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© 2025 Revolution Medicines, Inc. On Target to Outsmart Cancer43rd Annual J.P. Morgan Healthcare ConferenceJanuary 13, 2025
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2Legal DisclaimerThis presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on our current expectations, estimates and projections about our industry and our Company, management's beliefs and certain assumptions we have made. The words "plan," "anticipate," "believe," "continue," "estimate," "expect," "intend," "may," "will" and similar expressions are intended to identify forward-looking statements. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and financial position, 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 growth and development of our commercial and operational capabilities, 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 and the impact of global events and other macroeconomic conditions on our business are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. The information included in these materials is provided as of January 13, 2025, unless specified elsewhere herein, and is qualified as such. Except as required by applicable law, we undertake no obligation to update any forward-looking statements or other information contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.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, 2024, and its future periodic reports to be filed with the Securities and Exchange Commission. This presentation concerns product candidates that are under clinical investigation and which have not yet been approved for marketing by the U.S. Food 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.This presentation includes certain information regarding publicly available results from clinical trials by third parties evaluating other product candidates. Such trials were not head-to-head trials with any of Revolution Medicines' product candidates and include differences in study protocols, patient populations and reporting standards, and caution should be exercised when comparing data across trials. All copyrights and trademarks used herein are the property of their respective owners.
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3 Compelling pipeline from pioneering science Proven execution and patient-centric strategy Financial strength to enable vision Our MissionTo revolutionize treatment for patients with RAS-addicted cancers through the discovery, development and delivery of innovative, targeted medicines. DaraxonrasibRMC-6236 | MULTI ElironrasibRMC-6291 | G12C ZoldonrasibRMC-9805 | G12D
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4 Our StrategyTo maximize the impact of our RAS(ON) inhibitor portfolio for patients with RAS-addicted cancers by:01 02 03 04Commercializing daraxonrasib (RMC-6236) initially in late-stage disease Moving aggressively to develop RAS(ON) inhibitors in earlier lines of therapy (first line metastatic, locally-advanced unresectable, adjuvant) Developing optimal, biologically rational RAS(ON) inhibitor combinations for earlier lines Continuously innovating for patients by producing new, differentiated drug candidates
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5 2025 Priorities Toward Creating Industry-Leading Targeted Medicines Franchise for Patients with RAS-Addicted Cancers 2L, second line; 1L first line; PDAC, pancreatic ductal adenocarcinoma; NSCLC, non-small cell lung cancer. Established select partnerships; manufacturing daraxonrasib at commercial scaleGrow commercial and operational capabilities in support of U.S. launchExpand and reinforce select partnerships Sophisticated RAS cancer drug discovery and biological sciencesAdvance fourth development candidate to clinic readiness Progress next-generation programs Pioneering drug candidates and proven capabilitiesExecute daraxonrasib (RMC-6236) pivotal trials in 2L PDAC and NSCLC Advance daraxonrasib into 1L PDAC pivotal trialCommit to initial pivotal trial(s) with mutant-selective inhibitor DiscoveryDevelopmentDelivery
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6 RAS(ON) Proteins are Key Therapeutic Targets in RAS-Addicted Cancers•Major cancers with RAS drivers1 •Pancreatic ductal adenocarcinoma (>90%)•Non-small cell lung cancer (~30%)•Colorectal cancer (~50%) •Optimized clinical impact•One or more RAS inhibitors•Deep and durable inhibition of RAS(ON) signaling•Suppression of dominant RAS-mediated drug resistance NormalRAS Tumors= RAS(OFF) = RAS(ON) 1 Estimated using tumor mutation frequencies from Foundation Medicine Insights March 2022. •Primary RAS mutation•Drug resistance mechanisms•Secondary RAS mutations•Activation of wild-type RAS CellMembrane Tightly regulatedRAS(ON) proteins control cell growthExcessive RAS(ON) signaling drives uncontrolled cell growth
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7 Pipeline Led by Three Pioneering, Clinical-Stage RAS(ON) InhibitorsAPPROACHFOCUSEARL Y CLINICAL DEVELOPMENT(1) REGISTRATIONAL TRIALDaraxonrasib (RMC-6236 | MULTI) MonotherapyPDACNSCLCOther solid tumors Combination+ Chemotherapy, PDAC and CRC+ Pembrolizumab, NSCLC+ anti-EGFR, CRCElironrasib (RMC-6291 | G12C)MonotherapySolid tumorsCombination+ Pembrolizumab, NSCLC+ daraxonrasib, solid tumorsZoldonrasib (RMC-9805 | G12D)MonotherapySolid tumorsCombination+ SOC therapies, solid tumors+ daraxonrasib, solid tumorsAdditional RAS(ON) Mutant-Selective Inhibitors (RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C)) and next-generation programs PDAC, pancreatic ductal adenocarcinoma; NSCLC, non-smallcell lung cancer; CRC, colorectal cancer. SOC, standard of care. (1) Long bar indicates that registrational intent has been announced.
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8 (1) Incidence from ACS Cancer Facts and Figures 2024, includes all stages of disease.(2) RMC-6236-001: 2L patients with KRAS G12X PDAC treated with RMC-6236 300 mg daily (data cutoff: 7/23/2024).(3) RMC-6236-001: 2L/3L patients with RAS G12X NSCLC treated with RMC-6236 at 120-220 mg daily. (data cutoff: 9/30/2024).PDAC, pancreatic ductal adenocarcinoma; POC, proof-of-concept; 2L, second line; PFS, progression-free survival; OS, overall survival; 3L, third line; 1L, first line, NSCLC, non-small cell lung cancer. Active against Diverse RAS driver mutations Multiple drug resistance mechanisms, including secondary RAS mutations and wildtype RAS PDAC (~55,000 new RAS U.S. patients per year)(1)•2L monotherapy POC: median PFS 8.8 mo | OS Rate at 6 mo: 100%(2)•2L monotherapy registrational study is enrolling•Evaluating multiple combinations in 1L NSCLC (~60,000 new RAS U.S. patients per year)(1)•2/3L monotherapy POC : median PFS 9.8 mo | mOS 17.7 mo(3)•2/3L monotherapy registrational study pending•Initial combinability with pembrolizumab has been demonstrated•Evaluating multiple combinations in 1L Other RAS-Addicted Tumors•Combination strategies in colorectal cancer•Ongoing evaluation of antitumor activity in additional solid tumors Daraxonrasib (RMC-6236): RAS(ON) Multi-Selective Inhibitor
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9 Encouraging Durability in 2L Patients with PDAC Treated with Daraxonrasib at 300 mg Daily (1) RAS Mutant defined as patients with G12X, G13X or Q61X PDAC.2L in the metastatic setting includes patients who progressed on prior therapy in an earlier setting within 6 months of last dose. Median follow-up is 6.1m and 6.6m for KRAS G12 and RAS mutant in the 2L setting at 300mg, respectively. 2L, second line; PDAC, pancreatic ductal adenocarcinoma; PFS, progression-free survival; OS, overall survival, CI, confidence interval; NE, not estimable.ENA 2024 data set(Data cutoff: Jul 23, 2024) Median PFS, months(95% CI)Median OS, Months(95% CI)OS Rate at 6 months, % (95% CI)KRAS G12X8.8 (8.5, NE)NE (NE, NE)100 (100, 100)RAS Mutant(1)8.5 (5.9, NE)NE (8.5, NE)97 (79, 100)
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10 Encouraging Durability in 2L/3L Patients with RAS G12X NSCLC Treated with Daraxonrasib at 120-220 mg Daily Population includes patients with RAS G12X mutant NSCLC who have received 1 or 2 prior lines of therapy which must include prior immunotherapy and platinum chemotherapy administered either concurrently or sequentially, and have not received docetaxel previously. Adjuvant therapy or multimodal therapy with curative intent is considered prior therapy ifdisease progression occurred ortreatment completion was within 6 months of first dose of RMC-6236. Median follow-up is 10.8months.2L, second line; 3L, third line; NSCLC, non-small cell lung cancer; PFS, progression-free survival; OS, overall survival, CI, confidence interval; NE, not estimable.Data cutoff: Sept 30, 2024. Median PFS, months(95% CI)Median OS, Months(95% CI)9.8 (6, 12.3)17.7 (13.7, NE)
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11 (1) Incidence from ACS Cancer Facts and Figures 2024, includes all stages of disease.(2) P. Janne et al, Preliminary Safety and Anti-Tumor Activity of RMC-6291, a First-in-Class, Tri-Complex KRASG12C(ON) Inhibitor in Patients With or Without Prior KRASG12C(OFF) Inhibitor Treatment, ENA 2023.(3) RMC-LUNG-101 (data cutoff: 10/28/2024).(4) Incidence from ACS Cancer Facts and Figures 2023; includes all stages of disease.(5) RMC-6291-101 (data cutoff: 10/28/2024). NSCLC, non-small cell lung cancer; CRC, colorectal cancer; 1L, first line; SOC, standard of care. Active against Primary RAS G12C mutation Tumors in patients naïve to, or previously treated with, first generation RAS(OFF) inhibitors NSCLC (~60,000 new RAS U.S. patients per year, ~12% G12C mutations)(1)•Highly active in patients both naïve to and previously treated with G12C(OFF) inhibitors(2)•Initial tolerability observed in combination with pembrolizumab(3) CRC (~75,000 new RAS U.S. patients per year, ~4% G12C mutations)(4)•Initial validation of RAS(ON) inhibitor doublet, with daraxonrasib, in patients previously treated with G12C(OFF) inhibitors(5) Exploring Combination Strategies•Early data with pairwise combinations provides support for triplet combination (elironrasib + daraxonrasib + pembrolizumab) in 1L NSCLC(3)•Combination studies ongoing with SOC Elironrasib (RMC-6291): RAS(ON) G12C-Selective Inhibitor
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12Elironrasib + Daraxonrasib Case Report: Patient with KRAS G12C CRC Treatment History RAS(ON) Doublet Treatment Course BaselineWeek 27 Target Lesion Baseline (mm)Week 6 (mm)Week 27(mm)Lung, left upper lobe28.814.10Lung, right middle lobe2513.40Sum of Diameters53.827.5(-49%)0 (-100%)Overall Response-PRCR Lung, left upper lobe •Laparoscopic low anterior resection in 2019 (Stage I)•Metastatic recurrence and left hepatectomy in 2021•FOLFIRINOX + bevacizumab•Adagrasib + cetuximab•Investigational agent + pembrolizumab •Started treatment with RMC-6291 100 mg BID + daraxonrasib 200 mg QD on Mar 11, 2024 in Dose Exploration Phase•C3D1: Partial Response •C5D1: Confirmed Partial Response with complete resolution of all non-target lesions•C10D1: Complete Response•Continued on treatment with no Grade 3 or higher TRAEs Baseline Characteristics•55 year-old male initially diagnosed with colorectal adenocarcinoma in 2019•ECOG 1•KRAS G12C, KRAS Y96N and RTK rearrangements (ALK and MET fusions) detected in baseline ctDNA Week 6 Lung, right middle lobe CRC, colorectal cancer; ECOG, Eastern Cooperative Oncology Group; BID, twice daily; QD, once daily; TRAE, treatment-related adverse event, PR, partial response, CR, complete response.Data cutoff: Oct 28, 2024.
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13 (1) Incidence from ACS Cancer Facts and Figures 2024, includes all stages of disease.(2) David S. Hong et al., Preliminary Safety, Pharmacokinetics, and Antitumor Activity of RMC-9805, an Oral, RAS(ON) G12D-Selective, Tri-Complex Inhibitor in Patients with KRAS G12D Pancreatic Ductal Adenocarcinoma (PDAC) from a Phase 1 Study in Advanced Solid Tumors, ENA 2024.PDAC, pancreatic ductal adenocarcinoma; ORR, objective response rate; QD, once daily. Active against Primary RAS G12D mutation – the single most common RAS driver in solid tumors PDAC (~55,000 new RAS U.S. patients per year, ~40% with G12D mutations)(1)•Promising initial monotherapy clinical profile in PDAC (30% ORR)(2); follow-up ongoing for durability assessment•Highly encouraging initial tolerability Executing Monotherapy Opportunities•1200 mg QD identified as a recommended Phase 2 dose in PDAC•Monotherapy studies ongoing across multiple tumors Exploring Combination Strategies•Compelling profile also supports development in combination with chemotherapies and targeted agents, including RAS(ON) inhibitor doublet with daraxonrasib Zoldonrasib (RMC-9805): RAS(ON) G12D-Selective Inhibitor
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14 Demographics and Baseline Characteristics Treatment History •36-year-old Asian woman •Diagnosed with KRAS G12D NSCLC in Sept 2022•Metastatic progression after 2023Resolution of extensive lung and lymphangitic carcinomatosis RMC-9805 Treatment Course•C1D1: Received RMC-9805 at 1200 mg QD•C3D1: Partial Response per RECIST 1.1 (-70%)•C5D1: Confirmed Partial Response (-84%)•C7D1: Confirmed Partial Response (-84%)•C9D1: Confirmed Partial Response (-84%)•Treatment-emergent G3 increase in CPK, dose held and resumed at 900 mg QD suspected due to vigorous exercise•Within 1 week of C1D1, came off oxygen with resolved cough•Exercising daily in the gym Baseline CT C3D1 CT •Carboplatin, pemetrexed, nivolumab (neoadjuvant)•VATS lobectomy LLL, LUL wedge resection MLND in 2022•Atezolizumab (adjuvant)•Left lung radiotherapy (neoadjuvant)•Carboplatin, paclitaxel, atezolizumab, bevacizumab (1L) Zoldonrasib Case Report: Patient with KRAS G12D NSCLC NSCLC, non-small cell lung cancer; VATS, video-assisted thoracic surgery; LLL, left lower lobe; LU, left upper lobe; MLND, mediastinal lymph node dissection; CPK, creatine phosphokinase; QD, once daily, RECIST, Response Evaluation Criteria in Solid Tumors.Data as of 1/6/2025 EDC
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15 POC, proof-of-concept; CRC, colorectal cancer; NSCLC, non-small cell lung cancer; SOC, standard of care; 1L, first line. Highly Active RAS(ON) Inhibitors Drive Combination Opportunities to Support Development in Earlier Lines of Therapy•Initial POC with elironrasib (RMC-6291) in CRC•Evaluation underway with zoldonrasib (RMC-9805)•RMC-5127 (G12V) offers third planned doublet partnerRAS(ON) inhibitor doubletsDaraxonrasib (RMC-6236) + mutant-selective inhibitors•Initial combinability demonstrated for daraxonrasib or elironrasib + pembrolizumab in previously treated patients•Evaluation underway in 1L NSCLC•Safety assessment underway for zoldonrasib + pembrolizumab ImmunotherapyDaraxonrasib or mutant-selective inhibitor + checkpoint inhibitor •Collaboration to evaluate RAS(ON) inhibitors + PRMT5 inhibitor, TNG462•Collaboration to evaluate RAS(ON) inhibitors + cetuximabTargeted agentsDaraxonrasib or mutant-selective inhibitor + targeted agents •Safety evaluation underway for daraxonrasib or zoldonrasib with 1L chemotherapiesChemotherapyDaraxonrasib or mutant-selective inhibitor + SOC ≫ ≫ ≫ ≫
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16 Track Record of Innovation Against RAS Cancers Signals Great Promise of Pipeline and Organization Daraxonrasib(multi-selective) Zoldonrasib RMC-5127 Elironrasib RMC-0708 (Q61H)RMC-8839(G13C)Q61H represents ~40% of Q61X. G13C represents ~14% of G13X. POC, proof-of-concept; PDAC, pancreatic ductal adenocarcinoma; NSCLC, non-small cell lung cancer. G12D G12CG13XQ61XG12 other Frequency of RAS Variants Among RAS Mutant Solid TumorsPipeline and Organizational ProgressPioneered RAS(ON) inhibitor classCompelling daraxonrasib POC in PDAC and NSCLCCompelling zoldonrasib activity and safety in PDACMechanistic POC for first RAS(ON) inhibitor doubletCombinability of daraxonrasib or elironrasib with pembrolizumabManufacturing daraxonrasib at commercial scaleForged broad range of select partnershipsExceptionally strong balance sheet ≫≫≫≫ ≫ ≫≫≫ G12V
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17 Entering 2025 with Momentum and Conviction to Embrace Responsibility 2025 priorities include:•Executing daraxonrasib pivotal trials in previously treated PDAC and NSCLC•Advancing daraxonrasib into pivotal trial in 1L PDAC•Committing to first pivotal trial(s) with mutant-selective inhibitor(s)•Data-driven prioritization of combination strategies for early lines of therapy •Advancing fourth RAS(ON) inhibitor development candidate to clinic readiness•Growing commercial and operational capabilities in support of U.S. launch•Progressing next-generation programs ≫≫≫ ≫≫≫≫ Robust pipeline, capabilities and financial capital fuel vision to create industry-leading targeted medicines franchise for patients with RAS-addicted cancers PDAC, pancreatic ductal adenocarcinoma; NSCLC, non-small cell lung cancer; 1L, first line.
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On Target to Outsmart Cancer® 18
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19Appendix•All RAS cancer epidemiology statistics are 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 (unless otherwise noted).•RAS mutations include: KRAS G12(A,C,D,F,L,R,S,V), KRAS G13(C,D,R,V), KRAS Q61(E,H,K,L,P,R) NRAS G12(A,C,D,R,S,V), NRAS G13(C,D,R,V), NRAS Q61(H,K,L,R), HRASG12(C,D,S,V), HRASG13(C,D,N,R,S,V), HRASQ61(K,L,R). •Includes 13 major solid cancer types: non-small cell lung cancer, colorectal, pancreatic ductal adenocarcinoma, renal, esophageal, head and neck squamous cell, ovarian, stomach, biliary, and carcinomas of unknown primary (CUP), and advanced melanoma, bladder and endometrial cancers causing mortality.•KRAS Q61H epidemiology statistics include multiple myeloma in addition to 13 major solid cancer types named above