zoldonrasib (RMC-9805) / Revolution Medicines, BeOne Medicines - LARVOL DELTA

Targeting dual CDK9 and KRASG12D selective inhibition as a novel combination therapy in pancreatic ductal adenocarcinoma (AACRPanCa 2026) - "Tri-complex RAS(ON) inhibitors are emerging in clinical practice including daraxonrasib (RMC-6236) and zoldonrasib (RMC-9805), a KRASG12D selective inhibitor with favorable toxicity. SLS009 in combination with RMC-6236 significantly augments the induction of apoptosis and necrosis compared to single agent activity. Apoptosis staining as assessed for % area positive for the combination group increased to 36.49% relative to the negative control (6.965%, p<0.001), and in comparison to single agent SLS009 (17.88%, p<0.001) and RMC-6236 (2.781%, p=0.0086). Necrosis staining as assessed by % area positive for the combination group increased to 30.62% relative to the negative control (6.723%, p<0.001), in comparison to single agent SLS009 (14.51%, p<0.001) and RMC-6236 (2.702%, p=0.0044)."

Combination therapy • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Polyendocrine Metabolic Ovarian Syndrome • Solid Tumor • CASP3 • CASP7 • CDK9 • KRAS • MCL1 • MYC

MUC16-directed DR5 activation by IMV-M induces selective tumor cell apoptosis and tumor regression and enhances the activity of KRAS inhibitors in preclinical pancreatic cancer models (AACRPanCa 2026) - "Furthermore, the antitumor activity of IMV-M was enhanced when combined with the RAS inhibitors RMC-6236 and RMC-9805, supporting the potential development of combination regimens with KRAS-directed therapies that have demonstrated promising clinical activity in pancreatic cancer. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026; 86(18_Suppl_2):Abstract nr B144."

Preclinical • Tumor cell • Oncology • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MUC16 • TNFRSF10B

Activity and specificity of KRAS variants-directed Revolution Medicines Company (RMC) compounds for pleural effusion-derived non-small cell lung cancer cell lines. (PubMed, Transl Lung Cancer Res) - "The clinical therapy for KRAS G12C mutated lung cancers has been revolutionized by the approval of the covalent inhibitors Sotorasib and Adagrasib...A series of Revolution Medicines Company (RMC) compounds were developed, targeting all KRAS variants and KRAS wildtype, namely (RMC-6236, daraxonrasib), KRAS G12C (RMC-6291, elironrasib), KRAS G12D (RMC-9805, zoldonrasib) and KRAS G12V (RMC-5217) with more agents under development...Increased resistance to RMC-6236 has been associated with elevated expression or likely monoubiquitylation of KRAS. The limited activity of the RMC KRAS(ON) compounds may be supplemented by conventional KRAS(OFF) compounds or other glues or degraders."

Journal • Pleural effusion • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Respiratory Diseases • Solid Tumor • KRAS

Study of Zoldonrasib + Chemo of Investigator's Choice vs Placebo + Chemo of Investigator's Choice as First-line Treatment in Metastatic KRAS G12D-mutated Pancreatic Adenocarcinoma ( RASolute 305 ) (clinicaltrials.gov) - P3 | N=670 | Recruiting | Sponsor: Revolution Medicines, Inc.

New P3 trial • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • KRAS

RMC-LUNG-101D: Study of zoldonrasib in Previously Treated Patients with RAS G12D-Mutant Non-Small Cell Lung Cancer (NSCLC) (clinicaltrialsregister.eu) - P1/2 | N=84 | Recruiting | Sponsor: Revolution Medicines Inc.

New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RAS

RMC-LUNG-101D: Study of zoldonrasib in Previously Treated Patients with RAS G12D-Mutant Non-Small Cell Lung Cancer (NSCLC) (clinicaltrialsregister.eu) - P1/2 | N=84 | Active, not recruiting | Sponsor: Revolution Medicines Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RAS

RMC-GI-102: Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors (clinicaltrials.gov) - P1/2 | N=1130 | Recruiting | Sponsor: Revolution Medicines, Inc. | Trial completion date: Jul 2027 ➔ Mar 2030 | Trial primary completion date: May 2027 ➔ Sep 2028

Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • RAS

Preliminary safety and clinical activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with previously treated KRAS G12D non-small cell lung cancer (NSCLC) (AACR 2026) - P1, P1/2 | "Clinical efficacy is reported for pts with NSCLC treated at 1200 mg QD, who had received a prior immune checkpoint inhibitor and platinum chemotherapy (concurrent or sequential), and had not previously received docetaxel (N=27). As of Dec 1, 2025, 40 pts were evaluated for safety and had received a median of 2 prior lines of therapy. Zoldonrasib (1200 mg QD) demonstrated durable clinical efficacy in pts with previously treated KRAS G12D NSCLC with a favorable safety and tolerability profile, requiring minimal dose modification. Further evaluation of zoldonrasib in KRAS G12D NSCLC is ongoing both as monotherapy in previously treated pts and in combination with standard of care in treatment naive pts (NCT06162221)."

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

Safety and efficacy of zoldonrasib (RMC-9805) plus daraxonrasib (RMC-6236) in patients with 2L+ KRAS G12D metastatic pancreatic adenocarcinoma (mPDAC) (ESMO-GI 2026) - P1 | "Clinical trial identification NCT06040541. Table: 341O Conclusions Zoldonrasib + daraxonrasib showed manageable safety and compelling preliminary efficacy in 2L+ KRAS G12D mPDAC. These results support initiation of RASolute 309, a global, randomized, phase 3 study evaluating zoldonrasib + daraxonrasib vs gemcitabine + nab-paclitaxel in 1L RAS G12D mPDAC."

Clinical • Metastases • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • KRAS

RASolute 309: Study of Zoldonrasib (RMC-9805) Plus Daraxonrasib (RMC-6236) Versus Gemcitabine and Nab-Paclitaxel as First-Line Treatment in Metastatic KRAS G12D-Mutated Pancreatic Adenocarcinoma (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Revolution Medicines, Inc.

New P3 trial • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • KRAS

Safety and efficacy of zoldonrasib (RMC-9805) plus chemotherapy in patients (pts) with 1L RAS G12D metastatic pancreatic adenocarcinoma (MPDAC) (ESMO-GI 2026) - P1/2 | "We present preliminary results of zoldonrasib + mFOLFIRINOX (mFFX) or + gemcitabine/nab-paclitaxel (GnP) in pts with 1L RAS G12D mPDAC from a Ph1/2 study (NCT06445062). Preliminary ORR and DCR data are encouraging (Table). Table: 340O Conclusions Zoldonrasib + chemo showed a manageable safety profile and compelling preliminary efficacy, supporting initiation of RASolute 305, a global, randomized, phase 3 study evaluating zoldonrasib + mFFX or + GnP vs placebo + mFFX or + GnP in pts with 1L RAS G12D mPDAC."

Clinical • Metastases • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma

Beyond KRASG12C: emerging therapeutic strategies, patent landscape, and clinical progress in targeting KRAS-mutant cancers. (PubMed, Med Oncol) - "For most of its history, KRAS has been regarded as "undruggable." Still, with recent developments in covalent inhibitors targeting KRAS^G12C, specifically sotorasib and adagrasib, it has now been validated as a viable therapeutic target...New classes of KRAS inhibitors have recently emerged, including non-covalent inhibitors (MRTX1133, RMC-9805), pan-RAS (ON) antagonists (RMC-6236), and KRAS-directed degraders (ASP3082), as well as planned rational combinations of these new KRAS inhibitors with agents targeting SHP2, SOS1, MEK, and immune checkpoint inhibitors...The regulatory environment and commercialization efforts present opportunities and challenges for precision oncology in KRAS-driven cancers globally. Overall, the rapid evolution of KRAS-targeted therapeutic agents represents a shift from allele-specific inhibition towards a strategy that is mutation/context-dependent, thereby creating further clinical translation opportunities and increased patient..."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

XPO1 inhibition enhances the efficacy and durability of RAS-targeted therapy in preclinical models of KRASG12D mutant pancreatic ductal adenocarcinoma. (PubMed, Cancer Lett) - "Antiproliferative synergistic effects of Eltanexor combined with MRTX1133, Zoldonrasib (RMC9805), or Daraxonrasib (RMC6236) were evaluated in PDAC 2D cultures, 3D spheroids, patient-derived organoids, and tumor-fibroblast co-culture models. In conclusion, XPO1 inhibitor Eltanexor enhances the efficacy and durability of KRAS and pan-RAS inhibition in PDAC models. These findings provide a preclinical rationale for clinically evaluating Eltanexor in combination with RAS-targeted therapies to delay or overcome adaptive resistance in KRAS-mutant PDAC."

IO biomarker • Journal • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • XPO1

Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors. (ASCO-GI 2025) - P1 | "Oral RMC-9805 showed encouraging initial antitumor activity with early and deep reductions in KRAS G12D ctDNA in patients with KRAS G12D PDAC. Tolerability was favorable relative to SOC chemotherapy for PDAC and manageable. This overall safety profile and antitumor activity support continued evaluation as monotherapy in patients with KRAS G12D PDAC, and in combination with chemotherapy and targeted therapies, including the RAS(ON) multi-selective inhibitor RMC-6236."

Circulating tumor DNA • Clinical • Metastases • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Preliminary safety, pharmacokinetics, and antitumor activity of RMC-9805, an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors (EORTC-NCI-AACR 2024) - P1 | "Oral RMC-9805 showed encouraging initial antitumor activity in patients with KRAS G12D PDAC. Tolerability was favorable relative to SOC chemotherapy for PDAC and manageable across all dose levels and tumor types evaluated. This overall safety profile and antitumor activity support continued evaluation as monotherapy in patients with KRAS G12D PDAC, and in combination with chemotherapy and targeted therapies, including the RAS(ON) multi-selective inhibitor RMC-6236."

Clinical • Late-breaking abstract • Metastases • P1 data • PK/PD data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Actuate Announces Promising Preclinical Data Showing Synergistic Activity of Elraglusib in Combination with RAS Inhibitors Zoldonrasib and Daraxonrasib - "'The emergence of direct RAS inhibitors represents a major advance in pancreatic cancer and creates an opportunity to identify combinations capable of further enhancing RAS-directed activity,' said Tanios 'Tony' Bekaii-Saab, MD, FASCO...'Importantly, the enhanced activity observed when elraglusib was combined with either zoldonrasib or daraxonrasib, two distinct RAS-targeted agents, highlights the potential for elraglusib to synergize with diverse RAS-directed therapies. Based on the unique and complementary mechanisms of action of elraglusib with these new RAS inhibition therapies, we are eager to evaluate the potential of combining elraglusib with RAS inhibition therapies in a clinical setting to expand treatment opportunities across RAS-driven diseases, including pancreatic cancer.'"

Media quote

Emerging Therapeutic Strategies for Non-G12C KRAS Mutations in Colorectal Cancer: Focusing on G12D and G12V. (PubMed, J Gastrointest Cancer) - "The non-G12C KRAS era is beginning, but durable benefit in CRC will likely require rational combinations tailored to allele, lineage, and resistance biology."

Journal • Review • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • KRAS

Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer (NSCLC) from a phase 1 study in advanced solid tumors (AACR 2025) - P1, P1/2 | "Zoldonrasib showed encouraging initial antitumor activity in patients with KRAS G12D NSCLC. Tolerability was manageable across all dose levels in the Phase 1 study, which enrolled various tumor types. This overall safety profile and antitumor activity support continued evaluation as monotherapy in patients with KRAS G12D NSCLC, and in combination with immunotherapy, chemotherapy, and targeted therapies (NCT06162221)."

Clinical • IO biomarker • Metastases • P1 data • 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) - "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

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies. (PubMed, Future Med Chem) - "Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805...Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

Revolution Medicines Advances RASolve 308 Lung Cancer Trial... (TipRanks) - "This phase 3 study, titled 'A Randomized, Double-blind, Phase 3 Study of Pembrolizumab + Pemetrexed + Platinum Chemotherapy With or Without Zoldonrasib (RMC-9805) as First Line Treatment in Patients With Metastatic Non-squamous RAS G12D-Mutated Non-small Cell Lung Cancer (RASolve 308)', tests if adding zoldonrasib to standard therapy improves outcomes. It targets metastatic non-squamous NSCLC with RAS G12D mutations, a hard-to-treat segment with limited targeted options....The study is listed as recruiting with an initial submission date of August 17, 2026, marking the formal start of trial setup and site activation."

Trial status • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer

RASolve 308: Study of Pembrolizumab + Pemetrexed + Platinum Chemotherapy With or Without Zoldonrasib as First Line Treatment in Metastatic Non-squamous RAS G12D-Mutated NSCLC (clinicaltrials.gov) - P3 | N=430 | Recruiting | Sponsor: Revolution Medicines, Inc.

New P3 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1 • RAS

BeOne Medicines and Revolution Medicines Announce Clinical Development and Regional Commercialization Collaboration (Businesswire) - "Potential drug combinations for development as part of the clinical collaboration will include certain BeOne assets and Revolution Medicines’ four clinical RAS(ON) inhibitors: daraxonrasib, a RAS(ON) multi-selective inhibitor; zoldonrasib, a RAS(ON) G12D-selective inhibitor; elironrasib, a RAS(ON) G12C-selective inhibitor; and RMC-5127, a RAS(ON) G12V-selective inhibitor. Planned combination studies include: BeOne’s MTA-cooperative PRMT5 inhibitor, BGB-58067, and an EGFR x MET x MET trispecific antibody, BG-T187, with either daraxonrasib or zoldonrasib....Under the regional rights agreement, Revolution Medicines has granted BeOne exclusive rights in select Asian markets to develop and commercialize or solely commercialize, depending on the market, these four clinical-stage RAS(ON) inhibitors."

Licensing / partnership • Solid Tumor

Today the company is reporting initial clinical data evaluating zoldonrasib in combination with standard of care pembrolizumab and platinum doublet chemotherapy in patients with first-line RAS G12D NSCLC. (GlobeNewswire) - "The analysis included 38 patients, with efficacy evaluable in 28 patients who had at least 8 weeks of follow-up. PD-L1 tumor proportion score (TPS) was <1% in 39% of patients, 1–49% in 39% of patients, ≥50% in 16% of patients, and TPS score missing in 5% of patients. As of a data cutoff of May 11, 2026, with a median follow-up of 3.4 months, the zoldonrasib plus standard of care combination demonstrated encouraging preliminary antitumor activity, including an overall response rate (ORR; confirmed and pending confirmation) of 82% and disease control rate (DCR) of 100%. Confirmed and pending ORRs ranged from 60% to 100% across PD-L1 TPS subgroups (<1% to ≥50%)."

P1/2 data • Non Small Cell Lung Cancer

Zoldonrasib: “Zoldonrasib plus chemotherapy demonstrated promising initial clinical activity in first line RAS GD12 PDAC”; Pancreatic ductal adenocarcinoma (Revolution Medicines) - Q2 2026 Results

P1/2 data • Oncology • Pancreatic Ductal Adenocarcinoma