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CURRENT REPORT
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Item 2.02 Results of Operations and Financial Condition.
On January 9, 2024, Revolution Medicines, Inc. (the “Company”) posted a corporate presentation to the investor section of the Company’s website at: ir.revmed.com/events-and-presentations. The Company’s corporate presentation is attached hereto as Exhibit 99.1.
The information furnished under this Item 2.02 and in the presentation attached as Exhibit 99.1 to this Current Report on Form 8-K shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section or Sections 11 or 12(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”). The information contained in this Item 2.02 and in the presentation attached as Exhibit 99.1 to this Current Report on Form 8-K shall not be incorporated by reference into any filing with the Securities and Exchange Commission (the “SEC”) made by the Company, whether made before or after the date hereof, regardless of any general incorporation language in such filing.
Item 7.01 Regulation FD Disclosure.
On January 9, 2024, the Company posted a corporate presentation to the investor section of the Company’s website at: ir.revmed.com/events-and-presentations. The Company’s corporate presentation is attached hereto as Exhibit 99.1.
The furnishing of the attached presentation is not an admission as to the materiality of any information therein. The information contained in the slides is summary information that is intended to be considered in the context of more complete information included in the Company’s filings with the SEC and other public announcements that the Company has made and may make from time to time by press release or otherwise. The Company undertakes no duty or obligation to update or revise the information contained in this Current Report on Form 8-K, although it may do so from time to time as its management believes is appropriate. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases or through other public disclosures. For important information about forward looking statements, see the slide titled “Legal Disclaimer” in Exhibit 99.1 attached hereto.
The information furnished under this Item 7.01 and in the presentation attached as Exhibit 99.1 to this Current Report on Form 8-K shall not be deemed “filed” for purposes of Section 18 of the Exchange Act or otherwise subject to the liabilities of that section or Sections 11 or 12(a)(2) of the Securities Act. The information contained in this Item 7.01 and in the presentation attached as Exhibit 99.1 to this Current Report on Form 8-K shall not be incorporated by reference into any filing with the SEC made by the Company, whether made before or after the date hereof, regardless of any general incorporation language in such filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits.
| Exhibit No. |
Description | |
| 99.1 | Company presentation dated January 9, 2024. | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document). | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| REVOLUTION MEDICINES, INC. | ||||||
| Date: January 9, 2024 | By: | /s/ Jack Anders | ||||
| Jack Anders Chief Financial Officer | ||||||
Exhibit 99.1 On Target to Outsmart Cancer January 9, 2024 © 2024 Revolution Medicines, Inc.
2 Legal Disclaimer This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act. 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 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 events and other macroeconomic conditions on our business, and the expected benefits of the transaction with EQRx, Inc. 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 9, 2024 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, 2023, 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. All copyrights and trademarks used herein are the property of their respective owners.
3 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-selective inhibitor (RMC-6236) and RAS(ON) G12C-selective inhibitor (RMC-6291) show promising and highly differentiated initial clinical profiles • On track toward late-stage development of RMC-6236 and advancement of mutant-selective inhibitors led by RMC-6291 and RMC-9805
4 Portfolio of RAS(ON) Inhibitors Designed to Target 30% of Human Cancers RAS-Mutant Cancers (1) Normal New patients per year (U.S.) RAS Cancer Mutations >200,000 including Cell 60,000 Membrane Lung cancer (29% of NSCLC) Excessive Tightly regulated RAS(ON) signaling drives = RAS(OFF) RAS(ON) proteins control 75,000 uncontrolled cell growth cell growth Colorectal cancer (49% of CRC) = RAS(ON) 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) cancer Oncogenic RAS(ON) Inhibited RAS(ON) drivers RAS(ON) Inhibitor • Deep and durable suppression of RAS GTP 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 Initial Clinical Profiles of RAS(ON) Inhibitors Support Broad Set of Potential Opportunities to Treat RAS-Addicted Cancers Target Multi-Selective Genotypes G12X and RMC-6236 Clinical validation in NSCLC and PDAC (1) expansion Mutant-Selective Evidence of differentiated clinical activity in RMC-6291 G12C NSCLC and CRC RMC-9805 Dose escalation begun 3Q23 G12D (1) 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
7 2024 Capital Allocation Priorities to Advance Pioneering RAS(ON) Inhibitor Pipeline … … driving to Industry-Leading Propel RMC-6236 Targeted into first pivotal trial(s) Expand reach Qualify mutant-selective Medicines of RMC-6236 inhibitors by clinically assessing led by RMC-6291 and Franchise for opportunities RMC-9805 for (1L, types, mutations) late-stage development RAS-Addicted Cancers
8 RAS(ON) Multi-Selective Inhibitor RMC-6236 © 2023 Revolution Medicines Confidential
9 RMC-6236-001 Phase 1 Study Design Key Eligibility Criteria Dose Escalation RMC-6236 administered orally QD • Advanced solid tumors (1) with KRAS G12X mutations (initially excluding KRAS G12C) 400 mg • Received prior standard therapy 300 mg Dose Optimization appropriate for tumor type and (2) 220 mg + stage RAS Genotype and Tumor • ECOG PS 0–1 160 mg Type Expansion Lowest dose/exposure • No active brain metastases 120 mg range projected to drive tumor regressions in 80 mg humans based on preclinical models 40 mg Key Endpoints 20 mg • Safety and tolerability 10 mg • Pharmacokinetics • Anti-tumor activity Additional patients with PDAC or NSCLC were enrolled at dose levels that cleared DLT evaluation RMC-6236-001 Clinical Trial: https://clinicaltrials.gov/study/NCT05379985 (1) KRAS G12X initially 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, once daily.
10 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) 08 (6) ‡ AST elevation 6 (5) 0 1 (1) 07 (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.
11 KRAS G12X NSCLC: Best Overall Response to RMC-6236 (1) Evaluable for Efficacy (n=40) RMC-6236-001: Clinical Activity in KRAS (2) G12X NSCLC Best overall response, n (%) Complete response 1 (3) Partial response 14 (35) Stable disease 19 (48) Progressive disease 5 (13) (3) Not evaluable 1 (3) ORR, n (%) 15 (38) Confirmed, n 12 DCR (CR+PR+SD), n (%) 34 (85) (4) SOC Benchmark Docetaxel, ORR (%) (13) DCR (%) (60) KRAS G12 Mutation Week of Most Recent scan (1) Patients who received first dose of RMC-6236 at least 8 weeks prior to data extract date. (2) Tumor response per RECIST 1.1. (3) One subject withdrew from study without post-baseline scans. (4) SOC=standard of care; efficacy benchmark for docetaxel taken from CodeBreaK 200, Lancet (2023) 401: 733-746. *Unconfirmed PR per RECIST 1.1. Data Extracted 12 Oct 2023. Best % Change from Baseline in Target Lesion
12 KRAS G12X PDAC: Best Overall Response to RMC-6236 (1) Evaluable for Efficacy (n=46) RMC-6236-001: Clinical Activity in KRAS (2) G12X PDAC Best overall response, n (%) Partial response 9 (20) Stable disease 31 (67) Progressive disease 3 (7) (3) Not evaluable 3 (7) ORR, n (%) 9 (20) Confirmed, n 5 DCR (CR+PR+SD), n (%) 40 (87) (4) SOC Benchmarks GnP, ORR (%) (11) DCR (%) (56) KRAS G12 Mutation Week of Most Recent Scan (1) Patients who received first dose of RMC-6236 at least 8 weeks prior to data extract date. (2) Tumor response per RECIST 1.1. (3) Two patients died prior to first post-baseline scan; 1 patient had scan after 11 days of treatment and subsequently died due to PD. (4) SOC=standard of care; no clearly established standard of care in 2L PDAC; GnP=Gemcitabine plus nab-paclitaxel; efficacy benchmarks for GnP taken from Br J Cancer (2022) 126:1394-1400. *Unconfirmed PR per RECIST 1.1. Data Extracted 12 Oct 2023. Best % Change from Baseline in Target Lesion
13 Zeroing In on RMC-6236 Monotherapy Dose Selection Mean Steady-State Blood PK Profiles Individual Steady-State Blood AUC 10000 400 mg 300 mg 8000 200/220 mg 160 mg 6000 Exposure in mice at 25 120 mg mg/kg* 80 mg 4000 40 mg 20 mg Exposure in mice at 10 2000 10 mg mg/kg* 0 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. (1) Singh M, et al. Presentation at American Association for Cancer Research Annual Meeting, 8–13 April 2022, New Orleans, USA; abstract #3597. Data Extracted 22 Sep 2023. 10 mg 20 mg 40 mg 80 mg 1 0 g 2 m 160 mg 200/220 mg 300 mg 400 mg Steady-State Whole Blood Concentration (nM) Whole Blood Steady-State AUC (nM x h)
14 Key RMC-6236-001 Monotherapy Expansion Cohorts Underway Patients Cohort Purpose Enrolled NSCLC G12X dose optimization (300 mg and below) Dose selection for pivotal trial ✔ RAS G13X and Q61X expansion (300 mg) Pivotal trial design ✔ PDAC G12X dose optimization (300 mg and below) Dose selection for pivotal trial ✔ RAS G13X and Q61X expansion (300 mg)✔ Pivotal trial design CRC G12X expansion (300 mg) Signal seeking ✔ RAS G13X and Q61X expansion (300 mg) Signal seeking ✔ • G12C included in G12X across all tumor types and cohorts 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
15 Proposed Global Randomized Phase 3 Trial in Patients with Previously-Treated RAS Mutant NSCLC (1) (1,2) Trial Design Potential Patient Populations RMC-6236 Endpoints PFS R G12X-C 13% Core Population: OS G12X Patients Docetaxel Patient Reported Outcomes • N > 400 patients • Prior therapies: Anti-PD-(L)1 and platinum-containing G12C regimen in metastatic setting; RAS inhibitor naïve (including 12% G12C inhibitor) • Biomarker: RAS G12X, G13X, or Q61X mutation Expanded Population: • Study Initiation: Aiming for 2024 G13X - 2% G12X + G13X + Q61X Q61X - 3% Patients (1) • Potential for nested trial design to enable evaluation of core and expanded patient populations R = Randomized (1) Study design subject to change based on regulatory authority feedback (2) Percentages of all NSCLC patients with tumors bearing RAS G12X, G13X, or Q61X genotypes; 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); G12X - 25%
16 Potential Global Randomized Phase 3 Trial of RMC-6236 in Patients with Previously-Treated PDAC (1) (1,2) Trial Design Potential Patient Populations Endpoints RMC-6236 R PFS Physician’s choice: OS e.g., GnP or mFOLFIRINOX Patient Reported Outcomes G12X - 85% Core Population: G12X Patients • N > 500 patients • Prior therapies: Fluoropyrimidine or gemcitabine-based regimen; RAS inhibitor naïve (including G12C inhibitor) • Biomarker: All comers, RAS mutation testing (G12X, G13X, or Q61X) to allow stratification • Study Initiation: Potentially in 2024 Expanded Populations: G13X/Q61X - 7% • G12X + G13X + Q61X patients WT - 8% • All PDAC patients (1) • Potential for nested trial design to enable evaluation of core and expanded patient populations R = Randomized; WT=wild-type (1) Study design subject to change based on regulatory authority feedback (2) Percentages of all PDAC patients with tumors bearing RAS G12X, G13X, Q61X or WT genotypes; 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);
17 Complementary RAS(ON) Inhibitors Designed for Monotherapy and Combination Strategies Against RAS-Addicted Cancers RAS Multi-Selective RAS Mutant-Selective • Monotherapy with broad potential • Alternative monotherapy for RAS-addicted cancers approaches • Backbone of RAS(ON) inhibitor • Complementary to RAS multi- doublets with mutant-selective selective inhibitor in RAS(ON) RAS(ON) inhibitors inhibitor doublets • Targeted agent for SOC • Differentiated targeted agent combinations, including profiles for SOC combinations, immunotherapies including immunotherapies
18 RAS(ON) G12C-Selective Inhibitor RMC-6291 © 2023 Revolution Medicines Confidential
19 RMC-6291-001 Phase 1 Study Design Key Eligibility Criteria Dose Escalation RMC-6291 administered orally QD or BID • Advanced solid tumors G12C with KRAS mutations 400 mg BID • Received prior standard therapy including treatment with 300 mg BID G12C KRAS (OFF) inhibitors 200 mg BID • ECOG PS 0–1 Dose Optimization 100 mg BID • No active brain metastases 200 mg QD 100 mg QD Key Endpoints Lowest dose projected to drive 50 mg QD tumor regressions in humans based • Safety and tolerability on preclinical models • Pharmacokinetics • Anti-tumor activity Additional patients with NSCLC or CRC were enrolled at dose levels that cleared DLT evaluation (backfill enrollment and dose optimization) RMC-6291-001 Clinical Trial: https://clinicaltrials.gov/study/NCT05462717 DLT=dose-limiting toxicity; ECOG PS=Eastern Cooperative Oncology Group Performance Status; QD=once daily; BID=twice daily
20 RMC-6291-001: Summary of Treatment-Related Adverse Events Total (n=63) Maximum Severity of TRAEs Grade 3 Any Grade Grade 1 Grade 2 TRAEs occurring in ≥10% of patients, n (%) Diarrhea 1 (2) 18 (29) 10 (16) 7 (11) Nausea 0 17 (27) 14 (22) 3 (5) ECG QT prolonged 7 (11) 16 (25) 8 (13) 1 (2) –– – QTcF* ≥501 ms 1 (2) Fatigue 0 8 (13) 4 (6) 4 (6) Vomiting 0 8 (13) 6 (10) 2 (3) AST increased 0 7 (11) 7 (11) 0 TRAEs leading to dose reduction, n (%) 9 (14) 0 1 (2) 8 (13) 1 (2) TRAEs leading to treatment discontinuation, n (%) 1 (2) 00 • No treatment-related Grade 4 or 5 AEs or SAEs have been reported • No patients had cardiac sequelae (e.g., torsade de pointes) associated with an ECG QT prolonged event *QTcF refers to QT interval corrected for heart rate by Fridericia's formula. AE, adverse event; AST, aspartate transferase; ECG, electrocardiogram; SAE, serious adverse event, TRAE, treatment-related adverse event. Data Extracted 05 October 2023.
21 G12C G12C KRAS NSCLC Previously Treated with or Naïve to a KRAS (OFF) Inhibitor: Best Overall Response to RMC-6291 (1) Evaluable for Efficacy* (n=17) RMC-6291-001: Clinical Activity in KRAS G12C (2) NSCLC Prior Naïve to Best overall response, G12Ci G12Ci n (%) (n=10) (n=7) (3) Partial response 5 (50) 3 (43) Stable disease 5 (50) 4 (57) Progressive disease 0 0 ORR, n (%) 5 (50) 3 (43) DCR (CR+PR+SD), 10 (100) 7 (100) n (%) (1) All treated patients who received a first dose of RMC-6291 at least 8 weeks prior to data extract date. (2) Tumor response per RECIST 1.1. (3) PR includes 5 confirmed and 3 unconfirmed. Data Extracted 05 October 2023. Pru=Unconfirmed PR per RECIST 1.1; G12Ci=G12C inhibitor. Best % Change in SOD from Baseline in Target Tumor Burden
22 G12C G12C KRAS CRC Naïve to KRAS (OFF) Inhibitor: Best Overall Response to RMC-6291 (1) Evaluable for Efficacy* (n=19) RMC-6291-001: Clinical Activity in KRAS G12C (2) CRC † Best overall response, n (%) n=20 (3) Partial response 8 (40) Stable disease 8 (40) (4) Progressive disease 4 (20) ORR, n (%) 8 (40) DCR (CR+PR+SD), n (%) 16 (80) (1) All treated patients who received first dose of RMC-6291 at least 8 weeks prior to data extract date. (2) Tumor response per RECIST 1.1. (3) PR includes 5 confirmed and 3 unconfirmed. (4) One patient had PD due to a new lesion and target lesion measurements were not available. Data Extracted 05 October 2023. Pru=Unconfirmed PR per RECIST 1.1. Best % Change in SOD from Baseline in Target Tumor Burden
23 RAS(ON) G12D-Selective Inhibitor RMC-9805 © 2023 Revolution Medicines Confidential
24 RMC-9805: Clinical Stage, RAS(ON) Mutant-Selective, Covalent Inhibitor for RAS G12D Cancers Selective Covalent Binding to KRAS G12D WT G12D G13D G12C G13C KRAS: X-linked KRAS KRAS H/NRAS In Vivo Anti-Tumor Activity across KRAS G12D Cancer Models 200 61,000 CRC 150 NSCLC New KRAS G12D patients mPD (1) PDAC 100 per year (U.S.) 50 mSD 0 -50 mPR mCR -100 (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) RVMD preclinical research as of 11/02/22; NSCLC = non-small cell lung cancer; PDAC = pancreatic ductal adenocarcinoma; CRC = colorectal cancer RMC-9805 dosed at 100 mg/kg po qd; n=3-8/group; Responses assigned according to mRECIST: mPD = progressive disease; mSD = stable disease; mPR = partial response; mCR = complete response RMC-9805-001 Clinical Trial: https://clinicaltrials.gov/study/NCT06040541 Mean Tumor Volume % Change From Baseline KP-4 CRC1018 CTG-2393 CRC043 LUN232 CRC054 PAN026 CRC044 CRC047 CRC012 CTG-1932 PAN038 LXFL625 PAN010 GP2d AsPC-1 PAN031 PAN009 LXFA2889 HPAC LXFA2204 CTG-2803 LUN137 LUN020 PAN001
25 Phase 1b Combo: RMC-6236 + RMC-6291 Doublet Designed to Overcome Resistance and Prolong Durability in KRAS G12C NSCLC (1) (2) Preclinical Validation RMC-6291-101 Clinical Trial 100 Objectives: evaluate safety, tolerability and preliminary activity of RMC-6236 combined with RMC-6291 75 Patient Population: KRAS G12C solid tumors, primarily NSCLC and CRC 50 Study Status: First patient dosed 4Q23 Control RMC-6291 25 RMC-6236 RMC-6291 + RMC-6236 0 0 2040 6080 100 Days on Treatment • RAS(ON) inhibitor doublet evaluated across seven models, including five identified as resistant to RMC-6291 monotherapy (1) RVMD preclinical research; NSCLC = non-small cell lung cancer; RMC-6236 dosed at 25 mg/kg po qd (n=52); RMC-6291 dosed at 100 or 200 mg/kg po qd (n=52); Combination (n=51). For each group, n = total number of animals from the seven models that comprise the dataset. Progression defined as tumor doubling from baseline. (2) RMC-6291-101 Clinical Trial: https://www.clinicaltrials.gov/study/NCT06128551
26 Phase 1b Combos: RAS(ON) Inhibitor Combinations with Pembrolizumab to Inform Potential Evaluation in 1L NSCLC (1) (2) Preclinical Validation RMC-LUNG-101 Clinical Trial: Pembrolizumab Objectives: evaluate safety, tolerability and preliminary activity of RMC-6236 and RMC-6291 each combined with Control Control pembrolizumab Anti-PD1 Anti-PD1 RMC-6236 RMC-6291 Patient Population: RMC-6236 in KRAS-mutant NSCLC, RMC- Combination Combination 6291 in KRAS G12C NSCLC 100 Study Status: Recruiting 75 50 25 0 0 25 50 75 100 0 25 50 75 100 Days post-tumor implant G12C (1) RVMD preclinical research; RMC-6236 and RMC-6291 experiments conducted in CT26 model engineered to express KRAS ; RMC-6236 (25 mg/kg po qd) or RMC-6291 (200 mg/kg po qd) dosed for 14 days; Vertical dashed lines represent treatment stop; Kaplan-Meier progression defined as tumor doubling from baseline (2) RMC-LUNG-101 Clinical Trial: https://www.clinicaltrials.gov/study/NCT06162221 % Tumors progression-free
27 Key RAS(ON) Inhibitor Combination Cohorts Cohort Status Purpose (1) NSCLC RMC-6236 + pembrolizumab +/- chemotherapy recruiting qualification for potential 1L RMC-6291 + pembrolizumab +/- chemotherapy recruiting qualification for potential 1L (2) Solid tumors RMC-6236 + RMC-6291 qualification for potential 1L dosing PDAC RMC-6236 + chemotherapy qualification for potential 1L pending CRC RMC-6236 + anti-EGFR pending signal seeking RMC-6236 + chemotherapy pending signal seeking (1) RMC-LUNG-101 Clinical Trial: https://www.clinicaltrials.gov/study/NCT06162221 (2) RMC-6291-101 Clinical Trial: https://www.clinicaltrials.gov/study/NCT06128551
28 Highlights of 2H-2023 RAS(ON) Multi-Selective Inhibitor • Encouraging initial RMC-6236 monotherapy safety, tolerability and antitumor activity profiles in both NSCLC and PDAC reported in October • Favorable safety and response trends continue to build, including in 300 mg daily cohort • Favorable dose intensity observed across doses, including 300 mg daily • Clinical profiles from dose escalation, including exposures, support 300 mg daily and below for ongoing dose optimization in both NSCLC and PDAC to inform dose selection for pivotal trials RAS(ON) Mutant-Selective Inhibitors • Encouraging initial RMC-6291 adverse event and monotherapy antitumor activity profiles in NSCLC and CRC reported in October • Dose optimization underway at 200-300 mg daily • RMC-9805 exhibiting good oral bioavailability, including dose-dependent increases in exposure, consistent with preclinical projections Financial • EQRx transaction completed, 2023 EOY estimated “flash” cash and marketable securities balance $1.85 billion (unaudited)
29 Broad Clinical Validation Across RAS Genotypes and Tumor Types in 2023 Driving Late-Stage Development in 2024 Expand reach Qualify mutant-selective inhibitors of RMC-6236 led by RMC-6291 and by clinically assessing RMC-9805 for Propel RMC-6236 opportunities late-stage development into first pivotal trial(s) (1L, types, mutations) • Mono cohorts • Dose selection • Mono profiles and dose selection • Combination cohorts • Durability of response • Combination cohorts • Trial designs • Late-stage plans
30 Deep Pipeline of Targeted Therapies for Majority of RAS-Addicted Cancers PRECLINICAL IND-ENABLING PHASE 1 PHASE 2 PHASE 3 RAS(ON) INHIBITORS MULTI RMC-6236 G12C RMC-6291 RMC-9805 G12D RMC-5127 G12V Q61H RMC-0708 (1) G13C RMC-8839 Pipeline G12R, G13D, other Expansion RAS COMPANION INHIBITORS (1) SHP2 RMC-4630 mTORC1/4EBP1 RMC-5552 (1) Development activities paused.
31 Financial Information Financial Position Preliminary estimate of cash, cash equivalents and marketable securities as (1,2) $1.85 billion of December 31, 2023 (unaudited) 2023 Financial Guidance (3) 2023 net loss of $385 million to $415 million (1) Includes cash, cash equivalents and marketable securities acquired in the EQRx transaction. We have not yet completed our year-end financial close and review processes, and the results of our ongoing review of our financial statements could result in changes to this amount. (2) With current cash, cash equivalents and marketable securities, the company projects it can fund planned operations into 2027. (3) Includes non-cash stock-based compensation expense of approximately $45 million to $50 million. 2023 net loss guidance does not include impact of the acquisition of EQRx. The company has not provided net loss guidance that includes the impact of the acquisition of EQRx because the company is not able to quantify the impact of this acquisition on the company’s net loss without unreasonable effort.
32 On Target to TM Outsmart Cancer
33 Appendix • 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: • 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. • KRASQ61H epidemiology statistics include multiple myeloma in addition to 13 major solid cancer types named above • RAS mutations drive 30% of human cancers per Prior et al., Cancer Research 2020 • Mouse tumor responses assigned according to mRECIST (modified from Gao et al. Nat Med. 2015): • mPD = progressive disease; mSD = stable disease; mPR = partial response; mCR = complete response