Drug Development Pipeline - The company is developing a pipeline of RAS(ON) inhibitors, including daraxonrasib (RMC-6236), elironrasib (RMC-6291), and zoldonrasib (RMC-9805), which are in clinical development stages[89]. - Daraxonrasib is currently undergoing a global Phase 3 trial (RASolute 302) for metastatic pancreatic ductal adenocarcinoma, with expected enrollment completion in 2025 and clinical readout in 2026[91]. - Elironrasib is designed as a G12C-selective inhibitor and has shown acceptable tolerability and encouraging preliminary antitumor activity in patients with solid tumors harboring RAS G12C mutations[101]. - Zoldonrasib is a G12D-selective inhibitor that has demonstrated acceptable tolerability and initial antitumor activity in patients with previously treated solid tumors harboring KRAS G12D mutations[106]. - The company plans to initiate pivotal combination studies in 2026 that will incorporate either zoldonrasib or elironrasib[107]. - RMC-5127, a G12V-selective inhibitor, is expected to advance to a clinic-ready stage in 2025, with a first-in-human trial anticipated in 2026[108]. - RMC-0708 and RMC-8839 are designed as selective inhibitors for Q61H and G13C mutations, respectively, with their clinical development subject to ongoing portfolio assessments[109][110]. - The company is also developing RAS companion inhibitors, including RMC-4630, RMC-5552, and RMC-5845, aimed at targeting pathways that sustain RAS-addicted cancers[111]. - The ongoing research includes exploratory combination regimens involving daraxonrasib, elironrasib, and pembrolizumab to assess their potential in earlier lines of therapy[96][102]. - The company emphasizes its innovative drug discovery capabilities and precision medicine approaches to address RAS-addicted cancers[85]. Financial Performance - Research and development expenses increased by $87.7 million, or 74%, to $205.7 million for the three months ended March 31, 2025, compared to $118.0 million in the same period of 2024[124]. - Operating expenses totaled $240.8 million for the three months ended March 31, 2025, up from $140.9 million in the same period of 2024, resulting in a loss from operations of $240.8 million[122]. - Interest income rose by $1.2 million to $24.9 million for the three months ended March 31, 2025, compared to $23.8 million in the same period of 2024[126]. - General and administrative expenses increased by $12.2 million, or 53%, to $35.0 million for the three months ended March 31, 2025, compared to $22.8 million in the same period of 2024[125]. - As of March 31, 2025, the company had $2.1 billion in cash, cash equivalents, and marketable securities[131]. - The accumulated deficit as of March 31, 2025, was $2.0 billion, with primary cash usage for operating expenses related to research and development[132]. - The company expects research and development expenses to continue increasing as it advances product candidates into later stages of development[118]. - Cash used in operating activities was $194.4 million for the three months ended March 31, 2025, compared to $160.6 million in the same period of 2024[135]. - The company anticipates requiring substantial additional financing for ongoing development efforts and potential commercialization of its product candidates[133]. - Cash used in operating activities for the three months ended March 31, 2024, was $160.6 million, attributed to a net loss of $116.0 million and a net change of $47.2 million in operating assets and liabilities[138]. - Non-cash charges included stock-based compensation expense of $16.2 million and a $2.8 million impairment of a long-term asset acquired as part of the EQRx Acquisition[138]. - Cash used in investing activities for the three months ended March 31, 2024, was $248.0 million, with maturities of marketable securities at $456.9 million and purchases of marketable securities at $701.7 million[140]. - Cash provided by financing activities during the three months ended March 31, 2024, was $0.8 million from the issuance of common stock upon the exercise of stock options[141]. - The company held cash, cash equivalents, and marketable securities of $2.1 billion as of March 31, 2025, down from $2.3 billion as of December 31, 2024[149]. - The company experienced a $29.0 million decrease in accounts payable and a $21.3 million decrease in accrued expenses and other current liabilities during the three months ended March 31, 2024[138]. - The company is exposed to interest rate risk, but historical fluctuations in interest income have not been significant due to the short-term maturities of cash equivalents and marketable securities[149]. - Foreign currency transaction gains and losses have not been material to the company's consolidated financial statements, with expenses generally denominated in U.S. dollars[150]. - The company incurred a $1.5 million increase in accrued expenses and other current liabilities, with non-cash charges primarily consisting of stock-based compensation expense of $25.1 million[137]. Strategic Initiatives - The company completed the acquisition of EQRx, Inc. in November 2023, issuing 54,786,528 shares and receiving $1.1 billion in net cash[128]. - The company has plans to acquire or in-license other programs or technologies as part of its strategic initiatives[136].

Corporate Progress and Highlights [2025 Strategic Priorities & Execution](index=1&type=section&id=2025%20Strategic%20Priorities%20%26%20Execution) Revolution Medicines progresses pivotal daraxonrasib trials, plans new studies, and builds commercial capabilities - The company is executing two ongoing Phase 3 trials of daraxonrasib: **RASolute 302 trial** in pancreatic cancer expected to be **substantially completed in 2025** with a **data readout anticipated in 2026**, and **RASolve 301 trial** for NSCLC currently activating study sites[2](index=2&type=chunk)[3](index=3&type=chunk)[4](index=4&type=chunk) - Planning continues for **new registrational trials** for daraxonrasib in **first-line metastatic PDAC** and as an **adjuvant treatment**, both expected to begin in the **second half of 2025**[5](index=5&type=chunk) - The company plans to initiate one or more **pivotal combination trials in 2026** featuring either the G12D-selective inhibitor **zoldonrasib** or the G12C-selective inhibitor **elironrasib**[6](index=6&type=chunk) - The pipeline is advancing with **RMC-5127**, a RAS(ON) G12V-selective inhibitor, on track to be **clinic-ready later in 2025**, enabling a potential **Phase 1 start in 2026**[9](index=9&type=chunk) - To support a potential launch, the company is **building its commercial capabilities** and has appointed **Anthony Mancini** as **Chief Global Commercialization Officer**[10](index=10&type=chunk)[11](index=11&type=chunk) Clinical Data Highlights [Zoldonrasib Monotherapy in G12D NSCLC](index=3&type=section&id=Zoldonrasib%20Monotherapy%20in%20G12D%20NSCLC) Zoldonrasib monotherapy in G12D NSCLC showed encouraging antitumor activity with a 61% ORR and favorable safety Zoldonrasib Monotherapy Efficacy in G12D NSCLC | Metric | Result (%) | | :--- | :--- | | **Objective Response Rate (ORR)** | 61% | | **Disease Control Rate (DCR)** | 89% | - The safety profile was favorable, with treatment-related adverse events (TRAEs) being predominantly low-grade, and Grade 3 TRAEs reported in only **2% of patients**, with no Grade 4 or 5 events[15](index=15&type=chunk) [Elironrasib Monotherapy in G12C NSCLC](index=4&type=section&id=Elironrasib%20Monotherapy%20in%20G12C%20NSCLC) Elironrasib monotherapy in G12C NSCLC demonstrated promising efficacy with a 56% ORR and 9.9 months PFS Elironrasib Monotherapy Efficacy in G12C NSCLC | Metric | Result | | :--- | :--- | | **Objective Response Rate (ORR)** | 56% | | **Disease Control Rate (DCR)** | 94% | | **Median Progression-Free Survival (PFS)** | 9.9 months (estimated) | - The treatment was generally well-tolerated, with predominantly low-grade TRAEs, and Grade 3 TRAEs reported in **19% of patients**, with no Grade 4 or 5 events[18](index=18&type=chunk) [Combination Therapies in NSCLC](index=4&type=section&id=Combination%20Therapies%20in%20NSCLC) Combination therapies in RAS mutant NSCLC show encouraging antitumor activity and acceptable tolerability [Daraxonrasib with Pembrolizumab (+/- Chemotherapy)](index=4&type=section&id=Daraxonrasib%20with%20Pembrolizumab) Daraxonrasib with pembrolizumab (+/- chemo) showed encouraging 1L NSCLC activity and no new safety signals Daraxonrasib with Pembrolizumab (+/- Chemo) Efficacy in 1L NSCLC | Patient Group (1L NSCLC) | Treatment | ORR (%) | DCR (%) | | :--- | :--- | :--- | :--- | | TPS ≥ 50% | Daraxonrasib + Pembrolizumab | 86% | 100% | | TPS < 50% | Daraxonrasib + Pembrolizumab + Chemo | 60% | 90% | - The combination showed an acceptable safety profile, with **no new safety signals**, no evidence of significant hepatotoxicity (no Grade 3+ AST/ALT elevations), or increased immune-related adverse events like colitis or pneumonitis[22](index=22&type=chunk)[23](index=23&type=chunk) [Elironrasib with Pembrolizumab](index=5&type=section&id=Elironrasib%20with%20Pembrolizumab) Elironrasib with pembrolizumab achieved 100% ORR in 1L KRAS G12C NSCLC (TPS ≥50%) with acceptable tolerability - Among five efficacy-evaluable patients with 1L NSCLC and TPS ≥50%, the **ORR and DCR were both 100%**[28](index=28&type=chunk) - The combination showed acceptable tolerability, with Grade 3 or higher TRAEs reported in **25% of patients** and **no new safety signals** observed[27](index=27&type=chunk) [RAS(ON) Inhibitor Doublet (Elironrasib + Daraxonrasib)](index=5&type=section&id=RAS%28ON%29%20Inhibitor%20Doublet) RAS(ON) inhibitor doublet showed encouraging activity in NSCLC with 62% ORR, supporting a triplet regimen RAS(ON) Inhibitor Doublet Efficacy in NSCLC | Metric | Result (%) | | :--- | :--- | | **Objective Response Rate (ORR)** | 62% | | **Disease Control Rate (DCR)** | 92% | - The combination was acceptably tolerated, with **46% Grade 3 TRAEs** and **no Grade 4 or 5 events**, and hepatotoxicity was not observed as a safety signal[30](index=30&type=chunk) - These preliminary results support the company's goal of developing a chemotherapy-sparing triplet combination including elironrasib, daraxonrasib, and pembrolizumab for first-line metastatic RAS G12C NSCLC[31](index=31&type=chunk) Financial Performance [First Quarter 2025 Financial Results](index=6&type=section&id=First%20Quarter%202025%20Financial%20Results) Q1 2025 net loss increased due to higher R&D expenses, maintaining a strong cash position First Quarter 2025 Financial Summary | Financial Metric (in millions USD) | Q1 2025 | Q1 2024 | | :--- | :--- | :--- | | R&D Expenses | $205.7 | $118.0 | | G&A Expenses | $35.0 | $22.8 | | **Net Loss** | **$213.4** | **$116.0** | - The company's cash, cash equivalents, and marketable securities totaled **$2.1 billion** as of March 31, 2025[32](index=32&type=chunk) - The increase in R&D expenses was mainly due to higher clinical trial and manufacturing costs for daraxonrasib, zoldonrasib, and elironrasib, as well as increased personnel-related expenses, while G&A expenses rose due to headcount growth and commercial preparation activities[33](index=33&type=chunk)[34](index=34&type=chunk) [2025 Financial Guidance](index=7&type=section&id=2025%20Financial%20Guidance) Revolution Medicines reiterates 2025 GAAP net loss guidance, with cash funding operations into the second half of 2027 - The company reiterated its full-year 2025 GAAP net loss guidance of **$840 million to $900 million**, which includes an estimated **$115 million to $130 million** in non-cash stock-based compensation expense[36](index=36&type=chunk) - Based on the current operating plan, the company projects its cash, cash equivalents, and marketable securities can fund operations into the **second half of 2027**[36](index=36&type=chunk) Appendix: Financial Statements [Condensed Consolidated Statements of Operations](index=9&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations) This section details the unaudited income statement for Q1 2025, showing a net loss of $213.4 million Condensed Consolidated Statements of Operations | (in thousands USD, except per share data) | Three Months Ended March 31, 2025 | Three Months Ended March 31, 2024 | | :--- | :--- | :--- | | **Operating expenses:** | | | | Research and development | 205,749 | 118,021 | | General and administrative | 35,011 | 22,838 | | Total operating expenses | 240,760 | 140,859 | | **Loss from operations** | **(240,760)** | **(140,859)** | | Interest income | 24,915 | 23,760 | | Other income (expense), net | 2,429 | 1,096 | | **Net loss** | **$ (213,416)** | **$ (116,003)** | | Net loss per share - basic and diluted | $ (1.13) | $ (0.70) | [Selected Condensed Consolidated Balance Sheets](index=10&type=section&id=Selected%20Condensed%20Consolidated%20Balance%20Sheets) This section presents the condensed balance sheet as of March 31, 2025, highlighting cash and equivalents Selected Condensed Consolidated Balance Sheets | (in thousands USD) | March 31, 2025 | December 31, 2024 | | :--- | :--- | :--- | | Cash, cash equivalents and marketable securities | $ 2,102,675 | $ 2,289,299 | | Working capital | 1,975,983 | 2,163,718 | | Total assets | 2,365,353 | 2,558,301 | | Total liabilities | 287,203 | 293,097 | | Total stockholders' equity | 2,078,150 | 2,265,204 |

Core Insights - Revolution Medicines, Inc. reported financial results for Q1 2025, highlighting progress in clinical trials and strategic priorities for the year [1][30][31] Clinical Development - The company is executing pivotal trials for daraxonrasib in previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), with strong enrollment in the U.S. and initiation in the EU and Japan [1][2] - Plans are underway to advance daraxonrasib into first-line metastatic and earlier-line randomized pivotal trials for PDAC, expected to start in the second half of 2025 [3] - The company anticipates initiating pivotal combination trials for elironrasib and zoldonrasib in 2026 [4] - Recent data from zoldonrasib and elironrasib monotherapy in KRAS G12D and G12C mutant NSCLC patients show promising tolerability and antitumor activity [5][16] Combination Therapies - Clinical updates indicate encouraging results for combinations of daraxonrasib with pembrolizumab and elironrasib with pembrolizumab in NSCLC [6][19] - The combination of elironrasib with daraxonrasib demonstrated preliminary antitumor activity in patients previously treated with a KRAS G12C(OFF) inhibitor, with an objective response rate (ORR) of 62% [27][29] Financial Performance - As of March 31, 2025, the company reported cash, cash equivalents, and marketable securities totaling $2.1 billion [31][42] - Research and development expenses increased to $205.7 million from $118.0 million year-over-year, primarily due to clinical trial and manufacturing costs [32] - General and administrative expenses rose to $35.0 million from $22.8 million, attributed to personnel-related costs and commercial preparation activities [33] - The net loss for Q1 2025 was $213.4 million, compared to a net loss of $116.0 million in Q1 2024 [34] Strategic Initiatives - The company is enhancing its commercialization capabilities, appointing Anthony Mancini as chief global commercialization officer to strengthen its strategy in the U.S. and evaluate options for international reach [10][11] - Revolution Medicines is focused on advancing its pipeline of RAS(ON) inhibitors, with plans for future clinical development of RMC-5127, a G12V-selective inhibitor [37]

Core Insights - Revolution Medicines, Inc. is a late-stage clinical oncology company focused on developing targeted therapies for RAS-addicted cancers [3] - The company will report its financial results for Q1 2025 on May 7, 2025, after market close, followed by a webcast to discuss these results and corporate progress [1] Company Overview - Revolution Medicines is developing a pipeline of RAS(ON) inhibitors aimed at suppressing various oncogenic variants of RAS proteins [3] - Current clinical candidates include daraxonrasib (RMC-6236), elironrasib (RMC-6291), and zoldonrasib (RMC-9805), with RMC-5127 anticipated to be the next to enter clinical development [3] - The company is also exploring additional RAS(ON) mutant-selective inhibitors such as RMC-0708 (Q61H) and RMC-8839 (G13C) [3]

Core Insights - Zoldonrasib, a RAS(ON) G12D-selective inhibitor, shows acceptable tolerability and promising initial antitumor activity in patients with KRAS G12D mutant non-small cell lung cancer (NSCLC) [1][2] Group 1: Clinical Data - New clinical data for zoldonrasib was presented at the American Association for Cancer Research (AACR) Annual Meeting, highlighting its potential as a treatment for NSCLC [1][2] - The Phase 1 study (RMC-9805-001) involved 90 solid tumor patients treated with 1200 mg once daily, demonstrating an acceptable safety profile consistent with previous data in pancreatic cancer [3] - The most common treatment-related adverse events (TRAEs) included nausea (39%), diarrhea (24%), vomiting (18%), and rash (12%), primarily Grade 1 or 2 in severity [3] Group 2: Efficacy Results - Preliminary antitumor activity was assessed in 18 efficacy-evaluable NSCLC patients, showing an objective response rate of 61% (11 patients) and a disease control rate of 89% (16 patients) [4] - The data indicates a high unmet need for new treatments in this patient population, as there are currently no approved targeted therapies for RAS G12D mutant cancers [5] Group 3: Company Overview - Revolution Medicines is focused on developing targeted therapies for RAS-addicted cancers, with a pipeline that includes multiple RAS(ON) inhibitors [6] - The company is advancing zoldonrasib as a monotherapy and in combination therapies, aiming to provide innovative treatment options for hard-to-treat cancers [2][6]

Core Insights - Revolution Medicines, Inc. is set to present 11 oral and poster presentations at the AACR Annual Meeting in Chicago from April 25 – 30, 2025, focusing on targeted therapies for RAS-addicted cancers [1][7]. Oral Presentations - The first clinical data from the Phase 1 study of zoldonrasib, a RAS(ON) G12D-selective inhibitor, will be presented in a late-breaking oral session on April 27, 2025 [2]. - The presentations include topics such as the preliminary safety and antitumor activity of zoldonrasib in KRAS G12D non-small cell lung cancer, and the discovery of RMC-5127, a RAS(ON) G12V-selective inhibitor [2]. Poster Presentations - Key poster presentations will cover early reductions in circulating tumor DNA (ctDNA) associated with clinical activity of daraxonrasib in RAS mutant non-small cell lung cancer, and mechanisms of resistance to daraxonrasib [3][4]. - Additional topics include the combination of RAS(ON) inhibitors to enhance immunotherapy efficacy in RAS-driven preclinical models [3]. Collaborator Presentations - Collaborator presentations will discuss distinct regulation of Cyclin D in colorectal cancer models and overcoming resistance to sotorasib through combination therapies [5][6]. - Other presentations will focus on long-term tumor control through combination therapy and preclinical evaluations of RMC-7977 for KRAS-mutant cholangiocarcinoma [5][6]. Company Overview - Revolution Medicines is a late-stage clinical oncology company developing targeted therapies for RAS-addicted cancers, with a pipeline that includes daraxonrasib, elironrasib, and zoldonrasib currently in clinical development [7]. - The company is also advancing RMC-5127, a RAS(ON) G12V-selective inhibitor, and exploring additional RAS(ON) mutant-selective inhibitors [7].

Core Insights - Revolution Medicines, Inc. is a late-stage clinical oncology company focused on developing targeted therapies for RAS-addicted cancers [2] - The company is participating in two upcoming investor conferences, indicating active engagement with the investment community [1][3] Company Overview - Revolution Medicines specializes in RAS(ON) inhibitors aimed at suppressing various oncogenic variants of RAS proteins [2] - The current R&D pipeline includes daraxonrasib (RMC-6236), elironrasib (RMC-6291), and zoldonrasib (RMC-9805), all of which are in clinical development [2] - The company plans to advance RMC-5127, a RAS(ON) G12V-selective inhibitor, into clinical development next [2] - Additional pipeline opportunities include RMC-0708 (Q61H) and RMC-8839 (G13C), focusing on RAS(ON) mutant-selective inhibitors [2] Upcoming Events - The company will participate in the Needham 24 Annual Virtual Healthcare Conference on April 7 at 2:15 p.m. ET [3] - Additionally, Revolution Medicines will be part of the Stifel 2025 Virtual Targeted Oncology Forum on April 9 at 1:00 p.m. ET [3]

Financial Data and Key Metrics Changes - The company ended Q4 2024 with $2.3 billion in cash and investments, including $823 million from an equity offering [32] - R&D expenses for Q4 2024 were $188.1 million, up from $148.5 million in Q4 2023, primarily due to clinical trial-related expenses [33] - G&A expenses for Q4 2024 were $28.2 million, down from $32.2 million in Q4 2023, with the decrease attributed to prior year wind-down costs [34] - The net loss for Q4 2024 was $194.6 million, compared to $161.5 million in Q4 2023, driven by higher operating expenses [35] - Full year 2025 GAAP net loss is projected to be between $840 million and $900 million, reflecting increased expenses for clinical development programs [36][37] Business Line Data and Key Metrics Changes - The company has made substantial progress in advancing its RAS(ON) inhibitor pipeline, with promising clinical data reported for daraxonrasib and zoldonrasib in pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer [11][12] - Initial clinical proof-of-concept was reported for a RAS inhibitor doublet combining elironrasib with daraxonrasib, indicating potential for innovative treatment strategies [12] - The company is actively pursuing pivotal trials for daraxonrasib in both previously treated metastatic PDAC and non-small cell lung cancer [19][20] Market Data and Key Metrics Changes - The company is focusing on the PDAC market, which represents a significant opportunity, particularly in the adjuvant setting where approximately 15% of newly diagnosed cases are resectable [21][50] - The company is also exploring the potential for early detection initiatives to expand the proportion of resectable cases in the future [50][54] Company Strategy and Development Direction - The company aims to revolutionize treatment for patients with RAS-addicted cancers through a strategic roadmap focused on discovery, development, and delivery of innovative therapies [7][9] - The company is committed to building strong commercialization capabilities in preparation for the potential launch of daraxonrasib, pending regulatory approval [9][29] - The company is exploring partnerships to enhance its capabilities and ensure global access to its therapies [30] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the advancement of clinical development programs and the potential impact of their RAS(ON) inhibitors on patient outcomes [16][39] - The company anticipates 2025 to be a pivotal year for advancing its strategy and maximizing the impact of its therapies for patients with RAS-addicted cancers [16][39] Other Important Information - The company has established collaborations to explore combination therapies and expand treatment strategies for RAS-addicted cancers [14] - The company is focused on retaining control of U.S. commercial rights as a key element of its strategy [30] Q&A Session Summary Question: Can you walk us through the decision to move forward with the 2 Phase III studies in the earlier line PDAC? - Management expressed strong conviction based on existing data that pursuing the entire PDAC space across all lines of therapy is appropriate [43][45] Question: How does the frequency of RAS mutations differ in the adjuvant setting versus advanced disease? - Management indicated that almost all pancreatic cancer patients have a RAS driver, suggesting no significant difference in mutation representation [47] Question: Has the proportion of resectable PDAC cases changed over time? - Management does not expect the number to change in the short term due to the lack of screening methods for pancreatic cancer [54] Question: What are the plans for the pivotal study in the adjuvant setting? - Management is committed to defining the largest patient population possible for daraxonrasib and aims to pursue a broad approach [66][67] Question: How does the company balance moving quickly versus avoiding redundant trials? - Management emphasized the urgency to serve patients and the need to move swiftly while using data to prioritize development [70][72] Question: What are the latest thoughts on incorporating zoldonrasib into the pancreatic cancer registration strategy? - Management indicated that zoldonrasib may have a separate registration path and is evaluating its combination with daraxonrasib [82] Question: Will there be updates on colorectal cancer data this year? - Management stated that there are no specific updates on colorectal cancer data disclosures at this time [96] Question: What are the plans for the first-line lung opportunity? - Management confirmed interest in exploring earlier lines of therapy for lung cancer and will share strategies as they develop [125][129]

Pipeline Development - The company is developing a pipeline of RAS(ON) inhibitors, including daraxonrasib (RMC-6236), elironrasib (RMC-6291), and zoldonrasib (RMC-9805), which are in clinical development stages[25][36][40]. - The ongoing RASolute 302 study is a Phase 3 trial for daraxonrasib in metastatic pancreatic ductal adenocarcinoma (PDAC), with expected enrollment completion in 2025 and clinical readout in 2026[27]. - The RASolve 301 study is a Phase 3 trial comparing daraxonrasib to docetaxel in RAS-mutated non-small cell lung cancer (NSCLC), also utilizing a nested trial design[28]. - The company plans to initiate pivotal combination studies incorporating zoldonrasib or elironrasib in 2026, with clinical data expected in 2025[43]. - RMC-5127, a G12V-selective inhibitor, is expected to advance to a clinic-ready stage in 2025, with a first-in-human trial planned for 2026[44]. - The company is also developing RAS companion inhibitors, including RMC-4630, RMC-5552, and RMC-5845, to target pathways sustaining RAS-addicted cancers[47][48]. - The overall strategy aims to revolutionize treatment for RAS-addicted cancers through innovative, targeted medicines, addressing a significant unmet need in oncology[49]. - The company’s RAS(ON) inhibitors are the first in clinical development targeting the activated form of oncogenic RAS proteins, potentially offering deeper antitumor activity compared to first-generation RAS inhibitors[50]. - The company’s pipeline includes daraxonrasib, elironrasib, and zoldonrasib, with various combinations being explored in clinical trials[54]. Clinical Data and Efficacy - Preliminary data from the RMC-6236-001 study indicated that daraxonrasib was well tolerated and showed encouraging antitumor activity in previously treated RAS-mutant PDAC patients[30]. - In the RMC-6236-001 study, the median progression-free survival (PFS) for patients with KRAS G12X mutations treated with daraxonrasib was 8.5 months (95% CI: 5.3 – 11.7 months)[57]. - The overall response rate (ORR) for patients with KRAS G12X mutations was 36% and 27% for those with G12X, G13X, or Q61X mutations[63]. - The median overall survival (OS) for patients with KRAS G12X mutations was not estimable, while the OS rate at 6 months was 100% for these patients[73]. - The median overall survival (OS) for NSCLC efficacy-evaluable patients was reported at 17.7 months (95% CI: 13.7, NE) as of the data cutoff date of September 30, 2024[95]. - The objective response rate (ORR) for NSCLC efficacy-evaluable patients was 38% (15 of 40 patients) who received the first dose of daraxonrasib at least 14 weeks prior to the data cutoff date[83]. - The median progression-free survival (PFS) for NSCLC efficacy-evaluable patients was 9.8 months (95% CI: 6.0, 12.3) as of the data cutoff date of September 30, 2024[91]. - The objective response rate (ORR) for patients with colorectal cancer (CRC) previously treated with a KRAS(OFF) G12C inhibitor was 25%, with a disease control rate (DCR) of 92%[109]. - For patients treated with 1,200 mg of zoldonrasib daily, the ORR was 30% and the DCR was 80%[129]. Safety and Tolerability - The most common treatment-related adverse events (TRAEs) in patients treated with daraxonrasib at 300 mg daily included rash (91%) and diarrhea (53%)[61]. - A total of 124 patients with NSCLC were evaluated for safety and tolerability, with 98% experiencing any treatment-related adverse events (TRAEs)[80]. - Among patients treated with daraxonrasib at doses ranging from 120 mg to 220 mg daily, the median treatment duration was 5.5 months, and the median cumulative duration of dose interruption was 8.5 days[79]. - The combination of daraxonrasib with pembrolizumab was generally well tolerated, with TRAEs of Grade 1 AST elevation reported in 10% of patients[102]. - In the RMC-6291-101 study, the combination of daraxonrasib with elironrasib was generally well tolerated, with one Grade 4 TRAE (hypokalemia) observed[105]. - The overall treatment-related adverse events (TRAEs) for the combination of daraxonrasib and elironrasib showed that 77% of patients experienced any grade of TRAEs, with 19% at Grade 1, 35% at Grade 2, 22% at Grade 3, and 1% at Grade 4[106]. - Elironrasib demonstrated a mean dose intensity of 95% and was well tolerated across dose levels, with preliminary evidence of clinical activity in patients with KRAS G12C non-small cell lung cancer (NSCLC)[116][117]. - In the RMC-9805-001 study, the most common TRAEs for zoldonrasib were gastrointestinal-related, with 30% of patients experiencing nausea and 16% experiencing diarrhea[125]. - The combination of elironrasib and pembrolizumab was generally well tolerated, with only 7% of patients experiencing Grade 1 elevations in AST and ALT[119]. - TRAEs leading to dose reduction occurred in approximately 3% of patients treated with zoldonrasib, with no TRAEs leading to treatment discontinuation[123]. - The maximum severity of TRAEs for zoldonrasib included 27% experiencing nausea and 20% experiencing diarrhea[125]. - The treatment-related adverse events leading to dose modifications occurred in 52% of patients treated with daraxonrasib[80]. Regulatory and Commercialization Strategy - The company plans to retain significant development and commercialization rights for its product candidates and is building necessary capabilities in the U.S. for a potential commercial launch[134]. - The company relies on contract manufacturing organizations (CMOs) for drug substance and product, with all manufacturing currently outsourced to established third-party manufacturers[135]. - The company faces competition from major pharmaceutical and biotechnology companies, as well as academic institutions and research organizations, in the rapidly evolving oncology sector[138]. - The company’s patent portfolio includes rights to several patent families related to RAS tri-complex inhibitors, with expected expiration dates ranging from 2031 to 2044[149]. - The company is subject to extensive regulation by the FDA and other authorities, requiring substantial time and financial resources for compliance and approval processes[152]. - The FDA approval process involves multiple stages, including preclinical studies, IND submission, and NDA preparation, which must be completed before marketing a new drug[154]. - The company’s competitors may have greater financial resources and expertise in R&D, manufacturing, and regulatory approvals, posing challenges for market entry[144]. - The company’s commercialization plans may be influenced by clinical data, patient population sizes, and manufacturing needs[134]. - The company seeks to protect its trade secrets and proprietary information through confidentiality agreements and security measures, although risks remain regarding potential breaches[147]. - The company intends to pursue orphan drug designation for certain oncology indications, aiming for orphan drug exclusivity if approved[179]. - The FDA may grant orphan designation to drugs intended to treat rare diseases affecting fewer than 200,000 individuals in the U.S.[180]. - Orphan drug exclusivity prevents the FDA from approving other applications for the same drug for the same disease for seven years, with certain exceptions[181]. - The company plans to seek fast track designation for product candidates intended to treat serious or life-threatening conditions, allowing for more frequent interactions with the FDA[173]. - Products with breakthrough therapy designation may receive expedited development and review, including intensive FDA interaction from early phases[175]. - The FDA's priority review for eligible NDAs aims for action within six months, compared to twelve months under standard review[176]. - Accelerated approval may be granted if a product shows effects on a surrogate endpoint likely to predict clinical benefit, with confirmatory studies required post-approval[177]. - The company must submit a Pediatric Study Plan (iPSP) for certain NDAs to assess safety and efficacy in pediatric populations[183]. - The FDA requires that all relevant data, including negative results, be included in NDA submissions to establish safety and effectiveness[164]. - The FDA conducts inspections of manufacturing facilities and clinical trial sites before approving an NDA to ensure compliance with regulatory standards[168]. - Pediatric market exclusivity in the U.S. can add six months to existing exclusivity periods and patent terms[184]. - After NDA approval, products are subject to ongoing FDA regulation, including drug listing, recordkeeping, and adverse event reporting[185]. - In the EU, new products receive eight years of data exclusivity and an additional two years of market exclusivity upon receiving marketing authorization[199]. - The overall market exclusivity period in the EU can be extended to a maximum of 11 years if new therapeutic indications are authorized within the first eight years[200]. - Orphan medicinal products in the EU are entitled to ten years of market exclusivity for the approved indication[202]. - The EU Clinical Trials Regulation (CTR) became applicable on January 31, 2022, harmonizing clinical trial assessment across member states[194]. - The centralized procedure for marketing authorization in the EU is compulsory for certain medicinal products, ensuring a single decision across member states[199]. - The Medicines and Healthcare products Regulatory Agency (MHRA) has been the UK's standalone medicines regulator since January 1, 2021[206]. - The approval process for medicinal products varies by country, potentially impacting the regulatory process in others if delays occur[190]. - Non-clinical studies must comply with GLP principles as per EU regulations, ensuring quality and safety of new substances[192]. - The MHRA has introduced a 150-day assessment and a rolling review procedure to prioritize access to new medicines in the UK[207]. - The UK government proposed the Medicines for Human Use (Clinical Trials) Amendment Regulations 2024 to create a more flexible regime for clinical trials, expected to be adopted in early 2026[208]. Market and Reimbursement Challenges - The ACA increased the minimum Medicaid rebates for brand name drugs from 15.1% to 23.1%[220]. - The U.S. federal Anti-Kickback Statute prohibits remuneration to induce purchases of items reimbursable under federal healthcare programs[210]. - Third-party payors are increasingly reducing reimbursements for pharmaceutical products, impacting sales and physician usage[218]. - The UK has implemented an international recognition procedure for targeted assessments of marketing authorization applications based on approvals from trusted partner agencies[207]. - The coverage determination process for new products can be time-consuming and requires scientific support for each payor separately[217]. - The federal Physician Payments Sunshine Act mandates annual reporting of payments made to physicians by applicable manufacturers[213]. - Legislative changes in healthcare are expected to continue affecting financing and reimbursement structures in the U.S.[220]. - International markets have varying reimbursement systems, with many countries instituting price ceilings on pharmaceutical products[219].

Financial Performance - The company reported a net loss of $194.6 million for Q4 2024, compared to a net loss of $161.5 million for Q4 2023[31]. - Total revenue for the year ended December 31, 2024, was zero, down from $11.6 million in 2023, due to the termination of a collaboration agreement with Sanofi[32]. - The net loss for the year ended December 31, 2024, was $600,093,000, compared to a net loss of $436,367,000 in 2023, representing a 37.5% increase in losses[42]. - The company expects a full-year 2025 GAAP net loss between $840 million and $900 million, including estimated non-cash stock-based compensation of $115 million to $130 million[36]. Revenue and Assets - Total revenue for the year ended December 31, 2024, was $11,580,000, compared to $742,000 for the same period in 2023, indicating a significant increase in revenue[42]. - Cash, cash equivalents, and marketable securities were $2.3 billion as of December 31, 2024, up from $1.9 billion a year earlier[28]. - Total assets increased to $2,558,301,000 as of December 31, 2024, compared to $2,061,705,000 in 2023, marking a 24% growth[44]. - Cash, cash equivalents, and marketable securities as of December 31, 2024, totaled $2,289,299,000, an increase from $1,852,955,000 in 2023[44]. Research and Development - Research and development expenses for the year ended December 31, 2024, were $592.2 million, an increase from $423.1 million in 2023, primarily due to clinical trial expenses and increased personnel costs[33]. - The company is advancing its R&D pipeline with multiple RAS(ON) inhibitors currently in clinical development, including daraxonrasib, elironrasib, and zoldonrasib[38]. - The company plans to continue the development of elironrasib in combination with daraxonrasib for a broad range of G12C-mutant tumor types[39]. - The company aims to advance RMC-5127, a RAS(ON) G12V-selective inhibitor, to a clinic-ready stage in 2025[25]. - The company anticipates that RMC-5127, a RAS(ON) G12V-selective inhibitor, will be the next candidate to enter clinical development[38]. - The company is activating study sites for the Phase 3 RASolve 301 trial of daraxonrasib in NSCLC[22]. - The company anticipates completing enrollment in the RASolute 302 trial in 2025, with expected data readout in 2026[21]. - The company plans to initiate two pivotal trials for daraxonrasib in earlier lines of treatment for pancreatic cancer in the second half of 2025[23]. Liabilities and Shares - Total liabilities as of December 31, 2024, were $293,097,000, compared to $235,511,000 in 2023, indicating an increase in liabilities[44]. - The weighted-average common shares used to compute net loss per share increased to 173,758,250 in 2024 from 141,183,907 in 2023[42]. Financing Activities - The company completed a public equity offering in December 2024, raising $823 million in net proceeds to strengthen its financial position[27].