC-6291: Dose-Dependent Increases in Exposure
27 RMC-6291: Dose-Dependent Increases in Exposure Time (Hours) Dose • Exposure/target engagement relationship in preclinical studies predicts ≥ ~90% cross-linking of G12C KRAS in patients receiving 100 mg BID or higher *PK curves for 100 and 200 mg up to 10 hours post-dose represent combined QD and
Slide 28: RMC-6291: Summary of Treatment-Related Adverse Events
28 RMC-6291: Summary of Treatment-Related Adverse Events Total (n=63) Maximum Severity of TRAEs Grade 3 Any Grade Grade 1 Grade 2 TRAEs occurring in ≥10% of patients, n (%) Diarrhea 1 (2) 18 (29) 10 (16) 7 (11) Nausea 0 17 (27) 14 (22) 3 (5) ECG QT prolonged 7 (11) 16 (25) 8 (13) 1 (2) – – – QTcF* ≥
Slide 29: G12C KRAS NSCLC: Best Overall Response to RMC-6291
29 G12C G12C KRAS NSCLC Previously Treated with or Naïve to a KRAS (OFF) Inhibitor: Best Overall Response to RMC-6291 Evaluable for Efficacy* (n=17) Tumor Response (per RECIST 1.1) Best overall Prior Naïve to response, G12Ci G12Ci n (%) (n=10) (n=7) † Partial response 5 (50) 3 (43) Stable disease 5
Slide 30: G12C KRAS CRC: Best Overall Response to RMC-6291
30 G12C G12C KRAS CRC Naïve to KRAS (OFF) Inhibitor: Best Overall Response to RMC-6291 Evaluable for Efficacy* (n=19) Tumor Response (per RECIST 1.1) Best overall response, n † n=20 (%) ‡ Partial response 8 (40) Stable disease 8 (40) † Progressive disease 4 (20) ORR, n (%) 8 (40) DCR (CR+PR+SD), n (
Slide 31: Duration of Treatment and Responses to RMC-6291
31 G12C Duration of Treatment and Responses to RMC-6291 for KRAS Inhibitor-Treated or Naïve NSCLC and Naïve CRC NSCLC Median time to response: 1.3 months (range: 1.1–4.1 months) Median time on treatment: 3.5 months (range: 0.3–9.8 months) CRC Median time to response: 1.4 months (range: 1.2–4.1 month
Slide 32: Reduction in ctDNA of KRAS G12C Allele Correlates with Response
32 G12C Reduction in ctDNA of the KRAS Allele Across Doses Correlates with Clinical Response Visit G12C KRAS VAF at Cycle 1 Day 1 (pre-treatment) to Cycle 2 Day 1 or Cycle 3 Day 1 (on-treatment) determined by Guardant Health ctDNA (circulating tumor DNA) test. ctDNA, circulating tumor DNA; VAF, vari
Slide 33: RMC-9805: Clinical Stage RAS(ON) G12D Inhibitor
33 RMC-9805: Clinical Stage, Mutant-Selective, Covalent RAS(ON) G12D Inhibitor for KRAS Cancers G12D Selective Covalent Binding to KRAS (ON) WT G12D G12C G13C G13D KRAS: X-linked KRAS KRAS H/NRAS G12D In Vivo Anti-Tumor Activity across KRAS Cancer Models 200 61,000 CRC 150 G12D New KRAS patients NSC
Slide 34: RMC-5127: First-in-Class RAS(ON) G12V Inhibitor
34 RMC-5127: First-in-Class Mutant-Selective RAS(ON) Inhibitor for G12V KRAS Cancers G12V NSCLC In Vivo Anti-Tumor Activity across KRAS Cancer Models 23% CRC CRC NSCLC 33% PDAC 50 48,000 G12V New KRAS patients mSD 0 (1) Other per year (U.S.) 10% -50 mPR mCR -100 PDAC 34% (1) Estimated using tumor mu
Slide 35: RMC-0708 and RMC-8839: Mutant-Selective RAS(ON) Inhibitors
35 Q61H First-in-Class Mutant-Selective RAS(ON) Inhibitors Targeting KRAS G13C and KRAS Cancers RMC-0708 RMC-8839 (2) (1) G13C Q61H KRAS NSCLC KRAS NSCLC 3000 Control Control RMC-0708 1500 RMC-8839 2000 1000 Dosing 1000 Start 500 0 0 0 10 20 30 0 10 20 30 40 Days on Study Days on Study RVMD preclini
Slide 36: Deep Pipeline of Targeted Therapies for RAS-Addicted Cancers
36 Deep Pipeline of Targeted Therapies for Majority of RAS-Addicted Cancers PRECLINICAL IND-ENABLING PHASE 1 PHASE 2 PHASE 3 RAS(ON) INHIBITORS MULTI RMC-6236 G12C RMC-6291 RMC-9805 G12D G12V RMC-5127 Q61H RMC-0708 G13C RMC-8839 Pipeline G12R, G13D, other Expansion RAS COMPANION INHIBITORS (1) RMC-4
Slide 37: Clinical Development Vision for RMC-6236
37 Clinical Development Vision for RMC-6236 Proven to be broadly active in patients in multiple common tumor types and RAS genotypes Parallel strategies to prioritize speed + breadth including both late-stage monotherapy trial(s) and combinations Pursuing multiple dimensions for efficient expansion:
Slide 38: RMC-6236 Clinical Development Plan
38 RMC-6236 Clinical Development Plan Designed to Benefit the Greatest Number of Patients RAS Mutations KRAS G12-mutant (K/N/H) RAS-mutant Randomized trials with nested design and hierarchical testing G13 Q61 G12 G12 Lines of Therapy Focused exploration of RAS(ON) 1L / Adjuvant Patients Inhibitor do
Slide 39: Efficacy Benchmarks from Standard of Care in Previously-Treated RAS NSCLC
39 Efficacy Benchmarks from Standard of Care for Patients with MUT Previously-Treated RAS NSCLC (1) Efficacy 2L+ Therapy Docetaxel Sotorasib (2) Benchmarks All patients N 174 171 Docetaxel ORR (%) 13.2 28.1 Docetaxel + ramucirumab mDOR (m) 6.8 8.6 G12C KRAS only mPFS (m) 4.5 5.6 Sotorasib (accelerat
Slide 40: Proposed Global Randomized Phase 3 Trial in Previously-Treated NSCLC
40 Proposed Global Randomized Phase 3 Trial in Patients with MUT Previously-Treated RAS NSCLC (1) (1,2) Trial Design Potential Patient Populations Endpoints RMC-6236 PFS R Core Population: G12X-C OS G12X Patients 13% Docetaxel Patient Reported Outcomes • N > 400 patients • Prior therapies: Anti-PD-(
Slide 41: Efficacy Benchmarks from Standard of Care in Previously-Treated PDAC
41 Efficacy Benchmarks from Standard of Care in Patients with Previously-Treated PDAC (1) Efficacy lipo-irino + 2L+ Therapy GnP (2) Benchmarks 5-FU FOLFIRINOX ORR (%) 7.7 11 mFOLFIRINOX Gemcitabine+nab-Paclitaxel (GnP) mPFS (m) 3.1 3.5 FOLFOX mOS (m) 6.1 7.1 FOLFIRI post-GnP only liposomal irinoteca
Slide 42: Potential Global Randomized Phase 3 Trial in Previously-Treated PDAC
42 Potential Global Randomized Phase 3 Trial of RMC-6236 in Patients with Previously-Treated PDAC (1) (1,2) Trial Design Potential Patient Populations RMC-6236 Endpoints R PFS Physician’s choice: OS e.g., GnP or G12X - 85% Patient Reported Outcomes mFOLFIRINOX Core Population: G12X Patients • N > 50
Slide 43: Parallel Execution of Multiple Approaches to Expand to Combinations
43 Parallel Execution of Multiple Approaches to Expand from Monotherapy to Combinations Chemo-free Combination with RAS(ON) Inhibitor Doublet Checkpoint Inhibitor RMC-6236 + RMC-6291 RMC-6236/RMC-6291 + Anti-PD1 Recruiting Pending RMC-6236 Monotherapy Combination with Other Combination with SOC Targ
Slide 44: First Two RAS(ON) Inhibitors Clinically Validated Against RAS Cancer Drivers
44 G12X First Two RAS(ON) Inhibitors Clinically Validated Against RAS Cancer Drivers and Major Tumor Types 80,000 Q61X G12X Validated - RAS 60,000 G13X Q61X • 150,000 new patients per year among (1,2) G13X Q61X PDAC, NSCLC and CRC * 40,000 Expansion – additional tumor types and G13X Q61X RAS + RAS G
Slide 45: Financial Information
45 Financial Information Financial Position Cash, cash equivalents and (1) $909.5 million marketable securities as of June 30, 2023 2023 Financial Guidance (2) 2023 GAAP net loss of $360 million to $400 million (1) With current cash, cash equivalents and marketable securities, the company projects i
Slide 46: Summary of Pending EQRx Transaction
46 Summary of Pending EQRx Transaction • RVMD to acquire EQRx in an all-stock transaction to gain more than $1B in additional capital • Strengthened balance sheet intended to support RVMD’s parallel, late-stage development for RAS(ON) Inhibitor pipeline • Shareholder meeting to vote on the transacti
Slide 47: On Target to Outsmart Cancer
47 On Target to TM Outsmart Cancer
Slide 48: Appendix
48 Appendix • All RAS cancer epidemiology statistics are estimated using tumor mutation frequencies from Foundation Medicine Insights March 2022 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2023: • RAS mutations include: KRAS G12(A,C,D,F,L,R,S,V),
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