On Target to Outsmart Cancer
November 6, 2023
© 2023 Revolution Medicines
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For a further description of the risks and uncertainties that could cause actual results to differ from those anticipated in these forward-looking statements, as well as risks relating to the business of Revolution Medicines in general, see Revolution Medicines' Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 6, 2023, and its future periodic reports to be filed with the Securities and Exchange Commission.
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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
- Unprecedented RASMULTI inhibitor (RMC-6236)and RASG12C-selectiveinhibitor (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
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Excessive RAS(ON) Signaling Drives 30% of Human Cancers, Targeted by Our RAS(ON) Inhibitors
- RAS(OFF)
RAS-Mutant Cancers
Normal
- RAS(ON)
Cell
Membrane
Tightly regulated
RAS(ON) proteins control cell growth
RAS Cancer Mutations
Excessive
RAS(ON) signaling drives uncontrolled cell growth
Oncogenic mutations in KRAS, NRAS or HRAS are common at positions
G12, G13 and Q61
New patients per year (U.S.)(1)
>200,000
including
60,000
Lung cancer
(29% of NSCLC)
75,000
Colorectal cancer
(49% of CRC)
53,000
Pancreatic cancer
(92% of PDAC)
- 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
Pioneering Tri-complex RAS(ON) Inhibitors Designed to Deliver Robust and Durable Anti-Tumor Activity
Oncogenic RAS(ON) | Inhibited RAS(ON) |
RAS(ON)
Inhibitor
GTP
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- Direct inhibition of RAS(ON) cancer drivers
- Deep and durable suppression of 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 |
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Development-Stage RAS(ON) Inhibitor Portfolio Designed to Treat Nearly All Patients with RAS-Addicted Cancers
MULTI
RAS Selectivity
>200,000
new patients
per year (U.S.)(1)
RMC-6236clinical
Mutant-Selective
RMC-6291clinical
RMC-9805clinical
RMC-5127IND-enabling
RMC-0708IND-enabling
multiple mutations
(initial focus on G12X) and WT
G12C
G12D
G12V
Q61H
G12C
G12D
G12V
G12
other
G12X
G13X
RMC-8839IND-enabling
G13C
Q61X
- 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).
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Complementary RAS(ON) Inhibitors Designed for Monotherapy and Combination Strategies Against RAS-Addicted Cancers
RASMULTI
- Monotherapy with broad potential for RAS-addicted cancers
- Backbone of RAS(ON) Inhibitor doublets with mutant-selective RAS(ON) Inhibitors
- Targeted agent for SOC combinations, including immunotherapies
RAS Mutant-Selective
- Alternative monotherapy approaches
- Complementary to RASMULTI Inhibitor in RAS(ON) Inhibitor doublets
- Differentiated targeted agent profiles for SOC combinations, including immunotherapies
SOC = standard of care
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RMC-6236:First-in-Class, RASMULTI(ON) Inhibitor with Broad Potential Against RAS-Addicted Cancers
166,000
New KRASG12X patients
per year (U.S.)(1)
- 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
- Unprecedented clinical profile with anti-tumor activity observed across diverse RAS cancer 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
- 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
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RMC-6236:Dose-DependentAnti-Tumor Activity at Low Doses in RAS-Addicted NSCLC Model
Control | |||||
3000 | RMC-6236 1 mg/kg | ||||
RMC-6236 10 mg/kg | |||||
) | |||||
RMC-6236 25 mg/kg | |||||
3 | |||||
(mm | |||||
Tumor Volume | 2000 | ||||
1000 | Dosing | ||||
Mean | start | ||||
0 | 20 | 30 | 40 | 50 | |
Days on Study
End of Study Responses
500 | Control | ||
Volume | 400 | RMC-6236 1 mg/kg | |
RMC-6236 10 mg/kg | |||
RMC-6236 25 mg/kg | |||
300 | |||
Tumor | |||
200 | |||
in | |||
Change | 100 | 8/10 R | 10/10 CR |
0 | |||
% | |||
-100 |
RVMD preclinical research
NSCLC = non-small cell lung cancer
NCI-H441 CDX (NSCLC, KRASG12V/WT); 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
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RMC-6236: Highly Active with Durable Responses Across Models of Major Human Cancers with RASG12X Drivers
NSCLC | PDAC | CRC |
53% ORR (8/15) | 61% ORR (11/18) | 44% ORR (8/18) |
100% DCR (15/15) | 89% DCR (16/18) | 56% DCR (10/18) |
PFS
RMC-6236 - Median not reached Control - Median 9 days
Mean Tumor Volume % Change From Baseline
300
200
100
0 | ||||||||||||||
-100 | ||||||||||||||
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 |
300 | |||||||||||||||||
200 | |||||||||||||||||
100 | |||||||||||||||||
0 | |||||||||||||||||
-100 | |||||||||||||||||
KP-4 | PAN022 | PAN026 | PAN1001 | PAN038 | PAN020 | PAN003 | PAN010 | PAN014 | PAN039 | Capan-2 | PAN001 | PAN045 | PAN031 | PAN028 | HPAC | PAN043 | PAN009 |
300 | |||||||||||||||||
200 | mPD | ||||||||||||||||
100 | |||||||||||||||||
0 | mSD | ||||||||||||||||
mPR | |||||||||||||||||
-100 | mCR | ||||||||||||||||
CRC007 | CRC043 | CRC078 | CRC022 | CRC060 | CRC1018 | CRC050 | CRC047 | CRC044 | CRC058 | GP2D | CRC051 | CRC039 | CRC012 | SW620 | CRC1009 | SW403 | CRC1005 |
Progression-Free | 100 | |||||||||||||||||||||||||||||||||||||
Tumors% | 75 | |||||||||||||||||||||||||||||||||||||
50 | ||||||||||||||||||||||||||||||||||||||
25 | ||||||||||||||||||||||||||||||||||||||
0 | ||||||||||||||||||||||||||||||||||||||
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
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Revolution Medicines Inc. published this content on 06 November 2023 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 06 November 2023 21:06:15 UTC.