elironrasib (RMC-6291) / Revolution Medicines - LARVOL DELTA

A cellular platform for systematic comparison of RAS inhibitors using PRISM multiplexed screening (AACR 2025) - "For example, all 10 KRAS G12C inhibitors or degraders tested showed significant selectivity for cell lines harboring the G12C mutation, with RMC-6291, adagrasib, divarasib, and sotorasib showing the greatest enrichment. Finally, we also explored orthogonal assay formats, including ultra-low adherent and extended-duration (10-day) screening, to investigate kinetic and environmental factors associated with inhibitor response. Collectively, our work provides a comprehensive profile of the cellular effects of current RAS-targeting therapeutics, and provides a foundation for the characterization of newly-emerging agents."

Oncology • KRAS

Combination of RAS(ON) mutant-selective and multi-selective inhibitors sensitizes immune-refractory, RAS-driven preclinical models to immunotherapy (AACR 2025) - "Here we evaluated if the RAS(ON) doublet combination of RMC-6291 or RMC-9805, a RAS(ON) G12C-selective inhibitor and a RAS(ON) G12D-selective inhibitor, respectively, with the RAS(ON) multi-selective inhibitor RMC-6236 can sensitize traditionally hard to treat, immune-refractory preclinical models to anti-PD-1. Collectively, these preclinical findings suggest that the RAS(ON) doublet combination of RAS(ON) mutant-selective and multi-selective inhibitors can reverse the immune-evasion mechanisms governed by oncogenic RAS and sensitize immune-refractory tumors to ICB to induce durable CRs. These preclinical data support the clinical evaluation of the RAS(ON) doublets in combination with ICB in patients with RAS driven cancers."

IO biomarker • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Mechanisms of resistance to the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) in RAS mutant PDAC and potential resolution with RAS(ON) combination therapies (AACR 2025) - "Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is driven by oncogenic RAS mutations in >90% of cases. We demonstrate that the combination of daraxonrasib with a mutant-selective RAS(ON) inhibitor (either the RAS(ON) G12C mutant selective inhibitor elironrasib (RMC-6291), or the RAS(ON) G12D mutant selective inhibitor zoldonrasib (RMC-9805)) drove combinatorial benefit and forestalled monotherapy resistance in a series of preclinical models. The RAS(ON) inhibitor doublets of elironrasib or zoldonrasib with daraxonrasib are currently being evaluated in patients with tumors harboring RAS G12C and RAS G12D, respectively."

Combination therapy • Late-breaking abstract • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • MYC

Evaluation of combination strategies with RAS-targeted inhibitors in multi-cell type spheroids (AACR 2025) - "As single agents, the KRAS-G12C inhibitors RMC-6291 and divarasib, along with the KRAS-G12D inhibitor MRTX-1133, demonstrated selective activity against the mct tumor spheroids harboring the targeted variants. In contrast, the pan-RAS(ON) inhibitor RMC-6236 demonstrated activity against the mct tumor spheroids harboring a range of KRAS variants or wild-type KRAS...In tumor models harboring different KRAS variants, the pan-RAS(ON) inhibitor showed increased cytotoxicity with the MEK inhibitor cobimetinib, as well as PI3K-AKT-mTOR pathway inhibitors, such as inavolisib (PI3Kα), ipatasertib (AKT), and sapanisertib (mTORC1/2). When the same agents were combined with variant-specific KRAS inhibitors similar effects were observed in mct tumor spheroids carrying the corresponding RAS variant. These preclinical findings might provide guidance for the selection of combination regimens with KRAS inhibitors to improve clinical efficacy."

Oncology • Solid Tumor • KRAS • PIK3CA

Revolution Medicines Reports Fourth Quarter and Full Year 2024 Financial Results and Update on Corporate Progress (GlobeNewswire) - "Strategic Priorities and Markers of Progress:...(i) The company expects to share additional clinical safety and antitumor activity on zoldonrasib in the second quarter of 2025. The company currently expects to initiate one or more pivotal combination trials in 2026 that incorporate either elironrasib or zoldonrasib and expects to share clinical data supporting these plans in the second or third quarter of 2025; (ii) The company expects to advance RMC-5127, a RAS(ON) G12V-selective inhibitor, to a clinic-ready stage in 2025 to enable the expected initiation of a first-in-human dose escalation Phase 1 clinical trial in 2026."

Clinical data • New trial • Solid Tumor

Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers. (PubMed, J Med Chem) - P1, P1/2 | "Here we report structure-guided medicinal chemistry efforts that led to the discovery of elironrasib, a potent, orally bioavailable, RAS(ON) G12C-selective, covalent, tri-complex inhibitor. The investigational agent elironrasib is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), with preliminary data indicating clinical activity in patients who had progressed on first-generation inactive state-selective KRASG12C inhibitors."

Journal • Oncology • KRAS

RMC-6291 with Pembrolizumab (GlobeNewswire) - P1b/2 | N=484 | RMC-LUNG-101A (NCT06162221) | Sponsor: Revolution Medicines, Inc. | "RMC-LUNG-101A is an arm of the Phase 1b study of RMC-6291, a RAS(ON) G12C-selective inhibitor, in combination with pembrolizumab, with or without chemotherapy, in patients with RAS G12C mutant NSCLC....The combination of RMC-6291 with pembrolizumab was generally well tolerated and the safety profile was consistent with previously reported results for the individual agents. A TRAE of Grade 1 AST elevation was reported in one patient (7%) and a TRAE of Grade 1 ALT elevation was reported in one patient (7%). There were no TRAEs of Grade 2 or higher AST or ALT elevations reported. The mean dose intensity for RMC-6291 was 98%."

P1 data • Non Small Cell Lung Cancer

RMC-6291 and RMC-6236 RAS(ON) Inhibitor Doublet (GlobeNewswire) - P1 | N=210 | RMC-6291-101 (NCT06128551) | Sponsor: Revolution Medicines, Inc. | "The combination of RMC-6291 with RMC-6236 was generally well tolerated across all dose levels evaluated. The most common TRAEs were rash and GI-related toxicities that were primarily Grade 1 or 2 in severity....In the combination study, patients with CRC who were previously treated with a KRAS(OFF) G12C inhibitor and who received their first doses of the two study drugs at least 8 weeks prior to data cutoff were included in the analyses (n=12). The ORR was 25%, including one patient with an unconfirmed complete response, and the DCR was 92%. The median treatment duration was 2.3 months."

P1 data • Colorectal Cancer

RMC-LUNG-101: Study of RAS(ON) Inhibitor Combinations in Patients with Advanced RAS-mutated NSCLC (clinicaltrials.gov) - P1/2 | N=484 | Recruiting | Sponsor: Revolution Medicines, Inc. | N=352 ➔ 484

Enrollment change • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Revolution Medicines Reports Third Quarter 2024 Financial Results and Update on Corporate Progress (GlobeNewswire) - "Upcoming Milestones:...(i) Evaluation of the company’s RAS(ON) doublet combination of RMC-6291 with RMC-6236 is ongoing, and the company currently expects to disclose initial clinical PK, safety/tolerability and antitumor activity data from this combination study in the fourth quarter of 2024; (ii) The company is evaluating the combination of RMC-6291 with pembrolizumab, with or without chemotherapy, in patients with advanced NSCLC, and currently expects to disclose initial clinical PK, safety/tolerability and antitumor activity data from this combination study in the first half of 2025."

P1 data • P1/2 data • Non Small Cell Lung Cancer • Solid Tumor

Targeting the oncogenic state of RAS with tri-complex inhibitors (AACRPanCa 2024) - "We have generated mutant-selective inhibitors that covalently engage RAS(ON) G12C (RMC-6291) or RAS(ON) G12D (RMC-9805). In addition, RMC-6236 is a RAS(ON) multi-selective inhibitor that non-covalently inhibits the active, GTP-bound state of mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS, and HRAS). Here we will describe the mechanism of action of these investigational agents and the preclinical profiles that support their clinical evaluation in patients with PDAC as monotherapies and in combination therapy regimens with standard-of-care agents or as novel RAS(ON) inhibitor doublets."

Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HRAS • KRAS • NRAS

RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade. (PubMed, Nat Commun) - "Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRASG12C-mutated previously treated advanced non-small cell lung cancer. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRASG12C-selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRASG12C(ON) inhibitor RMC-6291 alone or in combination with KRASG12C(OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Revolution Medicines Reports Second Quarter 2024 Financial Results and Update on Corporate Progress (GlobeNewswire) - "Clinical Development Highlights:...(i) Qualifying RMC-6291 for Late-Stage Development:...The company expects to disclose initial clinical PK, safety, tolerability and antitumor activity data for the combination of RMC-6291 with RMC-6236 in the fourth quarter of 2024 and for the combination RMC-6291 with pembrolizumab in the first half of 2025; (ii) Qualifying RMC-9805 for Late-Stage Development: Monotherapy Development. The company expects to disclose initial clinical PK, safety, tolerability and antitumor activity data for RMC-9805 in the fourth quarter of 2024."

P1 data • P1/2 data • Non Small Cell Lung Cancer

Revolution Medicines Announces Publication Demonstrating Robust Anti-Tumor Activity of RAS(ON) Inhibitors in Preclinical Models of Refractory KRAS-Mutated Non-Small Cell Lung Cancer (GlobeNewswire) - "Revolution Medicines...announced the publication of a peer-reviewed research paper in Cancer Discovery. The scientific paper demonstrates that the RAS(ON) multi-selective inhibitor RMC-7977 (a preclinical tool compound representative of the investigational drug candidate RMC-6236) exhibited robust and durable anti-tumor activity in multiple preclinical models of KRAS-mutated NSCLC. The data show this activity was further enhanced in the doublet combination with a RAS(ON) G12C-selective inhibitor RMC-4998 (a preclinical tool compound representative of the investigational drug RMC-6291), in preclinical models of KRAS G12C-mutated NSCLC."

Preclinical • Non Small Cell Lung Cancer

Impact of trial eligibility criteria on enrollment to KRAS G12C inhibitor trials in patients with non-small cell lung cancer. (ASCO 2024) - " We extracted EC for Phase I-III trials among six KRAS G12C inhibitors: sotorasib, adagrasib, LY3537982 , divarasib, JDQ443 and RMC-6291. Our findings suggest that most patients with KRAS G12C mutations would not have been eligible for relevant trials, including > 75% of patients who received KRAS G12C inhibitors off-trial after accelerated FDA approval. EC did not expand after early phase trials demonstrated evidence of safety. These data should guide sponsor and FDA considerations in the development of trial protocols for targeted therapies, as fewer barriers to trial participation would enable trials to be completed more quickly and would improve the generalizability of trial results."

Clinical • Lung Cancer • Nephrology • Non Small Cell Lung Cancer • Oncology • Renal Disease • Solid Tumor • KRAS

Dose Escalation and Dose Expansion Study of RMC-6291 Monotherapy in Subjects With Advanced KRASG12C Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=222 | Active, not recruiting | Sponsor: Revolution Medicines, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Monotherapy • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Revolution Medicines Reports First Quarter 2024 Financial Results and Update on Corporate Progress (GlobeNewswire) - "...The company plans to initiate a combination study of RMC-6291 + RMC-6236 + pembrolizumab as a unique RAS(ON) inhibitor doublet-based, chemotherapy-free regimen in 1L patients with RAS G12C mutated NSCLC. The company expects to disclose initial clinical PK, safety, tolerability and antitumor activity data for the combination of RMC-6291 + pembrolizumab in the first half of 2025."

New trial • P1/2 data • Non Small Cell Lung Cancer

Combination RASG12C(ON) and RASMULTI(ON) inhibition overcomes resistance and prolongs durability in preclinical models of mutant KRASG12C-driven cancers (AACR 2024) - "Inhibitors of the GDP-bound state of mutant KRASG12C protein (KRASG12C(OFF)), e.g., adagrasib and sotorasib, have shown clinical activity in patients with KRASG12C-driven NSCLC, CRC and PDAC. The addition of RMC-6236 to RMC-6291 shows combinatorial activity in preclinical models that are relatively less responsive to either inhibitor alone. A clinical trial combining RMC-6291 with RMC-6236 in patients with mutant KRASG12C tumors is currently enrolling."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Revolution Medicines Reports First Quarter 2023 Financial Results and Update on Corporate Progress (GlobeNewswire) - "The company presented early findings from its Phase 1/1b monotherapy trial (NCT05379985) during its Q4 earnings call....The company currently plans to provide further evidence of first-in-class single agent activity from the ongoing study in mid-2023, with multiple updates this year through a combination of corporate and scientific meeting presentations beginning in Q3....The company currently plans to provide a preliminary report of the clinical profile for RMC-6291 in the second half of 2023....The company currently expects to announce dosing of the first patient in a monotherapy dose-escalation study of RMC-9805 in mid-2023."

Clinical data • P1 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Revolution Medicines to Deliver Multiple Presentations at the Upcoming American Association for Cancer Research Annual Meeting 2024 (GlobeNewswire) - "Revolution Medicines...announced the company will deliver multiple presentations at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2024 being held April 5-10, 2024, in San Diego, California."

Preclinical • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Revolution Medicines Reports Second Quarter 2023 Financial Results and Update on Corporate Progress (GlobeNewswire) - "The company will provide a first report on initial clinical findings with RMC-6291, including preliminary evidence of differentiation from RAS(OFF) inhibitors, at the Triple Meeting.....With encouraging initial clinical experience thus far for RMC-6291, planning is underway for a Phase 1/1b clinical trial to evaluate the combination of RMC-6236 and RMC-6291 potentially to begin in early 2024, in parallel to the continuing single agent evaluation of RMC-6291."

New P1 trial • P1 data • Oncology • Solid Tumor

Revolution Medicines Reports Fourth Quarter and Full Year 2023 Financial Results and Update on Corporate Progress (GlobeNewswire) - "RMC-LUNG-101 (NCT06162221) is a clinical study of RMC-6236 or RMC-6291 in combination with pembrolizumab, with or without chemotherapy, in patients with advanced RAS-mutated NSCLC or KRAS G12C-mutated NSCLC, respectively. Patient dosing is underway in both the RMC-6236 and RMC-6291 cohorts, and the company expects to disclose initial clinical PK, safety, tolerability, and antitumor activity data from both cohorts in the second half of 2024."

P1/2 data • Trial status • Non Small Cell Lung Cancer

Revolution Medicines Reports Fourth Quarter and Full Year 2023 Financial Results and Update on Corporate Progress (GlobeNewswire) - "RMC-6291-101 (NCT06128551) is a clinical study of RMC-6291 in combination with RMC-6236 in patients with advanced KRAS G12C-mutated solid tumors. Patient dosing is underway, and the company expects to disclose initial clinical PK, safety, tolerability, and activity data in the second half of 2024. RMC-9805-001 (NCT06040541) is a clinical study of RMC-9805 monotherapy in patients with advanced KRAS G12D-mutated solid tumors....The company expects to disclose initial clinical PK, safety, tolerability, and activity data in the second half of 2024."

P1 data • Trial status • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Dose Escalation and Dose Expansion Study of RMC-6291 Monotherapy in Subjects With Advanced KRASG12C Mutant Solid Tumors (clinicaltrials.gov) - P1 | N=222 | Recruiting | Sponsor: Revolution Medicines, Inc. | N=117 ➔ 222

Enrollment change • Metastases • Monotherapy • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Study of RAS(ON) Inhibitor Combinations in Patients With Advanced RAS-mutated NSCLC (clinicaltrials.gov) - P1/2 | N=352 | Recruiting | Sponsor: Revolution Medicines, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor