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Revolution Medicines
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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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and Drug Administration (FDA). These product candidates are currently limited by Federal law to investigational use, and no representation is made as to their safety or effectiveness for the purposes for which they are is being investigated. All
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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 drug candidates designed to serve RAS-addicted cancer patients by targeting oncogenic RAS(ON) drivers of common, life-threatening
cancers MULTI Unprecedented RAS inhibitor (RMC-6236) and G12C RAS -selective inhibitor (RMC-6291) show highly differentiated and promising initial clinical profiles Innovative single agent and combination development strategies aim
to deliver durable clinical benefit broadly to patients with RAS-addicted 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) signaling drives
RAS(ON) proteins 75,000 uncontrolled cell growth control cell growth Colorectal cancer (49% of CRC) 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) 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 resistance
mechanisms Clinical validation of first two RAS(ON) Inhibitors studied as single agents Cell Cyclophilin A Membrane
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 RMC-9805 clinical
G12D G12V G12V IND-enabling RMC-5127 G12 IND-enabling Q61H RMC-0708 other G13X RMC-8839 IND-enabling G13C Q61X (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).
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) Inhibitor Inhibitor in RAS(ON) Inhibitor doublets with mutant-selective doublets RAS(ON) Inhibitors Differentiated targeted agent Targeted agent for SOC profiles for SOC combinations, combinations, including including
immunotherapies immunotherapies SOC = standard of care
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
Unprecedented clinical profile with anti-tumor G12X New KRAS patients (1) activity observed across diverse RAS cancer per year (U.S.) mutations; multiple potential monotherapy registrational paths Profound combinatorial activity with mutant-
selective RAS(ON) Inhibitors in preclinical models; potential for targeted RAS(ON) Inhibitor doublets in patients (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
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 20 30 40 50
-100 Days on Study RVMD preclinical research NSCLC = non-small cell lung cancer G12V/WT NCI-H441 CDX (NSCLC, KRAS ); All doses given orally, once daily R = number of regressions >10% from initial; CR = number of regressions 80% from
initial Each animal represented as a separate bar in waterfall plot 3 Mean Tumor Volume (mm ) % Change in Tumor Volume
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 300 300 300 100 200 200 200 75
mPD 100 100 100 50 mSD 25 0 0 0 mPR 0 mCR -100 -100 -100 0 20 40 60 80 100 Days on Treatment RMC-6236 (n=191, 51 models) Control (n=215, 51 models) RVMD preclinical research as of 06/01/22 NSCLC = non-small cell lung cancer; PDAC = pancreatic ductal
adenocarcinoma; CRC = colorectal cancer RMC-6236 dosed at 25 mg/kg po qd; n=1-10/group Progression defined as tumor doubling from baseline; Responses assigned according to mRECIST: mPD = progressive disease; mSD = stable disease; mPR = partial
response; mCR = complete response; ORR = objective response rate; DCR = disease control rate; PFS = progression-free survival Mean Tumor Volume % Change From Baseline LUN352 NCI-H2122 CTG-1903 LUN232 CTG-0743 CTG-1955 CTG-2393 CTG-1612 NCI-H2030
CTG-2803 NCI-H441 CTG-1358 NCI-H358 LUN020 LUN137 KP-4 PAN022 PAN026 PAN1001 PAN038 PAN020 PAN003 PAN010 PAN014 PAN039 Capan-2 PAN001 PAN045 PAN031 PAN028 HPAC PAN043 PAN009 CRC007 CRC043 CRC078 CRC022 CRC060 CRC1018 CRC050 CRC047 CRC044 CRC058 GP2D
CRC051 CRC039 CRC012 SW620 CRC1009 SW403 CRC1005 % Tumors Progression-Free
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
Optimization tumor type and stage 160 mg ECOG PS 0-1 Lowest dose/exposure No active brain metastases 120 mg range projected to drive tumor regressions in 80 mg humans based on Key Endpoints preclinical models 40 mg
Safety and tolerability 20 mg Pharmacokinetics 10 mg Additional patients with PDAC or NSCLC were enrolled at dose Anti-tumor activity levels that cleared DLT evaluation G12X (1) KRAS 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,
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 (69) Number
of prior anti-cancer therapies, median (range) 2 (1-7) G12A G12S 8 (6) 5 (4) PDAC = pancreatic ductal adenocarcinoma; NSCLC = non-small cell lung cancer; CRC = colorectal cancer ECOG PS, Eastern Cooperative Oncology Group Performance Status
Data Extracted 11 Sep 2023.
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 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. Data Extracted 22 Sep 2023. (1) Singh M, et al. Presentation at American Association for Cancer Research Annual
Meeting, 8-13 April 2022, New Orleans, USA; abstract #3597. Steady-State Whole Blood Concentration (nM) Whole Blood Steady-State AUC (nM x h)
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) 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) 0 8 (6) AST elevation 6 (5) 0 1 (1) 0 7 (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.
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) Confirmed, n 12 DCR
(CR+PR+SD), n (%) 34 (85) KRAS G12 Mutation Week of Most Recent scan *Unconfirmed PR per RECIST 1.1. (a) Patients who received first dose of RMC-6236 at least 8 weeks prior to data extract date. Data Extracted 12 Oct 2023. (b) One subject withdrew
from study without post-baseline scans. Best % Change from Baseline in Target Lesion
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 RMC-6236 at
least 8 weeks prior to data extract date. Data Extracted 12 Oct 2023. *Death due to PD (n=1), Death due to unrelated AE (n=1), Death due to unknown cause reported as unrelated to RMC-6236 (n=1). G12X Patients with KRAS Mutation
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 Target Lesion: Lung, Left Lower Lobe Carboplatin/pemetrexed Target Lesion Baseline On Treatment RMC-6236 Treatment Course Started at 300 mg QD 1. Lung (left upper lobe) 11.6 mm 0 mm Clinical improvement in cough 2.
Lung (left lower lobe) 49.8 mm 0 mm and dyspnea within one week of Sum of Diameters 61.4 mm 0 mm ( 100% ) start of treatment Dose reduced to 200 mg due to Overall Response -- CR Grade 2 fatigue (RECIST 1.1) Complete
response achieved at Week 6 (confirmed); ongoing
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 (%) 40 (87) KRAS G12
Mutation Week of Most Recent Scan *Unconfirmed PR per RECIST 1.1. (a) Patients who received first dose of RMC-6236 at least 8 weeks prior to data extract date. Data Extracted 12 Oct 2023. (b) Two patients died prior to first post-baseline scan; 1
patient had scan after 11 days of treatment and subsequently died due to PD. Best % Change from Baseline in Target Lesion
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-6236 at
least 8 weeks prior to data extract date. Data Extracted 12 Oct 2023. *Death due to PD (n = 9), Death due to unrelated AE (n = 2). G12X Patients with KRAS Mutation
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 with NSCLC and 12/13 (92%) patients with PDAC showed >50% reduction of the mutated KRAS allele G12X (a) 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 test;
G12X KRAS defined as mutation at codon 12 which encodes glycine (G) to X where X= A, D, R, or V; * Data Extracted 12 Oct 2023. Two patients were non-evaluable for best overall response; Unconfirmed partial response per RECIST 1.1.