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Revolution Medicines, Inc.
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business strategy, prospective products, availability of funding, ability to manage existing collaborations and establish new strategic collaborations, licensing or other arrangements, the scope, progress, results and costs of developing our product
candidates or any other future product candidates, conducting clinical trials, the potential market size and size of the potential patient populations for our product candidates, the timing and likelihood of success of obtaining product approvals,
plans and objectives of management for future operations, the scope of protection we are able to establish and maintain for intellectual property rights covering our product candidates, future results of anticipated products the impact of global
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3 Mission: to revolutionize treatment for patients with RAS-addicted
cancers through the discovery, development and delivery of innovative, targeted medicines. Pioneering class of RAS(ON) inhibitor drug candidates targeting oncogenic drivers of common, life-threatening cancers Unprecedented RAS(ON)
multi-selective inhibitor (RMC-6236) and RAS(ON) G12C-selective inhibitor (RMC-6291) show promising and highly differentiated initial clinical profiles On track toward late-stage development of RMC-6236 and advancement of mutant-selective
inhibitors led by RMC-6291 and RMC-9805
4 Portfolio of RAS(ON) Inhibitors Designed to Target 30% of Human
Cancers RAS-Mutant Cancers (1) Normal New patients per year (U.S.) RAS Cancer Mutations >200,000 including Cell 60,000 Membrane Lung cancer (29% of NSCLC) Excessive Tightly regulated RAS(ON) signaling drives = RAS(OFF) RAS(ON) proteins control
75,000 uncontrolled cell growth cell growth Colorectal cancer (49% of CRC) = RAS(ON) Oncogenic mutations in 53,000 KRAS, NRAS or HRAS Pancreatic cancer are common at positions (92% of PDAC) G12, G13 and Q61 (1) 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 (see appendix for additional detail); NSCLC = non-small cell lung cancer; CRC = colorectal
cancer; PDAC = pancreatic ductal adenocarcinoma
5 Pioneering Tri-complex RAS(ON) Inhibitors Designed to Deliver Robust
and Durable Anti- tumor Activity Direct inhibition of RAS(ON) cancer Oncogenic RAS(ON) Inhibited RAS(ON) drivers RAS(ON) Inhibitor Deep and durable suppression of RAS GTP cancer signaling designed to defy common drug resistance
mechanisms Clinical validation of first two RAS(ON) Inhibitors studied as single agents Cell Cyclophilin A Membrane
6 Initial Clinical Profiles of RAS(ON) Inhibitors Support Broad Set of
Potential Opportunities to Treat RAS-Addicted Cancers Target Multi-Selective Genotypes G12X and RMC-6236 Clinical validation in NSCLC and PDAC (1) expansion Mutant-Selective Evidence of differentiated clinical activity in RMC-6291 G12C NSCLC and CRC
RMC-9805 Dose escalation begun 3Q23 G12D (1) RMC-6236-001 protocol amended in August 2023 to broaden enrollment, now allowing patients with tumors bearing mutations in any of the three hotspots (G12X/G13X/Q61X) in any of the three major RAS isoforms
(KRAS/NRAS/HRAS); G12X broadened to include G12C
7 2024 Capital Allocation Priorities to Advance Pioneering RAS(ON)
Inhibitor Pipeline driving to Industry-Leading Propel RMC-6236 Targeted into first pivotal trial(s) Expand reach Qualify mutant-selective Medicines of RMC-6236 inhibitors by clinically assessing led by RMC-6291 and Franchise for
opportunities RMC-9805 for (1L, types, mutations) late-stage development RAS-Addicted Cancers
8 RAS(ON) Multi-Selective Inhibitor RMC-6236 2023 Revolution
Medicines Confidential
9 RMC-6236-001 Phase 1 Study Design Key Eligibility Criteria Dose
Escalation RMC-6236 administered orally QD Advanced solid tumors (1) with KRAS G12X mutations (initially excluding KRAS G12C) 400 mg Received prior standard therapy 300 mg Dose Optimization appropriate for tumor type and (2) 220 mg +
stage RAS Genotype and Tumor ECOG PS 0-1 160 mg Type Expansion Lowest dose/exposure No active brain metastases 120 mg range projected to drive tumor regressions in 80 mg humans based on preclinical models 40 mg Key Endpoints 20
mg Safety and tolerability 10 mg Pharmacokinetics Anti-tumor activity Additional patients with PDAC or NSCLC were enrolled at dose levels that cleared DLT evaluation RMC-6236-001 Clinical Trial:
https://clinicaltrials.gov/study/NCT05379985 (1) KRAS G12X initially defined as mutation at codon 12 which encodes glycine (G) to X where X = A, D, R, S, or V. (2) 220 mg cleared DLT evaluation and a dose of 200 mg was selected for further
expansion/optimization. DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group Performance Status; QD, once daily.
10 RMC-6236-001: 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) Vomiting 27
(21) 9 (7) 0 0 36 (28) Stomatitis 10 (8) 9 (7) 2 (2) 0 21 (16) Fatigue 12 (9) 4 (3) 0 0 16 (12) Other select TRAEs, n (%) ALT elevation 6 (5) 1 (1) 1 (1) 08 (6) AST elevation 6 (5) 0 1 (1) 07 (5) Electrocardiogram QT prolonged 1 (1)
0 0 0 1 (1) TRAEs leading to dose reduction , n (%) 0 9 (7) 2 (2) 0 11 (8) TRAEs leading to treatment discontinuation, n (%) 0 0 0 1 (1) 1 (1) Median duration of treatment at the time of data extraction was 2.27 months (range:
0.2-14) One Grade 4 TRAE occurred in a patient with PDAC treated at 80 mg who had a large intestine perforation at the site of an invasive tumor that reduced in size while on treatment (TRAE leading to treatment discontinuation)
No fatal TRAEs were observed. Two patients discontinued study treatment due to death: one patient with PDAC (120 mg) died due to PD; one patient with NSCLC (200 mg) died due to unknown cause reported as unrelated to RMC-6236
Post-data extraction, the Grade 3 ALT and AST elevations were associated with biliary obstruction and reported as unrelated to RMC-6236 *Includes preferred terms of dermatitis acneiform, rash maculopapular, rash, rash pustular, dermatitis
psoriasiform, erythema, rash erythematous; multiple types of rash may have occurred in the same patient; The most common TRAE leading to dose reduction was rash (acneiform or maculopapular); there were no reductions at doses 80 mg. AE,
adverse event; ALT, alanine transaminase; AST, aspartate transferase; PD, progressive disease; TRAEs, treatment-related adverse events. Data Extracted 11 Sep 2023.
11 KRAS G12X NSCLC: Best Overall Response to RMC-6236 (1) Evaluable for
Efficacy (n=40) RMC-6236-001: Clinical Activity in KRAS (2) G12X NSCLC Best overall response, n (%) Complete response 1 (3) Partial response 14 (35) Stable disease 19 (48) Progressive disease 5 (13) (3) Not evaluable 1 (3) ORR, n (%) 15 (38)
Confirmed, n 12 DCR (CR+PR+SD), n (%) 34 (85) (4) SOC Benchmark Docetaxel, ORR (%) (13) DCR (%) (60) KRAS G12 Mutation Week of Most Recent scan (1) Patients who received first dose of RMC-6236 at least 8 weeks prior to data extract date. (2) Tumor
response per RECIST 1.1. (3) One subject withdrew from study without post-baseline scans. (4) SOC=standard of care; efficacy benchmark for docetaxel taken from CodeBreaK 200, Lancet (2023) 401: 733-746. *Unconfirmed PR per RECIST 1.1. Data Extracted
12 Oct 2023. Best % Change from Baseline in Target Lesion
12 KRAS G12X PDAC: Best Overall Response to RMC-6236 (1) Evaluable for
Efficacy (n=46) RMC-6236-001: Clinical Activity in KRAS (2) G12X PDAC Best overall response, n (%) Partial response 9 (20) Stable disease 31 (67) Progressive disease 3 (7) (3) Not evaluable 3 (7) ORR, n (%) 9 (20) Confirmed, n 5 DCR (CR+PR+SD), n
(%) 40 (87) (4) SOC Benchmarks GnP, ORR (%) (11) DCR (%) (56) KRAS G12 Mutation Week of Most Recent Scan (1) Patients who received first dose of RMC-6236 at least 8 weeks prior to data extract date. (2) Tumor response per RECIST 1.1. (3) Two
patients died prior to first post-baseline scan; 1 patient had scan after 11 days of treatment and subsequently died due to PD. (4) SOC=standard of care; no clearly established standard of care in 2L PDAC; GnP=Gemcitabine plus nab-paclitaxel;
efficacy benchmarks for GnP taken from Br J Cancer (2022) 126:1394-1400. *Unconfirmed PR per RECIST 1.1. Data Extracted 12 Oct 2023. Best % Change from Baseline in Target Lesion
13 Zeroing In on RMC-6236 Monotherapy Dose Selection Mean Steady-State
Blood PK Profiles Individual Steady-State Blood AUC 10000 400 mg 300 mg 8000 200/220 mg 160 mg 6000 Exposure in mice at 25 120 mg mg/kg* 80 mg 4000 40 mg 20 mg Exposure in mice at 10 2000 10 mg mg/kg* 0 Time (Hours) Dose Level Dose-dependent
increases in exposure with minimal accumulation were observed after repeat daily dosing (1) G12X Dose levels 80 mg achieved exposures that induced tumor regressions in human xenograft models with KRAS mutations in mice 10
mg/kg QD induces tumor regressions in sensitive models 25 mg/kg QD induces tumor regressions in the majority of models *Exposure corrected with cross-species protein binding and blood/plasma partitioning. Left: steady-state concentrations
from Cycle 1 Day 15. Error bars represent standard deviation; right: steady-state AUC is Cycle 1 Day 15 AUC . Each circle represents an individual patient AUC. Horizontal bars represent mean AUC for each dose level (10 mg: n=2; 20 mg: n=4; last 40
mg: n=7; 80 mg: n=8; 120 mg: n=12; 160 mg: n=12, 200 mg: n=13; 220 mg: n=4; 300 mg: n=9; 400 mg: n=2); AUC, area under the curve; PK, pharmacokinetics. (1) Singh M, et al. Presentation at American Association for Cancer Research Annual Meeting,
8-13 April 2022, New Orleans, USA; abstract #3597. Data Extracted 22 Sep 2023. 10 mg 20 mg 40 mg 80 mg 1 0 g 2 m 160 mg 200/220 mg 300 mg 400 mg Steady-State Whole Blood Concentration (nM) Whole Blood Steady-State AUC (nM x h)
14 Key RMC-6236-001 Monotherapy Expansion Cohorts Underway Patients
Cohort Purpose Enrolled NSCLC G12X dose optimization (300 mg and below) Dose selection for pivotal trial RAS G13X and Q61X expansion (300 mg) Pivotal trial design PDAC G12X dose optimization (300 mg and below) Dose selection for
pivotal trial RAS G13X and Q61X expansion (300 mg) Pivotal trial design CRC G12X expansion (300 mg) Signal seeking RAS G13X and Q61X expansion (300 mg) Signal seeking G12C included in G12X across all tumor
types and cohorts RMC-6236-001 protocol amended in August 2023 to broaden enrollment, now allowing patients with tumors bearing mutations in any of the three hotspots (G12X/G13X/Q61X) in any of the three major RAS isoforms (KRAS/NRAS/HRAS); G12X
broadened to include G12C
15 Proposed Global Randomized Phase 3 Trial in Patients with
Previously-Treated RAS Mutant NSCLC (1) (1,2) Trial Design Potential Patient Populations RMC-6236 Endpoints PFS R G12X-C 13% Core Population: OS G12X Patients Docetaxel Patient Reported Outcomes N > 400 patients Prior therapies:
Anti-PD-(L)1 and platinum-containing G12C regimen in metastatic setting; RAS inhibitor na ve (including 12% G12C inhibitor) Biomarker: RAS G12X, G13X, or Q61X mutation Expanded Population: Study Initiation: Aiming for 2024 G13X
- 2% G12X + G13X + Q61X Q61X - 3% Patients (1) Potential for nested trial design to enable evaluation of core and expanded patient populations R = Randomized (1) Study design subject to change based on regulatory authority feedback (2)
Percentages of all NSCLC patients with tumors bearing RAS G12X, G13X, or Q61X genotypes; 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 (see appendix for additional detail); G12X - 25%
16 Potential Global Randomized Phase 3 Trial of RMC-6236 in Patients
with Previously-Treated PDAC (1) (1,2) Trial Design Potential Patient Populations Endpoints RMC-6236 R PFS Physician's choice: OS e.g., GnP or mFOLFIRINOX Patient Reported Outcomes G12X - 85% Core Population: G12X Patients N > 500
patients Prior therapies: Fluoropyrimidine or gemcitabine-based regimen; RAS inhibitor na ve (including G12C inhibitor) Biomarker: All comers, RAS mutation testing (G12X, G13X, or Q61X) to allow stratification Study
Initiation: Potentially in 2024 Expanded Populations: G13X/Q61X - 7% G12X + G13X + Q61X patients WT - 8% All PDAC patients (1) Potential for nested trial design to enable evaluation of core and expanded patient populations R
= Randomized; WT=wild-type (1) Study design subject to change based on regulatory authority feedback (2) Percentages of all PDAC patients with tumors bearing RAS G12X, G13X, Q61X or WT genotypes; 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 (see appendix for additional detail);
17 Complementary RAS(ON) Inhibitors Designed for Monotherapy and
Combination Strategies Against RAS-Addicted Cancers RAS Multi-Selective RAS Mutant-Selective Monotherapy with broad potential Alternative monotherapy for RAS-addicted cancers approaches Backbone of RAS(ON) inhibitor
Complementary to RAS multi- doublets with mutant-selective selective inhibitor in RAS(ON) RAS(ON) inhibitors inhibitor doublets Targeted agent for SOC Differentiated targeted agent combinations, including profiles for SOC
combinations, immunotherapies including immunotherapies
18 RAS(ON) G12C-Selective Inhibitor RMC-6291 2023 Revolution
Medicines Confidential
19 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 with 300 mg BID G12C KRAS (OFF) inhibitors 200 mg BID ECOG PS
0-1 Dose Optimization 100 mg BID No active brain metastases 200 mg QD 100 mg QD Key Endpoints Lowest dose projected to drive 50 mg QD tumor regressions in humans based Safety and tolerability on preclinical models
Pharmacokinetics Anti-tumor activity Additional patients with NSCLC or CRC were enrolled at dose levels that cleared DLT evaluation (backfill enrollment and dose optimization) RMC-6291-001 Clinical Trial:
https://clinicaltrials.gov/study/NCT05462717 DLT=dose-limiting toxicity; ECOG PS=Eastern Cooperative Oncology Group Performance Status; QD=once daily; BID=twice daily
20 RMC-6291-001: 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* 501 ms 1 (2) Fatigue 0 8 (13) 4 (6) 4 (6) Vomiting 0 8 (13) 6 (10) 2 (3) AST increased 0 7 (11) 7 (11) 0 TRAEs leading to dose reduction, n (%) 9 (14) 0 1 (2) 8 (13) 1 (2) TRAEs leading to treatment discontinuation, n (%) 1 (2)
00 No treatment-related Grade 4 or 5 AEs or SAEs have been reported No patients had cardiac sequelae (e.g., torsade de pointes) associated with an ECG QT prolonged event *QTcF refers to QT interval corrected for heart rate by