Slide 1: Targeting the Oncogenic State of RAS with Tri-Complex Inhibitors
Targeting the Oncogenic State of RAS with Tri-Complex Inhibitors Jan Smith, PhD October 23, 2025
Slide 2: Disclosure Information
Disclosure Information Jan Smith, PhD I have the following relevant financial relationships to disclose • Employee of Revolution Medicines • Stockholder in Revolution Medicines
Slide 3: Direct RAS Targeting Strategies
Direct RAS Targeting Strategies RAS(OFF) RAS(ON) Tri-Complex Inhibition Acts by Steric Inhibition RASMUT(ON) Tri-Complex RASMUT RASMUT RASMUT (OFF) (OFF) (ON) CYPA exchange RAS(OFF) inhibitor CRAF GAP TCI (RBD-CRD) hydrolysis RAS(ON) Daraxonrasib also stimulates Schulze et al., 2023 Science Ostrem e
Slide 4: Tri-Complex Platform Enables Selective Targeting of Oncogenic RAS(ON) Proteins
Tri-Complex Platform Enables Selective Targeting of Oncogenic RAS(ON) Proteins RAS(ON) Inhibitor RAS(ON) RAS(ON) Inhibitory Tri-Complexes RAF (RBD- Selected CRD) compounds Steric Occlusion Inside cell CYPA Cyclophilin A Binary complex Noncovalent Covalent
Slide 5: Using Structure-Guided Design to Build a Diverse Library of RAS(ON) Tri-Complex Inhibitors
Using Structure-Guided Design to Build a Diverse Library of RAS(ON) Tri-Complex Inhibitors Engineer Binding Site to Modify Potency, Reactivity and Selectivity CYPA Optimize CYPA affinity to enhance potency RMC-Cmpd Engineer binding site to facilitate Noncovalent interactions drive Q61 unprecedented
Slide 6: Complementary Investigational RAS(ON) Inhibitors Illustrate Spectrum of Selectivities
Complementary Investigational RAS(ON) Inhibitors Illustrate Spectrum of Mutant and Wild Type RAS(ON) Selectivities RAS(ON) G12C-selective: RAS(ON) G12D-selective: RAS(ON) multi-selective: elironrasib zoldonrasib daraxonrasib Q61H,R G12C G12D G12D,R,V G13D 125 KRASG12C Viability (% of control) 100 RA
Slide 7: RAS(ON) Inhibition Overcomes KRAS G12C(OFF) Inhibitor Clinical Resistance Mechanisms in Preclinical Models
RAS(ON) Inhibition Overcomes KRAS G12C(OFF) Inhibitor Clinical Resistance Mechanisms in Preclinical Models Potent anti-proliferative activity in context Deep regressions in preclinical model with of RTK mediated pathway activation acquired resistance to G12C(OFF) inhibitor Sotorasib Parental Resista
Slide 8: Compelling Preliminary Clinical Activity of Elironrasib in 2L+ NSCLC Patients
Compelling Preliminary Clinical Activity of Elironrasib in 2L+ NSCLC Patients Following G12C(OFF) Inhibitor Baseline genomic alterations detected in ctDNA from Activity of elironrasib in 2L+ NSCLC patients who NSCLC patients who are treatment naïve or previously previously received G12C(OFF) inhibit
Slide 9: Preclinical Models Predicted Clinical Activity of Zoldonrasib
Preclinical Models Predicted Clinical Activity of RAS(ON) G12D-Selective Inhibitor: Zoldonrasib (RMC-9805) KRAS G12D NSCLC xenograft models treated with Objective responses to zoldonrasib in previously treated zoldonrasib at 100 mg/kg daily patients with KRAS G12D NSCLC Tumor Response for Patients w
Slide 10: Preclinical Models Predicted Clinical Activity of Daraxonrasib
Preclinical Models Predicted Clinical Activity of RAS(ON) Multi-Selective Inhibitor: Daraxonrasib (RMC-6236) RAS mutant PDAC xenograft models treated Objective responses in 2L patients with PDAC with daraxonrasib at 25 mg/kg daily treated with daraxonrasib at 300 mg daily RAS G12X RAS Mutant 300 KRA
Slide 11: 2L PDAC: Daraxonrasib Demonstrated Encouraging PFS and OS
2L PDAC: Daraxonrasib (300 mg) Demonstrated Encouraging Progression-Free Survival and Overall Survival Median, Months Median, Months PFS OS (95% CI) (95% CI) RAS G12X 8.5 (6.7, 10.5) RAS G12X 13.1 (10.9, NE) RAS Mutant 8.1 (5.9, 10.1) RAS Mutant 15.6 (10.9, NE) Median (range) follow-up is 16.7 (10.3
Slide 12: RAS(ON) Inhibitors are Generally Well Tolerated in Patients Across Cancer Types
RAS(ON) Inhibitors are Generally Well Tolerated in Patients Across Cancer Types Daraxonrasib monotherapy was generally well tolerated at the doses selected for ongoing Phase 3 studies, with anticipated on target TRAEs • TRAEs were manageable with routine clinical interventions • The most common TR
Slide 13: A Translational Platform to Interrogate the Effects of RAS(ON) Inhibition in Tumors
A Translational Platform to Interrogate the Effects of RAS(ON) Inhibition in Tumors Daraxonrasib
Slide 14: Daraxonrasib Clinical Resistance Mechanisms Converge Upon RAS Pathway Activation
Daraxonrasib Clinical Resistance Mechanisms Converge Upon RAS Pathway Activation RTK 84 patients with PDAC, CRC, NSCLC, melanoma or other solid tumors treated with 160 to 300 mg of daraxonrasib with PFS > 3 months who subsequently progressed and with paired baseline and EOT ctDNA sequenced successfu
Slide 15: Elironrasib and Daraxonrasib Doublet Drives Deep Responses in KRAS G12C Amplified NSCLC Model
Elironrasib and Daraxonrasib RAS(ON) Doublet Drives Deep and Durable Responses in a KRAS G12C Amplified NSCLC Model LUN055 PDX (KRASG12C Amp, NSCLC) KRAS Mutant Amplification at Baseline and upon Treatment Antitumor Activity 2000 Mean tumor volume (mm3) KRAS FISH RAS 1500 1000 Control # 500 300 0 50
Slide 16: Clinical Activity of Elironrasib and Daraxonrasib Doublet in 2L+ NSCLC
Compelling Preliminary Clinical Activity of Elironrasib and Daraxonrasib RAS(ON) Inhibitor Doublet in 2L+ NSCLC Patients Following G12C(OFF) Inhibitor Elironrasib Elironrasib + Daraxonrasib (N=24)1 (N=26)1 ORR2, % (n) 42% (10) ORR2, % (n) 62% (16) DCR3, % (n) 79% (19) DCR3, % (n) 92% (24) # Post 1 1
Slide 17: Zoldonrasib and Daraxonrasib Doublet Provides Durable Responses in KRAS G12D PDAC Models
Zoldonrasib and Daraxonrasib RAS(ON) Inhibitor Doublet Provides Durable Responses in GEMM-Derived Models of KRAS G12D PDAC KPCY (KrasG12D; Trp53R172H - PDAC) Deep RAS pathway suppression Durable antitumor responses KPCYc3 (2838c3) p-ERK 4h post-dose Vehicle Zoldonrasib Daraxonrasib Combination Zoldo
Slide 18: RAS(ON) Doublet Overcomes Acquired Resistance in KRAS G12D PDAC Model
RAS(ON) Inhibitor Doublet Overcomes Acquired Resistance to RAS(ON) Multi-Selective Inhibitor in a Model of KRAS G12D PDAC Tumor RAS signaling sustained in presence RAS(ON) doublet demonstrates durable of RAS(ON) multi-selective inhibitor tumor control in resistant model 2000 Control Mean tumor volum
Slide 19: Oncogenic RAS Signaling is a Major Driver of Tumor Immune Escape
Oncogenic RAS Signaling is a Major Driver of Tumor Immune Escape Myeloid cell-recruiting Favors Immune cytokines Decreases Tumor Evasion Recognition Immunosuppressive PD-L1 Antigen presentation myeloid cells CD8+ T cell MDSC TAM KRAS mutant tumor Lymphocyte-recruiting cytokines T cell infiltration T
Slide 20: RAS(ON) Doublet Maximizes Antigen Presentation in T Cell Excluded NSCLC Model
RAS(ON) Inhibitor Doublet Maximizes Antigen Presentation and Primes TME for Tumor Immune Recognition in a T Cell Excluded NSCLC Model e3LL (NSCLC, KrasG12C/G12C, NrasKO) ↑ Antigen processing and presentation genes ↑ MHC I ↑ T cells ↑ GzmB+ cells ns ns Scaled TMM log(CPM) ns 2 ns 1 0 -1 -2 Vehicle El
Slide 21: RAS(ON) Doublet Sensitizes Immuno-Refractory KRAS G12C NSCLC Model to Anti-PD-1
RAS(ON) Inhibitor Doublet Sensitizes an Immuno- Refractory KRAS G12C NSCLC Model to Anti-PD-1 e3LL (NSCLC, KrasG12C/G12C, NrasKO) Anti-PD-1 Elironrasib + Anti-PD-1 Daraxonrasib + Anti-PD-1 Elironrasib + Daraxonrasib + Anti-PD-1 CR-complete regressions defined as at least three consecutive measuremen
Slide 22: Using RAS(ON) Mutant-Selective Covalent Inhibitors to Direct Immune-Mediated Cell Killing
Using RAS(ON) Mutant-Selective Covalent Inhibitors to Direct Immune-Mediated Cell Killing of RAS Mutant Tumors T cell engagers (TCE) to target T cell-mediated cell killing in vitro zoldonrasib–haptenated KRAS G12D peptides with zoldonrasib companion TCE KRASG12D Cell Line Zoldonrasib Companion TCE 1
Slide 23: Conclusions
Conclusions Human RAS mutant cancers are RAS-addicted Investigational RAS(ON) mutant-selective and multi-selective inhibitors have shown encouraging early clinical activity with manageable safety profiles in patients with RAS mutant cancers RAS pathway reactivation in response to RAS-targeted
Slide 24: Acknowledgements
Acknowledgements The patients, their families, and investigators who are making clinical evaluation of daraxonrasib, elironrasib, and zoldonrasib possible Revolution Medicines Research and Development Teams Revolution Medicines Research Collaborators
Slide 25: The information included in these materials is provided as part of an oral
The information included in these materials is provided as part of an oral presentation on Oct 23, 2025 and is qualified as such. Revolution Medicines disclaims any duty to update the information contained in this presentation. This presentation concerns anticipated products that are under clini
Slide 26: Appendix
27 Appendix © 2023 Revolution Medicines Confidential
Slide 27: On Target to Outsmart Cancer
On Target to Outsmart Cancer August 2025 © 2025 Revolution Medicines, Inc.
Slide 28: Significant Need for Improved Treatment(s) for Previously Treated 2L+ NSCLC
29 Significant Need for Improved Treatment(s) for Patients with Previously Treated (2L+) Locally Advanced or Metastatic NSCLC Timing relative to CPI Study Treatment arm No. of patients ORR (%) approval in 1L REVEL(1) prior Docetaxel, 2L+ 625 14% CheckMate 057(2) prior Docetaxel, 2L+ 290 12% OAK(3) p
Slide 29: Elironrasib Safety Tables
30 Elironrasib Safety Tables © 2023 Revolution Medicines Confidential
Slide 30: Elironrasib Monotherapy: Generally Well Tolerated in Previously Treated RAS G12C NSCLC
NSCLC 31 Elironrasib Monotherapy: Generally Well Tolerated in Patients with Previously Treated RAS G12C NSCLC Elionrasib 200 mg BID (N=36) Maximum Severity of Treatment-Related AEs Any Grade Grade ≥3 Any TRAE 28 (78%) 7 (19%) TRAEs in ≥ 15% of patients, n (%) Diarrhea 11 (31%) 2 (6%) Nausea 8 (22%)
Slide 31: Elironrasib + Pembrolizumab: Generally Well Tolerated in 1L RAS G12C NSCLC
NSCLC 32 Elironrasib + Pembrolizumab: Generally Well Tolerated with Favorable Dose Intensity in Patients with 1L RAS G12C NSCLC Elironrasib 200 mg BID + Pembrolizumab (N=8) Median time on treatment, mo (range) 2.7 (0.7-3.2) Any Grade Grade ≥3 Any TRAE 6 (75%) 2 (25%) TRAEs in ≥ 15% of patients, n (%
Slide 32: Elironrasib + Daraxonrasib: Generally Well Tolerated in 2L+ NSCLC
NSCLC 33 Elironrasib + Daraxonrasib: Generally Well Tolerated in 2L+ NSCLC Patients Previously Treated with G12C(OFF) Inhibitor Elironrasib 200 mg BID + Daraxonrasib 100-200 mg QD (N=33) Median time on treatment, mo (range) 3.61 (0.20-8.67) Any Grade Grade ≥3 Any TRAE 31 (94%) 15 (43%) TRAEs in ≥ 20
Slide 33: Zoldonrasib Safety Table
34 Zoldonrasib Safety Table © 2023 Revolution Medicines Confidential
Slide 34: Zoldonrasib Monotherapy: Generally Well Tolerated Across Indications
35 Zoldonrasib Monotherapy: Generally Well Tolerated Across Indications Patients Treated with 1200 mg QD Zoldonrasib (N=90)1 Maximum Severity of Treatment-Related AEs Grade 1 Grade 2 Grade 3 Any Grade Any TRAE 49 (54%) 16 (18%) 2 (2%) 67 (74%) TRAEs occurring in ≥10% of patients, n (%) Nausea 30 (33
Slide 35: On Target to Outsmart Cancer: Daraxonrasib in Metastatic Pancreatic Cancer
On Target to Outsmart Cancer: Daraxonrasib in Metastatic Pancreatic Cancer September 10, 2025 © 2025 Revolution Medicines, Inc.
Slide 36: Significant Need for Treatment(s) with Improved Efficacy and Tolerability in 2L+ PDAC
Significant Need for Treatment(s) with Improved Efficacy and Tolerability in Patients with 2L+ PDAC Reported Efficacy Median PFS Median OS Study Regimen ORR (%) (months) (months) NAPOLI 1” 5-FU+LV+Nal-IRI 8 3A 64 SWOG $1513 FOLFIRI 10 29 6.5 SWOG S1115° ~~ FOLFOX 2b 62 7 2.0 67 SEQUOIA” FOLFOX 2L 28
Slide 37: Daraxonrasib at 300 mg Daily Generally Well Tolerated in 2L+ PDAC
38 Daraxonrasib at 300 mg Daily Generally Well Tolerated in Patients with 2L+ PDAC N=83 Any Grade Grade ≥3 Patients with Any TRAE, N (%) 80 (96%) 28 (34%) TRAEs occurring in ≥15% of patients, N (%) Rash* 75 (90%) 6 (7%) Stomatitis/mucositis* 45 (54%) 3 (4%) Diarrhea 43 (52%) 3 (4%) Nausea 32 (39%) 0
Slide 38: Acceptable Dose Modification and Dose Intensity in 2L+ PDAC Receiving Daraxonrasib
39 Acceptable Dose Modification and Dose Intensity Achieved in Patients with 2L+ PDAC Receiving Daraxonrasib at 300 mg Daily N=83 Patients with dose modification due to TRAEs, N (%) 40 (48%) Dose interruption 36 (43%) Dose reduction 25 (30%) Patients with dose discontinuation due to TRAEs, N (%) 0 M