Summary of Revolution Medicines FY Conference Call Company Overview - **Company**: Revolution Medicines (NasdaqGS:RVMD) - **Focus**: Development of daraxonrasib for pancreatic cancer and other RAS-driven cancers Key Points Industry and Product Development - **Ongoing Trials**: The company is conducting pivotal studies for daraxonrasib, particularly focusing on pancreatic cancer with the RESOLUTE 302 trial nearing completion of enrollment [1][2] - **Patient Population**: The phase one/two trial patient population is similar to those in phase three trials, with slightly worse prognostic factors, suggesting a representative sample for the upcoming phase three study [2] Trial Mechanics and Endpoints - **Primary Goal**: The main goal of the RESOLUTE 302 trial is to demonstrate an overall survival (OS) benefit, which is prioritized by the FDA for pancreatic cancer [4] - **Statistical Modeling**: The trial is powered for OS, with a high likelihood of reaching significance for progression-free survival (PFS) in interim analyses [5] - **Hierarchical Testing Strategy**: The trial will first evaluate the G12 mutation subset (85% of pancreatic cancer cases) before analyzing broader RAS mutation groups [6] Regulatory Designations - **Breakthrough Therapy Designation**: Daraxonrasib has received breakthrough therapy designation and orphan drug designation, which may accelerate the regulatory review process [9] - **Priority Review Voucher**: The company has received a priority review voucher, potentially allowing for a streamlined review process post-NDA filing [10] Future Trials and Strategies - **First-Line Pancreatic Cancer**: Plans to initiate the RESOLUTE 303 study, a three-arm trial comparing standard chemotherapy, daraxonrasib monotherapy, and daraxonrasib plus chemotherapy [11][12] - **Efficacy Data**: Phase one/two data showed promising overall response rates (ORR) of approximately 47% for monotherapy and 55% for combination therapy with gemcitabine [13] Treatment Paradigm - **RAS-Driven Cancers**: The underlying biology of pancreatic cancer is RAS-driven, leading to the design of trials that leverage effective RAS inhibitors [14] - **Patient-Centric Approach**: The company emphasizes providing multiple treatment options to cater to diverse patient needs and preferences [17][18] Other Cancer Studies - **Non-Small Cell Lung Cancer**: The RESOLVE 301 study is enrolling patients with any RAS mutation, targeting a significant portion of non-small cell lung cancer cases [25][26] - **Combination Therapies**: Plans to initiate a registration study in first-line non-small cell lung cancer combining daraxonrasib with chemotherapy and pembrolizumab [27][31] New Developments - **Zoldonrasib**: A RAS G12D-selective ON inhibitor is being developed, with potential applications in combination with daraxonrasib and aggressive chemotherapies [39][41] - **Clinical Strategy**: The company is exploring various combination regimens to maximize treatment efficacy for patients with RAS mutations [42] Additional Insights - **Market Positioning**: The company aims to differentiate its products in a competitive landscape by combining therapies that enhance patient outcomes [31][35] - **Long-Term Vision**: Revolution Medicines is focused on addressing unmet needs in RAS-driven cancers, with ongoing evaluations of its pipeline and potential new therapies [35][36]

Summary of Revolution Medicines Conference Call - September 10, 2025 Company Overview - **Company**: Revolution Medicines (NasdaqGS: RVMD) - **Focus**: Development of innovative targeted medicines for RAS addicted cancers, particularly pancreatic cancer, lung cancer, and colorectal cancer [4][5][46]. Key Points Industry Context - **Pancreatic Cancer**: - Third leading cause of cancer death in the U.S. with over 56,000 new cases annually [6][7]. - Over 90% of pancreatic adenocarcinoma (PDAC) tumors harbor a RAS driver mutation [6]. - Current five-year survival rate is only 3% despite existing therapies [7]. - Standard treatment involves cytotoxic chemotherapy, which has significant limitations [8][12]. Clinical Development - **Investigational Drugs**: - **Doraxonerasib**: The most advanced investigational RasOn inhibitor targeting RAS mutations [5][13]. - **Combination Therapy**: Evaluating doraxonerasib in combination with standard chemotherapy (GMP) for first-line treatment of metastatic PDAC [14][39]. Clinical Trial Insights - **Current Trials**: - **RAASILUTE-303**: A planned Phase III trial comparing doraxonerasib monotherapy and its combination with GMP against standard chemotherapy [40][49]. - **RAASILUTE-302**: Ongoing trial for second-line PDAC, expected to complete enrollment in 2025 [48][49]. Efficacy and Safety Data - **Monotherapy Results**: - In second-line PDAC, doraxonerasib showed a median overall survival (OS) of 13.1 months for RAS G12X and 15.6 months for all RAS mutants [20]. - Objective response rate (ORR) of 35% in RAS G12X and 29% in broader RAS mutant populations [17][18]. - **First-Line Treatment**: - In first-line PDAC, doraxonerasib monotherapy achieved an ORR of 47% and a disease control rate (DCR) of 89% [26][39]. - Combination with GMP showed an ORR of 55% and a DCR of 90% [39]. Safety Profile - **Adverse Events**: - Grade 3 or higher treatment-related adverse events (TRAEs) were reported at approximately 60% for the combination therapy [36]. - Common TRAEs included diarrhea, anemia, and liver enzyme elevations, with manageable rates [36][37][22]. Strategic Insights - **Market Positioning**: - Revolution Medicines aims to establish doraxonerasib as a new global standard of care for PDAC, addressing significant unmet medical needs [46][49]. - The company is focused on educating physicians about RAS inhibition to enhance uptake in community settings [104][106]. Future Directions - **Trial Design**: - The upcoming trials will evaluate the efficacy of doraxonerasib both as monotherapy and in combination with GMP, with a focus on overall survival as the primary endpoint [40][42]. - The company plans to reserve combination studies with FOLFIRINOX for mutant selective inhibitors due to the higher toxicity profile of FOLFIRINOX compared to GMP [44][45]. Conclusion - Revolution Medicines is making significant strides in the development of targeted therapies for RAS addicted cancers, particularly pancreatic cancer, with promising clinical data supporting the efficacy and safety of doraxonerasib. The company is poised to change the treatment landscape for PDAC through innovative trial designs and strategic market positioning [46][49].