KRAS G12D

First clinical results for RMC-9805, a RAS(ON) G12D-selective inhibitor, demonstrate encouraging tolerability and antitumor activity in patients with PDAC Investor webcast to be held Friday, October 25 at 12:00 p.m. Eastern Time (ET) Oct. 25, 2024 -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, today announced preliminary safety and antitumor data for RMC-9805, its RAS(ON) G12D-selective inhibitor, in patients with previously treated pancreatic ductal adenocarcinoma (PDAC). These initial results were presented during the late-breaking oral session at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona on October 25, 2024. “We are pleased to report the first clinical data for RMC-9805, our novel, oral RAS(ON) G12D-selective covalent inhibitor, which demonstrate encouraging initial safety, tolerability and antitumor activity evidenced by tumor regressions,” said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. “While preliminary, these data bolster our belief that RMC-9805 has the potential to play a role in an emerging treatment paradigm for patients living with pancreatic cancer, both as monotherapy and in combinations. With today’s presentation, RMC-9805 becomes the third tri-complex compound from the Revolution Medicines pipeline to demonstrate clinical proof-of-concept, and it reaffirms our commitment to bringing novel RAS(ON) inhibitors to patients with RAS-addicted cancers.” The RMC-9805-001 Phase 1/1b study is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-9805 in patients with advanced solid tumors harboring a KRAS G12D mutation. As of the September 2, 2024 data cutoff date, 179 patients were treated with escalating doses of RMC-9805 (ranging from 150-1200 mg once daily (QD) and 300-600 mg twice daily (BID)). Study patients had received a median of two prior therapies (range 0-9) and all had previously been treated with standard of care. As of the data cutoff date, RMC-9805 demonstrated an encouraging safety profile and was generally well tolerated across dose levels. For patients receiving 1200 mg of RMC-9805 daily (n = 99), the most common treatment-related adverse events (TRAEs) occurring in greater than 10% of patients were GI-related toxicities (nausea, diarrhea and vomiting) and rash that were primarily Grade 1 in severity and typically of limited duration. One Grade 3 TRAE of ALT elevation was reported, and no Grade 4 or 5 TRAEs were observed. Four patients (4%) experienced TRAEs that led to dose reduction and no patients discontinued treatment as a result of TRAEs. No dose limiting toxicities were observed and the maximum tolerated dose was not reached. Preliminary efficacy was assessed in PDAC patients. At a candidate recommended Phase 2 dose of 1200 mg daily (20 patients at 1200 mg QD and 20 patients at 600 mg BID), patients who received a first dose of RMC-9805 at least 14 weeks prior to the data cutoff date achieved a 30% (n = 12) objective response rate (confirmed or pending), with a disease control rate of 80% (n = 32). “Pancreatic cancer is the most RAS-addicted of all major cancers and the G12D variant is the most common RAS mutation in pancreatic cancer. No approved targeted therapies are available for these patients, making this an area of significant unmet need,” said David Hong, M.D. of MD Anderson Cancer Center, principal investigator and lead author for the RMC-9805-001 presentation. “This is a challenging disease, but we observed a promising level of antitumor activity at generally tolerable doses in this Phase 1 study." Revolution Medicines will host an investor webcast on Friday, October 25, 2024 at 12:00 p.m. Eastern Time / 6:00 p.m. Central European Standard Time to discuss the RMC-6236 and RMC-9805 monotherapy data in PDAC presented at the EORTC-NCI-AACR (“Triple”) meeting. To participate in the live webcast, participants may register in advance here. A live webcast of the call will be available on the Investors section of Revolution Medicines’ website at https://ir.revmed.com/events-and-presentations. Following the live webcast, a replay will be available on the company’s website for at least 14 days. Pancreatic cancer is one of the most lethal malignancies, characterized by its typically late-stage diagnosis, resistance to standard chemotherapy, and high mortality rate. In the U.S., recent estimates indicate that in 2024, approximately 60,000 people will be diagnosed with pancreatic cancer, and about 50,000 people will die from this aggressive disease. The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) and its variants, accounts for approximately 92% of all pancreatic cancer cases. Due to the lack of early symptoms and detection methods, approximately 80% of patients are diagnosed with PDAC at an advanced or metastatic stage. It is the most RAS-addicted of all major cancers, and more than 90% of patients have tumors that harbor RAS mutations. Metastatic PDAC remains one of the most common causes of cancer-related deaths in the U.S., with a five-year survival rate of approximately 3%. Revolution Medicines is a clinical-stage oncology company developing novel targeted therapies for RAS-addicted cancers. The company’s R&D pipeline comprises RAS(ON) inhibitors designed to suppress diverse oncogenic variants of RAS proteins. The company’s RAS(ON) inhibitors RMC-6236, a RAS(ON) multi-selective inhibitor, RMC-6291, a RAS(ON) G12C-selective inhibitor, and RMC-9805, a RAS(ON) G12D-selective inhibitor, are currently in clinical development. Additional development opportunities in the company’s pipeline focus on RAS(ON) mutant-selective inhibitors, including RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C), in addition to RAS companion inhibitors RMC-4630 and RMC-5552. The content above comes from the network. if any infringement, please contact us to modify.

In an interview Friday, Revolution Medicines CEO Mark Goldsmith, who says he prefers to understate rather than exaggerate, floated a lofty goal: cure pancreatic cancer — or get close. “That’s our aim, and we don’t think that’s right around the corner, but we’re off to a very good start,” he told Endpoints News. It’s an ambitious vision, given that the five-year survival rate for pancreatic cancer is 13%, according to the American Cancer Society. Revolution is developing a suite of RAS inhibitors, and the company’s shares have more than doubled in the past 12 months because of excitement over their potential to treat solid tumors, particularly pancreatic cancer. The Redwood City, CA-based company reported results this week from early-stage trials of two of its experimental treatments in pancreatic cancer, where more than 90% of cases harbor RAS mutations. In a late-breaking presentation Friday, Revolution Medicines said that 12 of 40 previously treated pancreatic cancer patients who received a 1,200 mg daily dose of its KRAS G12D inhibitor, called RMC-9805, saw their tumors shrink at least 30%. (The company included confirmed responses as well as unconfirmed responses still on treatment.) That’s good for a 30% response rate, and the company said it would use a 1,200 mg dose in a Phase 2 trial for pancreatic cancer. The data, presented at what’s known as the Triple Meeting, were the first clinical results from RMC-9805. They’re from a broader Phase 1/1b study looking at the drug in patients with solid tumors harboring KRAS G12D mutations who had received a median of two previous treatments. The company, which informally goes by RevMed, said that 179 patients have been dosed with the drug. At the 1,200 mg daily dose, with which 99 patients have been treated, the most common side effects were nausea, diarrhea and vomiting and rash. It described those adverse events as low-grade and limited, though there was one grade 3 case of elevated liver enzymes. The company also has a multi-RAS inhibitor that can tackle a range of mutations in a Phase 3 trial. Known as RMC-6236, RevMed announced it dosed a first pancreatic cancer patient in that trial on Monday. The study will include a core population of pancreatic cancer patients with RAS G12X mutations, as well as other mutations. RevMed shared updated results from 127 patients in an earlier Phase 1/1b study of RMC-6236. In that study, overall survival rates were 14.5 months in both previously treated pancreatic cancer patients with any RAS mutation, as well as with those with a mutation at codon 12 (which is referred to as KRAS G12X). While the study didn’t have a control arm, Jefferies analyst Kelly Shi said the benchmark for survival in those patients with chemotherapy is about six to seven months. Grade 3 or greater side effects related to the drug were rash (which impacted 8% of patients), stomatitis and diarrhea, and 35% of patients required dose modifications because of side effects, but none dropped out because of that. Goldsmith said the two experimental compounds have “overlapping but also distinct profiles, and two overlapping but also distinct ranges of target.”

~33% ORR by RECIST 1.1: 1 CR + 8 PRs out of 27 evaluable heavily pre-treated (median 2-3 prior lines, ranging from 1-7) MTAP-deletion UC and NSCLC patients 9 of 9 responses have confirmed by RECIST 1.1 (5 confirmed responses out of 18 evaluable patients reported on July 8, 2024, IDE397 webcast) MTAP-deletion UC: 40% (4 of 10) confirmed ORR and 3 pts on treatment >250 days MTAP-deletion SqNSCLC: ~38% (3 of 8) confirmed ORR and 4 pts on treatment >200 days Multiple PRs with genetic co-alterations, including MTAP-deletion and KRAS G12D mutation in NSCLC, and MTAP-deletion and FGFR-TACC3 fusion in UC Median DOT not yet reached and >6.2 months, and median TTR ~2.7 months ~81% (17 of 21) ctDNA MRR, and high DCR of 93% (25 of 27 with SD or better) AE Profile: No drug-related SAEs or discontinuations at 30 mg once-a-day expansion dose Targeting expansion of Phase 1/2 study of IDE397 in combination with Trodelvy® in MTAP-deletion UC in Q4 2024; patient case study of PR by RECIST 1.1 and rapid >95% ctDNA reduction of combination will be presented at ENA 2024 IDE397 demonstrated deep and durable regressions in combination with PRMT5 inhibitors BMS-986504 and AMG 193 in preclinical models SOUTH SAN FRANCISCO, Calif., Oct. 25, 2024 /PRNewswire/ -- IDEAYA Biosciences, Inc. (Nasdaq: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, announces Phase 1 expansion data for IDE397 in methylthioadenosine phosphorylase (MTAP)-deletion urothelial cancer (UC) and non-small cell lung cancer (NSCLC) patients as a late breaker abstract (LBA) oral presentation at the 36th edition of the EORTC-NCI-AACR Symposium (ENA 2024) in Barcelona, Spain. In addition, IDEAYA had additional poster presentations at ENA 2024 highlighting preclinical data for the MAT2A and PARG programs. IDE397 is a potent and selective potential first-in-class methionine adenosyltransferase 2 alpha (MAT2A) inhibitor in Phase 2 clinical trials for the treatment of MTAP-deletion solid tumors. "We are excited by the clinical efficacy and safety profile observed with the potential first-in-class MAT2A inhibitor IDE397 at the 30mg once-a-day RP2D, including multiple confirmed responses observed as a monotherapy agent in non-small cell lung cancer and urothelial cancer patients with MTAP-deletion. In addition, at the 30mg once-a-day expansion dose, we observed a manageable safety profile with no drug-related serious adverse events or discontinuations. These data support potential combination development," said Dr. Benjamin Herzberg, M.D., Assistant Professor of Medicine, Columbia University. "The clinical data update from the late breaker oral presentation at ENA 2024 provides further clinical proof-of-concept for IDE397 in the setting of MTAP-deletion urothelial cancer and non-small cell lung cancer to deliver a high disease control rate and confirmed RECIST responses, with an overall manageable adverse event profile," said Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences. "IDE397 is rapidly advancing as a monotherapy agent in MTAP-deletion urothelial cancer and non-small cell lung cancer. Next, we are well positioned to advance our broad and potential first-in-class IDE397 rational combination strategy, including the targeted expansion in the fourth quarter with Trodelvy® in urothelial cancer, the ongoing combination with AMG 193 with targeted expansion in NSCLC, combinations with IDEAYA's internal MTAP-deletion pipeline that includes a targeted development candidate by year-end, among others," said Yujiro S. Hata, President and Chief Executive Officer, IDEAYA Biosciences. There are currently no FDA-approved therapies for patients with MTAP-deletion solid tumors, highlighting the unmet medical need. The priority MTAP-deletion solid tumor types for the IDE397 Phase 1/2 monotherapy program are UC and NSCLC. MTAP-deletion has been reported at over 15% in NSCLC and over 25% in UC, based on The Cancer Genome Atlas (TCGA) database. We estimate that the annual incidence of MTAP-deletion in the U.S. in UC and NSCLC is approximately 48,000 patients, based on the 2024 Surveillance, Epidemiology, and End Results (SEER) database. In addition, there are several potential expansion MTAP-deletion solid tumor types that are also being considered for monotherapy and combination development, including pancreatic, gastric, esophageal, and head and neck cancer, among others. Based on the TCGA database, MTAP-deletion in pancreatic cancer has been reported in more than 20% of patients, representing a U.S. annual incidence of approximately 14,000 patients. ENA 2024 Clinical Data Update – IDE397 Phase 2 Expansion in Subjects with MTAP-Deletion UC and NSCLC The company observed encouraging clinical activity at the 30 mg once-a-day (QD) Recommended Phase 2 Dose (RP2D) in its Phase 1 clinical trial evaluating its potential first-in-class MAT2A inhibitor IDE397 in heavily pre-treated MTAP-deletion UC and NSCLC patients. The patients evaluated had a median of two (2) to three (3) prior lines-of-therapy, ranging from one (1) to seven (7). The reported Phase 1 clinical expansion data are based on twenty-seven (27) evaluable MTAP-deletion patients, including ten (10) UC, nine (9) adenocarcinoma NSCLC, and eight (8) squamous (sq) NSCLC patients at the expansion dose of 30 mg QD of IDE397. The clinical efficacy and tolerability data are preliminary and based on investigator review from an unlocked database as of the data analysis cutoff date of August 22, 2024. The clinical data update in the twenty-seven (27) evaluable patients by RECIST 1.1 include: ~33% Overall Response Rate (ORR). One (1) complete response (CR) and eight (8) partial responses (PRs) by RECIST 1.1 evaluation out of twenty-seven (27) evaluable patients. Nine (9) of nine (9) responses have been confirmed by RECIST 1.1, including four (4) UC patients, of which one was a CR, three (3) squamous NSCLC patients, and two (2) adenocarcinoma NSCLC patients. Two patients confirmed after the data cutoff date. In the earlier reported July 8, 2024, IDE397 webcast program update, five (5) confirmed responses were reported out of eighteen (18) evaluable patients. There were zero (0) non-evaluable patients reported as of the data analysis. Confirmed ORR% by RECIST 1.1 by Solid Tumor Type: MTAP-deletion UC = 40% (4 of 10) confirmed ORR%; MTAP-deletion squamous NSCLC = ~38% (3 of 8) confirmed ORR%; MTAP-deletion adenocarcinoma NSCLC = ~22% (2 of 9) confirmed ORR% Multiple confirmed partial responses by RECIST 1.1 harbor genetic co-alterations, including MTAP-deletion and KRAS G12D mutation in NSCLC, and MTAP-deletion and FGFR-TACC3 fusion in UC ~93% Disease Control Rate (DCR). One (1) CR, eight (8) PRs, and sixteen (16) stable disease (SD) by RECIST 1.1 evaluation out of twenty-seven (27) evaluable patients Preliminary durability assessment: Fifteen (15) of twenty-seven (27) patients still on treatment. Seven (7) of nine (9) RECIST 1.1 responses remain on treatment. Median duration of treatment (DOT) has not been reached and is greater than 6.2 months and median time to response (TTR) is ~2.7 months. The median duration of response and median progression free survival data is still immature. Three (3) UC patients on treatment greater than 250 days, four (4) squamous NSCLC patients on treatment greater than 200 days, and three (3) adenocarcinoma NSCLC patients on treatment greater than 200 days ~81% ctDNA Molecular Response Rate (MRR). Seventeen (17) of twenty (21) patients with 50% or greater ctDNA reduction, and ~33% (7 of 21) with deep 90% or greater ctDNA reduction. All MRs (17 of 17) were rapid occurring at the first ctDNA sample analysis. There were several quality control failures of patient samples that led to unavailability for MR analysis Favorable adverse event (AE) profile. Approximately 18% grade 3 or higher drug-related AEs and no drug-related serious adverse events (SAEs) observed at the IDE397 30mg once-a-day expansion dose. No drug-related AEs leading to discontinuations were observed. We anticipate that the favorable AE profile and dosing convenience of a 30 mg once-a-day tablet has the potential to enable long-term dosing and combination development, including with MTA-cooperative PRMT5 inhibitors and topoisomerase payload antibody drug conjugates (ADCs) ENA 2024 IDE397 and Trodelvy Clinical Combination Case Study in MTAP-deletion UC IDEAYA reports the first preliminary clinical case study of the IDE397 and Trodelvy combination in MTAP-deletion UC, including a PR by RECIST 1.1 in a patient case report with a genetic co-alteration of MTAP-deletion and a FGFR3-TACC3 fusion, and rapid and deep first-evaluation molecular responses with ctDNA reduction of greater than 95% observed that will be presented at ENA 2024. IDEAYA is targeting to initiate the IDE397 and Trodelvy Phase 1/2 combination expansion in MTAP-deletion UC in Q4 2024. IDEAYA has activated over 35 clinical trial sites globally in the U.S., Canada, Europe, and Asia Pacific to enable potential rapid enrollment for the IDE397 Phase 2 monotherapy expansion in MTAP-deletion lung and bladder cancer in its ongoing trial (NCT04794699). There is also an ongoing Amgen-sponsored Phase 1/2 trial of the IDE397 and AMG 193 combination in MTAP-Deletion NSCLC (NCT05975073). IDEAYA published at ENA 2024 preclinical combination efficacy data and the combination mechanistic rationale for IDE397 with clinical stage PRMT5 inhibitors, including BMS-986504 and AMG 193. Next, IDEAYA is enrolling a Phase 1 clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of IDE397 in combination with Trodelvy in MTAP-deletion UC patients (NCT04794699). Pursuant to the clinical study collaboration and supply agreement, IDEAYA and Gilead retain the commercial rights to their respective compounds, including with respect to use as a monotherapy or combination agent. IDEAYA is the study sponsor and Gilead will provide the supply of Trodelvy to IDEAYA. IDE397 monotherapy or in combination with Trodelvy has not been approved by any regulatory agency and the efficacy and safety of this combination has not been established. 36th edition of the EORTC-NCI-AACR Symposium (ENA 2024) in Barcelona, Spain Details of the late breaker oral presentation today are as follows: Presenter: Dr. Benjamin Herzberg, MD, Assistant Professor, Columbia University Title: Phase 1 expansion results of IDE397, a first-in-class, oral, MAT2A inhibitor (MAT2Ai) in MTAP deleted(del) non-small cell lung cancer (NSCLC) and urothelial cancer (UC) Abstract #: 501 LBA Session: Plenary Session 7, Late Breaking Abstracts and Proffered Papers: Novel discoveries in drug development Date and Time: Friday, October 25, 2024 at 3:54pm CEST In addition, IDEAYA had additional poster presentations at ENA 2024 highlighting preclinical data for the MAT2A and PARG programs. In the ENA 2024 concomitant publication, IDE397 demonstrated deep and durable regressions in combination with clinical stage PRMT5 inhibitors BMS-986504 and AMG 193 in multiple MTAP-deletion preclinical models. Poster presentation details are below: Author: Garbett, D. et al. Title: The mechanistic basis of both deep and durable antitumor activity by combinatorial inhibition of MAT2A and PRMT5 in MTAP-deleted tumors Poster Number: PB204 Session Title: Combination Therapies Date and Time: Thursday, October 24, 2024, 9:00am - 5:30pm CEST, Exhibition Hall Author: Munoz, D. et al. Title: IDE161, a potential first-in-class clinical candidate PARG inhibitor, selectively targets solid tumors with replication stress and DNA repair vulnerabilities Poster Number: PB337 Session Title: DNA Repair Modulation (e.g. PARP, CHK, ATR, ATM) Date and Time: Friday, October 25, 2024, 9:00am - 3:00pm CEST, Exhibition Hall The IDE397 late breaker oral presentation at ENA 2024, as well as an updated corporate presentation, which will incorporate the IDE397 Phase 1 clinical data update from ENA 2024 at the 30mg RP2D in UC and NSCLC patients, will be available on the company's website, at its Investor Relations portal at approximately 10:15 am ET on Friday, October 25, 2024, after the presentation has concluded. About IDEAYA Biosciences IDEAYA is a precision medicine oncology company committed to the discovery and development of targeted therapeutics for patient populations selected using molecular diagnostics. IDEAYA's approach integrates capabilities in identifying and validating translational biomarkers with drug discovery to select patient populations most likely to benefit from its targeted therapies. IDEAYA is applying its research and drug discovery capabilities to synthetic lethality – which represents an emerging class of precision medicine targets. Forward-Looking Statements This press release contains forward-looking statements, including, but not limited to, statements related to (i) expectations regarding the clinical activity profile and potential advantages of IDEAYA's clinical programs, (ii) the timing of enrollment for the IDE397 Phase 2 monotherapy expansion in MTAP-deletion lung and bladder cancer, (iii) the timing of initiation of the IDE397 and Trodelvy Phase 1/2 combination expansion in MTAP-deletion UC and (iv) the timing and content of future presentations. Such forward-looking statements involve substantial risks and uncertainties that could cause IDEAYA's preclinical and clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the drug development process, including IDEAYA's programs' early stage of development, the process of designing and conducting preclinical and clinical trials, the regulatory approval processes, the timing of regulatory filings, the challenges associated with manufacturing drug products, IDEAYA's ability to successfully establish, protect and defend its intellectual property, and other matters that could affect the sufficiency of existing cash to fund operations. IDEAYA undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of IDEAYA in general, see IDEAYA's Annual Report on Form 10-K dated February 20, 2024 and any current and periodic reports filed with the U.S. Securities and Exchange Commission. Investor and Media Contact IDEAYA Biosciences Andres Ruiz Briseno SVP, Head of Finance and Investor Relations [email protected] SOURCE IDEAYA Biosciences, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED