On Target to Outsmart Cancer
May 8, 2024
© 2024 Revolution Medicines, Inc.
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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 RAS(ON) inhibitor drug candidates targeting oncogenic drivers of common, life-threatening cancers
- Unprecedented RAS(ON) multi-selectiveinhibitor (RMC-6236)and RAS(ON) G12C-selectiveinhibitor (RMC-6291) show promising and highly differentiated initial clinical profiles
- On track toward late-stagedevelopment of RMC-6236 and advancement of mutant-selective inhibitors led by RMC-6291 and RMC-9805
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Portfolio of RAS(ON) Inhibitors Designed to Target 30% of Human Cancers
RAS-Mutant Cancers
Normal
Cell
Membrane
Tightly regulated
= RAS(OFF)RAS(ON) proteins control cell growth
- RAS(ON)
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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Initial Clinical Profiles of RAS(ON) Inhibitors Support Broad Set of Potential Opportunities to Treat RAS-Addicted Cancers
Target | ||
Multi-Selective | Genotypes | |
RMC-6236 Clinical validation in NSCLC and PDAC | G12X and | |
expansion(1) | ||
Mutant-Selective | ||
RMC-6291 | Evidence of differentiated clinical | G12C |
activity in NSCLC and CRC | ||
RMC-9805 Dose escalation ongoing | G12D |
- KRAS G12X initially defined as mutation at codon 12 which encodes glycine (G) to X where X = A, D, R, S, or V. 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.
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2024 Capital Allocation Priorities to Advance | |
Pioneering RAS(ON) Inhibitor Pipeline … | … driving to |
Expand reach of RMC-6236
by clinically assessing
opportunities
(1L, types, mutations)
Propel RMC-6236
into first pivotal trial(s)
Qualify mutant-
selective inhibitors led by RMC-6291and RMC-9805for late-stagedevelopment
Industry-Leading
Targeted
Medicines
Franchise for RAS-Addicted Cancers
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RAS(ON) Multi-Selective Inhibitor
RMC-6236
RMC-6236-001 Phase 1 Study Design
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Key Eligibility Criteria
- Advanced solid tumors with KRAS G12X mutations(1) (initially excluding KRAS G12C)
- Received prior standard therapy appropriate for tumor type and stage
- ECOG PS 0-1
- No active brain metastases
Key Endpoints
- Safety and tolerability
- Pharmacokinetics
- Anti-tumoractivity
Dose Escalation
RMC-6236 administered orally QD
400 mg
300 mg
220 mg(2)
160 mg | Lowest dose/exposure |
120 mg | |
range projected to drive | |
80 mg | tumor regressions in |
humans based on | |
40 mg | preclinical models |
20 mg
10 mg
Additional patients with PDAC or NSCLC were enrolled at dose levels that cleared DLT evaluation
Dose Optimization
+
RAS Genotype and
Tumor Type Expansion
RMC-6236-001Clinical Trial: https://clinicaltrials.gov/study/NCT05379985
- KRAS G12X initially defined as mutation at codon 12 which encodes glycine (G) to X where X = A, D, R, S, or V.
- 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.
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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)‡ | 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-dataextraction, 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.
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Revolution Medicines Inc. published this content on 08 May 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 08 May 2024 20:30:38 UTC.